General supplier

General Supplier details

Summary

The general suppliers page details a list of the suppliers to health care providers and details about them for each aspect of the supply chain.  The areas include:
Pharmaceutical and biotechnology companies, Hospital clinical supplies, Hospital supplies distributors, Dialysis supplies, Lighting, Probe companies, Clinical devices, Robotic surgery, Scope suppliers, Diagnostics, Accountable care platforms, Clinical trials support, Clinical decision support, Clinical in patient, Oncology support, Surgical scheduling, Prescription support, Pharmacy kits,
HCIT solutions
Outsourcing, SIs,
Value chain performance,
Recruitment Payer integration and HR,
Insurance marketplaces, marketplace tools,
Personal genomics, Gene therapy, Anti-aging,
health research institutes, Standards bodies, Associations,
Charitable foundations & other finance;


Introduction

The Products sold to patients are tested and marketed by well capitalized pharmaceutical, diagnostics and medical equipment and supplies companies.  They are viewed as key aspects of U.S. value creation and are supported by the government in building global trading relationships for deployment of biologics are drugs made in living cells.  Typically they are proteins developed using genetic engineering to develop the cellular host, and to customize animal source, DNA to produce human target proteins.  Biologics solve the problem of previous protein sources, extracted from animals or human sources, of contamination and immune responses.  The strategy is very effective for blood transported proteins such as antibodies, hormones and blood factors.  But intra-cellular proteins still demand delivery and accurate cell targeting.  This creates analogous problems to those of gene therapy. 
and biosimilars are generic drugs made to copy biologics.  They could undermine the pharmaceutical industry's biologic profit model and so are subject to trade constraints: TRIPS, TPP. 
.  The applied science, product research and development are performed by a network of companies which flow product to these players. 

Innovation in the reimbursement framework are enabling providers to build new business models. 

The availability of private equity, venture, hedge fund and Wall Street finance and requirement for big returns ensure the pharmaceutical, biotechnology and medical equipment companies search out amplifiers that promise exponential growth in usage and market capitalization. 

Genomics combines recombinant DNA, DNA sequencing and bioinformatics  to sequence, assemble and analyse genomes.  , proteomics, artificial intelligence, robotics, open source, SaaS and the Internet of things are transforming the business models of the participating companies. 


  • The suppliers are also powerful players. 


Advances in genetic analysis have led to the development of a number of breakthrough drugs which are currently filling a drug pipeline.  Regulators approved 39 drugs in 2012, the most in 16 years.  Analyzing DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used. 
structures behind specific kinds of cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   and other diseases, has allowed companies to develop targeted medications:
Promising drugs are in the pipeline to treat many genetic diseases.  Six of the seven largest biotech companies are going through major product launches now or are expected to do so shortly. 

Immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
  • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
  • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
  • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
  • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
progress:

Gene therapy is the deployment of genes into patient's cells to treat or prevent diseases.  It can be performed outside the body (ex vivo) or in place (in vivo).  It requires a vector such as a: Virus, Ligandal style nanoparticle; to perform the deployment.  But viruses are: Difficult to sanitize (bringing in oncogenes etc.) and hard to target as needed,  Unable to target where the DNA is deployed into the target cell chromosomes, Key targets of the immune system.  The process is disease specific:
  • Blood cancers: NHL; can be treated with ex vivo CAR-T (Jul 2017, Oct 2017)
  • Cystic fibrosis requires a virus that infects the airways and then deploys a non-cystic fibrosis allele into the nucleus of the patient's cells.  The obstacles to this process have been challenging: 
    • The virus must not have any problematic effects.  In the case of cystic fibrosis one virus activated a cancer gene leaving several trial subjects with leukemia. 
    • Efficiency of delivery has to be very high and this has not proved possible as of 2015. 
    • The newly delivered DNA must remain intact and be replicated and transcribed.  This has not proved to be the case. 
    • The process has not been able to avoid an immune response.  Gene therapy has consequently been of limited value for cystic fibrosis. 
  • ADA based SCID was the first human treatment with gene therapy.  A normal ADA gene was inserted ex vivo into immune system cells.  Initially the updated cells did not live as long as needed. 
  • Sickle-cell anemia requires a non-sickle-cell trait allele of the hemoglobin gene to be vectored into the bone marrow of the affected person. 
has been slow to gain F.D.A. Food and Drug Administration. 
approved products:

HCIT is health care information technology.  The AHRQ argues HCIT consists of a complex set of technologies, policies, standards and user sets.  Technically they represent it as a set of layers: Application: CPOE, CDS, e-prescribing, eMAR, Results reporting, Electronic documentation, Interface engines, etc.; Communication: Messaging standards (HL7, ADT, NCPDP, X12, DICOM, ASTM, etc,) Coding standards (LOINC, ICD10, CPT, NDC, RxNorm, SNOMED CT, etc.), Process: HIE, MPI, HIPAA security & privacy, etc.; Device: Tablet and PC, ASP, PDAs, Bar Coding, etc.; 
suppliers and SAAS is software as a service. 
providers support:

The clinical technologies business supply: ED is emergency department.  Pain is the main reason (75%) patients go to an E.D.  It has traditionally been part of an acute care hospital but recently is being deployed standalone as a catchment funnel to the owning hospital.  The EMTALA legislation requires E.D. treatment to stabilize every person seeking treatment by most hospitals.  Unreimbursed care is supported from federal government funds.  E. D. profitability has been helped by hospitals contracting with 3rd party companies who are able to improve margins through surprise billing.  The standalone E.D. competes with the positioning and brand power of lower cost urgent care clinics.  Commercial nature of care requires walk-ins to register to gain access to care.  With the focus on treatment of pain, E.D.s are a major distributor of opioids (5% of opioid prescriptions) and a major starting point of addiction in patients but are cutting back (Jun 2016). 
s, ICU is intensive care unit.  It is now being realized that the procedures and environment of the ICU is highly stressful for the patients.  In particular sedation with benzodiazepines is suspected to enhance the risk of inducing PTSD.  Intubation and catheterization are also traumatic.  Sometimes seperated into MICU and SICU.  eICU skill centralization may bring down costs. 
s, Laboratories, Radiology departments, Pre-operation rooms, OR is operating room.  s, Inpatient rooms, Rehabilitation centers, PAC providers is a Post-Acute Care provider.  A three-day hospital admission and discharge are prerequisite requirements to receiving Medicare PAC services.  Acute care hospitals become portals to the PAC business.  Referrals are key.  PAC includes different types of facility focused on different severity of illness (high to low):
  • Long term care Hospital (LTCH),
  • Inpatient rehabilitation facility (IRF),
  • Skilled nursing facility (SNF),
  • Home health agency (HHA) - most acute care hospitals and EMR providers have strategies for integration with home based care,
  • Outpatient rehabilitation.  SNF and HHA represent 80% of discharges and expenditures. 
; with:

The food supply is now leveraging gene editing technologies. 

Investors have poored $5 billion into the biotech and healthcare sectors in 2013.  Investors have historically used the healthcare and biotech stocks as a destination to park money when the economy is down.  But in 2013 as the recovery continues the sectors are holding their investments.  Healthcare/biotech have outperformed all other sectors.  Many biotech investors favor giants like Amgen or Gilead Sciences (Apr 2016).  Janus Global Life Sciences also holds Aetna and Express Scripts

In contrast generic drug supplies suffer from structural problems that tend to encourage shortages

Counteracting the strong branded drug pipeline is the economics of healthcare: 



Individual agents from each aspect of the value delivery system are described within their class. 








Pharmaceutical and Biotechnology product manufacturers



Cortera Neurotechnologies

Cortera designs medical devices for incurable neurological conditions. 
Cortera co-founder Michel Maharbiz is a gadget oriented computer science and electrical engineering professor at Cal Berkeley



The pharmaceutical industry has had a lot of its practices qualified. Drug companies have to:
  • Report the payments, including meals and entertainment, that they make to doctors for research, consulting and giving promotional speeches. 
  • Disclose more results of their clinical trials
  • Provide raw data to outsiders. 
Next could be cost and pricing based on new State laws (Jul 2015).  The Pharmaceutical Research and Manufacturers of America and Biotechnology trade groups say transparency bills would be costly to comply with and would provide misleading information. 



Abbott Labs


Abbott describes itself as a global healthcare company.  It is based near Chicago Illinois. 
2015 CEO Miles White. 

Abbott agreed to acquire point-of-care diagnostic testing (PoCT) allows:
  • Immediate diagnosis in the PCP office, an ambulance, the home, the field or in hospital rather than waiting for the lab.  It includes over the counter: glucose monitoring and pregnancy testing and professional: critical care, infectious disease (HIV, Chlamydia), cardiac monitors, diabetes, lipids, coagulation and hematology; with 'over the counter' providing the largest market and infectious disease PoCT the fastest growth.  Devices range from: sticks and small hand-helds, to bench top versions of laboratory devices.  Timely diagnosis allows rapid treatment.  Predictive personalized and preemptive medicine can be designed based on PoCT.  It is difficult to deliver a: timely - within 5 minutes - flexible, cost effective - $20 for infectious disease, accurate, easy to use, safe; PoCT device.  PoCT patients require tests to be free or appropriate while clinicians want to maximize simplicity and coverage.  Diagnostics [will] include:
    • Operator interface
    • Bar code identification
    • Chemical reactors (large sample diagnostics: Early LOC, LFS; and molecular diagnostics: LOC, Paper-based;) which only require a small amount of blood.  Preparation of the sample avoiding contamination have been major challenges often requiring a laboratory-like facility.  
      • Molecular diagnostic sample amplification: PCR, LAMP, RCA;
    • Optical or electochemical probes
    • Low cost imaging devices
    • Reagent storage
    • Networking and storage
company Alere for $5.8 billion (Jan 2016). 
Abbott has agreed to acquire medical device company  St. Jude Medical (Apr 2016) helping Abbott expand in the cardiovascular refers to:
  • Conditions where narrowed and blocked blood vessels result in angina, hypertension, CHD and heart attacks and hemorrhagic/ischemic strokes.  Mutations of the gene PCSK9 have been implicated in cardiovascular disease.  Rare families with dominant inheritence of the mutations have an overactive protein, very high levels of blood cholesterol and cardiac disease. Other rare PCSK9 mutations result in an 88% reduced risk from heart disease.  Inflammation is associated with cardiovascular disease (Aug 2017). 
device maket.  But the two acquisitions have run into problems (Aug 2016). 

It develops pharmaceuticals (branded generics), medical devices, nutrition products (Ensure), diagnostics including point-of-care (PoCT) allows:
  • Immediate diagnosis in the PCP office, an ambulance, the home, the field or in hospital rather than waiting for the lab.  It includes over the counter: glucose monitoring and pregnancy testing and professional: critical care, infectious disease (HIV, Chlamydia), cardiac monitors, diabetes, lipids, coagulation and hematology; with 'over the counter' providing the largest market and infectious disease PoCT the fastest growth.  Devices range from: sticks and small hand-helds, to bench top versions of laboratory devices.  Timely diagnosis allows rapid treatment.  Predictive personalized and preemptive medicine can be designed based on PoCT.  It is difficult to deliver a: timely - within 5 minutes - flexible, cost effective - $20 for infectious disease, accurate, easy to use, safe; PoCT device.  PoCT patients require tests to be free or appropriate while clinicians want to maximize simplicity and coverage.  Diagnostics [will] include:
    • Operator interface
    • Bar code identification
    • Chemical reactors (large sample diagnostics: Early LOC, LFS; and molecular diagnostics: LOC, Paper-based;) which only require a small amount of blood.  Preparation of the sample avoiding contamination have been major challenges often requiring a laboratory-like facility.  
      • Molecular diagnostic sample amplification: PCR, LAMP, RCA;
    • Optical or electochemical probes
    • Low cost imaging devices
    • Reagent storage
    • Networking and storage
where Alere should add force;  Its research-based pharmaceuticals were spun-off into Abbvie;

Abbott Labs i-STAT handheld blood analyzer

i-STAT is an advanced, easy-to-use, integrated cartridge, portable PoCT is point-of-care testing.  It allows:
  • Immediate diagnosis in the PCP office, an ambulance, the home, the field or in hospital rather than waiting for the lab.  It includes over the counter: glucose monitoring and pregnancy testing and professional: critical care, infectious disease (HIV, Chlamydia), cardiac monitors, diabetes, lipids, coagulation and hematology; with 'over the counter' providing the largest market and infectious disease PoCT the fastest growth.  Devices range from: sticks and small hand-helds, to bench top versions of laboratory devices.  Timely diagnosis allows rapid treatment.  Predictive personalized and preemptive medicine can be designed based on PoCT.  It is difficult to deliver a: timely - within 5 minutes - flexible, cost effective - $20 for infectious disease, accurate, easy to use, safe; PoCT device.  PoCT patients require tests to be free or appropriate while clinicians want to maximize simplicity and coverage.  Diagnostics [will] include:
    • Operator interface
    • Bar code identification
    • Chemical reactors (large sample diagnostics: Early LOC, LFS; and molecular diagnostics: LOC, Paper-based;) which only require a small amount of blood.  Preparation of the sample avoiding contamination have been major challenges often requiring a laboratory-like facility.  
      • Molecular diagnostic sample amplification: PCR, LAMP, RCA;
    • Optical or electochemical probes
    • Low cost imaging devices
    • Reagent storage
    • Networking and storage
blood analyzer for health care professionals with access to real-time, lab quality results within minutes.  It is one of the first products to successfully deploy LOC is lab-on-a-chip a device that integrates one or several laboratory functions on a single chip.  LOCs allow the use of extreemly small fluid volumes.  It uses microfluidics via a microarray. 
, a technology which otherwise has been costly and difficult to commercialize. 

Abbott piccolo benchtop PoCT analyzer

The Abaxis piccolo PoCT is point-of-care testing.  It allows:
  • Immediate diagnosis in the PCP office, an ambulance, the home, the field or in hospital rather than waiting for the lab.  It includes over the counter: glucose monitoring and pregnancy testing and professional: critical care, infectious disease (HIV, Chlamydia), cardiac monitors, diabetes, lipids, coagulation and hematology; with 'over the counter' providing the largest market and infectious disease PoCT the fastest growth.  Devices range from: sticks and small hand-helds, to bench top versions of laboratory devices.  Timely diagnosis allows rapid treatment.  Predictive personalized and preemptive medicine can be designed based on PoCT.  It is difficult to deliver a: timely - within 5 minutes - flexible, cost effective - $20 for infectious disease, accurate, easy to use, safe; PoCT device.  PoCT patients require tests to be free or appropriate while clinicians want to maximize simplicity and coverage.  Diagnostics [will] include:
    • Operator interface
    • Bar code identification
    • Chemical reactors (large sample diagnostics: Early LOC, LFS; and molecular diagnostics: LOC, Paper-based;) which only require a small amount of blood.  Preparation of the sample avoiding contamination have been major challenges often requiring a laboratory-like facility.  
      • Molecular diagnostic sample amplification: PCR, LAMP, RCA;
    • Optical or electochemical probes
    • Low cost imaging devices
    • Reagent storage
    • Networking and storage
analyzers include rotary mixing of reagents to support a variety of diagnostic tests. 


Abbvie



Abbvie was considering a tax inversion allows a U.S. company to move its tax domicile overseas by purchasing a foreign company.  In 2015 the U.S. Treasury department adjusted the inversion rules to require 40% of the combined company is owned by the shareholders of the purchased foreign entity.  In Apr 2016 they clamped down on the option to serially acquire American companies.  In section 7874 of the tax code, Congress defined statutory hurdles that must be cleared to gain tax benefits: Shareholders of foreign acquirers owning less than 20% of the combined entity the inversion fails, If less than 40% and the acquirer does substantial business in the foreign jurisdiction the inversion works but with some pain, If they own more than 40% there are few negative consequences.  Companies purchased serially within three years would be disregarded by the new rules.  Companies invert because of lower foreign tax rates and earnings stripping.  Once foreign, the parent loans the US subsidiary money.  The loan repayments offset the US income and the US tax bill is vastly reduced.   by purchasing Shire, but the deal would not have passed the updated Treasury is the department of the treasury.  it is a federal government executive department created by Act of Congress in 1789 to manage government revenue.  The Secretary of the Treasury is a Cabinet officer.  To support funding of high cost investments: Disaster recovery, Wars, Famines; the treasury can issue debt instruments and manage the national debt. 
rules on inversion. 

Abbvie offered to acquire Stemcentrx to expand their oncology thrust (Apr 2016).

Executive Vice President Carlos Alban was hostile to generic leader Teva joining the PhRMA (Jul 2016).  


Abbvie's Imbruvica

It purchased Pharmacyclics for its attractive hematological cancer drug, the BTK is Bruton's tyrosine kinase which supports the operation of the B cell antigen receptor.  When the B cell has become cancerous - a lymphoma, the signalling from the receptor will support the extended life of the cell.  BTK inhibitors are used to inhibit the signalling. 
inhibitor Imbruvica. 

Abbvie's ViekiraPak

ViekiraPak is a competitor to Sovaldi is Gilead Sciences hepatitis-C drug.  It is the first effective cure with acceptable side effects.  In 2014 Sovaldi costs $84,000 for a typical course of treatment. 
and Harvoni

Abbvie's Humira

Humira is a block buster biologic are drugs made in living cells.  Typically they are proteins developed using genetic engineering to develop the cellular host, and to customize animal source, DNA to produce human target proteins.  Biologics solve the problem of previous protein sources, extracted from animals or human sources, of contamination and immune responses.  The strategy is very effective for blood transported proteins such as antibodies, hormones and blood factors.  But intra-cellular proteins still demand delivery and accurate cell targeting.  This creates analogous problems to those of gene therapy. 
rheumatoid arthritis drug.  It is under attack from Amgen's biosimilar are generic drugs made to copy biologics.  They could undermine the pharmaceutical industry's biologic profit model and so are subject to trade constraints: TRIPS, TPP. 
(Jul 2016). 


Humira is 61% of Abbvie's revenues in 2015. 
The main patent for Humira expires at the end of 2016, but AbbVie has amassed 70 newer patents, mostly in 2013 to 2016, covering formulations of the drug, manufacturing methods, and use for specific diseases.  Abbvie hopes the additional patents will protect the revenue stream until 2022. 
CEO Richard Gonzalez commented "Any company seeking to market a biosimilar version of Humira will have to contend with this extensive patent estate, which AbbVie intends to enforce vigorously.



Express Scripts is also restricting humira access and driving its deployment to Accredo (Sep 2016). 


Abbvie's Synthroid

Synthroid (levothyroxine is a manufactured form of thyroxine (thyroid hormone) to treat hypothyroidism. 
sodium) is the most prescribed medication in the US in 2017.  It is used to supplement natural thyroid is an endocrine gland in the neck, which secretes hormones: Thyroxine; controlling body wide metabolic and protein synthesis rates and calcium homeostatis.  The thyroid is under the direct control of the anterior pituitary (TSH signals) and indirectly the hypothalamus (TRH).   hormone are signalling molecules: ACTH, TRH, Melanocyte stimulating hormone, Testosterone, Oxytocin, Vasopressin, Insulin, Growth hormone, Estrogen, Progesterone, Angiotensin II, Asprosin, EPO, Irisin, Leptin, FGF21 hormone, Prostaglandins, TSH, Thyroxine, Glococorticoids; that are transported by the circulatory system to interact with target organs having appropriate receptors.  The levels of hormones can fluctuate massively, as in pregnancy. 
in hypothyroidism is under production of thyroxine by the thyroid. 



AFFiRiS AG

AFFiRiS develops antigen specific vaccines are a core strategy of public health and have significantly extended global wellbeing over 200 years.  Recent successes include: HPV vaccine.  They induce active acquired immunity to a particular disease.  But the development and deployment of vaccines is complex:
  • The business model for vaccine development has been failing (Aug 2015): 
    • No Zika vaccine was available as the epidemic grew (Mar 2016).  No vaccine for: CMV;
    • Major foundations: Michael J. Fox, Gates, Wellcome; are working to improve the situation including sponsorship of the GAVI alliance.  A geographic cluster is forming in Seattle including PATH (Apr 2016). 
    • Commercial developers include: Affiris, Cell Genesis, Chiron, CSL, Sanofi, Valeant;
  • Vaccine deployment traditionally benefited from centrally managed vertical health programs.  But political issues are now constraining success with less than 95-99% coverage required for herd immunity (Aug 2015, Sep 2015, Nov 2015, Nov 2016).  
    • Where clinics have been driven into local neighborhoods health improves (Apr 2016).  
    • Retail clinics (Mar 2016): CVS Minute Clinics focus on vaccination.  
  • Key vaccines include: BCG, C. difficile (May 2015), Cholera (El Tor), Dengvaxia (Mexico Dec 2015), Gvax, Malaria vaccine, Provenge;
  • Regulation involves: FDA (CBER), with CMS monitoring (star ratings, PACE (Aug 2016), Report cards (Sep 2015)) & CDC promoting vaccines: as a sepsis measure, To control C. difficile (May 2015);  
    • Coding : CVX, MVX;
  • Research on vaccines includes: 
    • NIH: AIDS vaccines (AVRC), Focus on using genetic analysis to improve vaccine response.  
      • NCI:
        • Roswell Park clinical trial of immuno-oncology vaccine cimavax. 
    • Geisinger: effective process leverage in treatment. 
    • Stanford Edge immuno-oncology for cancer vaccines.  
    • P53-driven-cancer focused, gene therapy (Jun 2015). 
for the prevention and treatment of chronic illnesses. 
They are developing peptide-based vaccines for Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form and set off the formation of tangled thread-like tau protein.
    • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
    • BACE inhibitors block an enzyme needed to form amyloid. 
  • The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
  • The brain becomes inflamed resulting in the killing of many more nerve cells. 
, atherosclerosis is the thickening of an artery wall due to invasion and accumulation of leukocytes.  , Parkinson's disease corresponds to the breakdown of certain interneurons in the brain.  It is not fully understood why this occurs.  Dopamine system neuron breakdown generates the classical symptoms of tremors and rigidity.  In some instances an uncommon LRRK2 gene mutation confers a high risk of Parkinson's disease.  In rare cases Italian and Greek families are impacted in their early forties and fifties resulting from a single letter mutation in alpha-synuclein which alters the alpha-synuclein protein causing degeneration in the substantia nigra.  But poisoning from MPTP has also been shown to destroy dopamine system neurons.  Paraquat has also been linked to Parkinson's disease.  Parkinson's disease does not directly kill many sufferers.  But it impacts swallowing which encourages development of pneumonia through inhaling or aspirating food.  And it undermines balance which can increase the possibility of falls.  Dememtia can also develop. 
, MSA is medical savings account a program in over 20 states for self-employed individuals, in which medical expenses can be paid with tax-deferred deposits.  The model was leveraged for HSAs. 
, diabetes includes type 1 and type 2.  Common side effects include: increased heart disease, hypertension, kidney disease, vision loss, nerve damage, and infections. 
;


Allergan

Allergan has most of its plant and operations in Parsippany New Jersey.  But it inverted and is domiciled in Dublin, Ireland. 
2017 Allergan CEO Brent Saunders

Allergan was purchased by Actavis which took its name.  Actavis had previously acquired Forest Labs, and Watson Pharmaceuticals.  Actavis agreed a $5 billion deal with Irish drug maker Warner Chilcot in 2013 that allowed it to domicile in Dublin. 

Allergan plans to sell its $40.5 billion generic's business to Teva Pharmaceuticals

Allergan to acquire Tobira for $1.7 billion Sep 2016. 


Allergan Eye Drops



Allergan's Restasis


Restasis is a cyclosporin ophthalmic emulsion for treatment of dry eyes. 


Allergan agreed to sell & lease back the patents for Restasis to the Saint Regis Mohawk Tribe.  The tribe will be paid $13.75 million by Allergan to claim sovereign immunity as grounds to dismiss a patent challenge filled by generic drug makers: Teva; under the AIA is the Leahy-Smith America Invents Act of 2011 which aimed to modernize the patent system.  A key provision of AIA was the creation of the Inter Partes Review process which third parties can use to contest the validity of a patent (for not being novel & non-obvious) within 9 months of its issuance to the Patent Trial and Appeal Board. 
.  The lease back will provide the tribe with $13 million annually as long as the patents remain valid. 

Allergan's Brent Saunders siad that the company made the move to avoid what he described as the "double jeopardy" of having the same issue heard in two venues.  "We did this to really make sure that we can defend these patents in only one forum." 

Restasis 2nd quarter 2017 revenues were $336.4 million. 




Allergan's Botox



Botox was Allergan's leading product by 2017 2nd quarter revenue. 




Amarin

New Jersey
Amarin markets the fish oil pill Vascepa for treating high triglyceride levels.  It competes with AstraZeneca's Epanova and GSK's Lovaza. 

Anacor

Anacor Pharmaceuticals develops small molecule therapeutics based on its boron chemistry platform.  It is based in Palo Alto California

2016 Its key product is Kerydin, an FDA Food and Drug Administration. 
antifungal ointment for toenails distributed and commercialized by Navartis's Sandoz in the US is the United States of America.  .

May 2016 Pfizer acquires Anacor for $4.5 billion (5.2 billion including debt). 

Astellas Pharma

Astellas is a major Japanese drug company with a US office in Atherton . 

Astellas has an agreement to market Xtandi for Medivation

Nov 2015 Astellas acquires Ocata Therapeutics in a tender offer of $8.50 a share. 



MedImmune (Yahoofin).


MedImmune is AstraZeneca's biopharmaceutical research hub, situated in Gaithersburg, Maryland. 

Medimmune's Imfinzi

Imfinzi (durvalumab is a human immunoglobulin G1 kappa MAB that blocks apoptosis through interactions with PD-L1 & PD-1.  It was developed by AstraZeneca's Medimmune marketed as Imfinzi. 
) is a checkpoint inhibitor release the immune system's checkpoints on attacking host cells: by 1) stopping T-cell division and 2) reducing their life spans.  They are used in immuno-oncology where, in 2016: They are approved for treatment of: Advanced melanoma, HL, lung, kidney, liver cancer; They have a general success rate of 20 - 40% and higher for melanoma.   Checkpoint inhibitors work best for tumors that have many mutations: melanomas, lung and bladder cancers.  They are enhanced by adjunct treatments that kill tumor cells generating debris to stimulate the immune system.  The drugs include: ipilimumab, nivolumab, pembrolizumab, atezolizumab;  They are costly and often have high copayments.  They cause auto-immune side effects including inflammation, rheumatoid arthritis and damage to glands: Adrenal, Thyroid, Pituitary.  Powerful steroids such as prednisone can help reduce the inflammation.  Damaged glands require sustained hormone treatment.  Checkpoint inhibitor research is funded by the CRI.  used as a immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
  • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
  • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
  • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
  • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
therapy. 


Neurocrine Biosciences

Cephalon (Yahoofin).



Cephalon's Actiq

Actiq is a brand of a solid lollipop of fentanyl is a synthetic opioid pain medication that acts on micro-opioid receptors in the brain.  It is 50 times more potent than morphine.  It was originally manufactured by Janssen Pharmaceutica in 1959 which was acquired by Johnson & Johnson.  It is branded as: Sublimaze, Actiq, Durogesic, Duragesic, Fentora, Matrifen, Instanyl, Abstral, Lazanda; with a variety of deployment formulations.  It is often used, in a transdermal patch such as durogesic, to treat severe ongoing pain which can be induced by cancer.  It has followed heroin into the back-street opioid epidemic (Jun 2017). 
citrate on a plastic stick. 

Cephalon's Fentora

Fentora is a brand of fentanyl is a synthetic opioid pain medication that acts on micro-opioid receptors in the brain.  It is 50 times more potent than morphine.  It was originally manufactured by Janssen Pharmaceutica in 1959 which was acquired by Johnson & Johnson.  It is branded as: Sublimaze, Actiq, Durogesic, Duragesic, Fentora, Matrifen, Instanyl, Abstral, Lazanda; with a variety of deployment formulations.  It is often used, in a transdermal patch such as durogesic, to treat severe ongoing pain which can be induced by cancer.  It has followed heroin into the back-street opioid epidemic (Jun 2017). 
buccal tablet. 


Genzyme (Yahoofin)

The company's broad product portfolio is focused on rare genetic disorders, renal disease is end-stage renal disease.  This is the last stage of CKD.  There are more than 200,000 cases a year in the U.S.  Richard Nixon encouraged and signed Social Security amendments that provided Medicare for anyone suffering from ESRD.  There are two main treatment strategies:
  1. Kidney transplants allow recovery from the disease but are limited by the availability of matching donated kidneys, enabled by UNOS, and the patient's awareness of the option to have a transplant.  
  2. Kidney dialysis performed at a dialysis center. 
, and osteoarthritis is a common inflammatory disease of the joints.  Prophylaxis can mitigate the eventual development (Sep 2016).  Factors that increase likelihood of developing osteoarthritis includes: Obesity, Joint injuries, Joint surgery to repair a torn meniscus; with athletes who develop a tear getting osteoarthritis at a rate five to ten times greater than people who do not have this surgery.  Osteoarthritis accounted for 95% of the 757,000 total knee replacements and 80% of the 512,000 total hip replacements in the US in 2011. 
, and includes an industry-leading array of diagnostic products and services. Genzyme's commitment to innovation continues today with research into novel approaches to cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).  , heart disease is cardiovascular disease which refers to:
  • Conditions where narrowed and blocked blood vessels result in angina, hypertension, CHD and heart attacks and hemorrhagic/ischemic strokes.  Mutations of the gene PCSK9 have been implicated in cardiovascular disease.  Rare families with dominant inheritence of the mutations have an overactive protein, very high levels of blood cholesterol and cardiac disease. Other rare PCSK9 mutations result in an 88% reduced risk from heart disease.  Inflammation is associated with cardiovascular disease (Aug 2017). 
, and other areas of unmet medical need. More than 5,000 Genzyme employees in offices around the globe serve patients in over 80 countries.

99 Another large cap name we favor is Genzyme General (GENZ). On a relative valuation basis, this stock appears inexpensive. The company only has a $3.5 billion market cap, which is somewhat extraordinary when you compare it to the market caps of some of the other companies with product sales and earnings.  Genzyme’s lead product dominates its market and has continued to demonstrate solid growth. This product has surprised everyone in terms of the size of the market. The product called Cerezyme for Gaucher’s disease, a rare genetic disease, addresses a relatively small patient population. Despite the small size of the patient population, the product is today a $420 million product and will probably approach $500 million by the end of this year.

The company has done an extraordinary job of expanding the market opportunity for the drug. Genzyme has also done an excellent job of leveraging their expertise with a robust pipeline of other products for rare genetic diseases. The company currently has six other products in the pipeline for rare genetic disease, two of which are in late stages of clinical development. With solid sales and earnings, a maturing pipeline, and a p/e at about 19x our 2000 EPS estimate as compared to the average of 40x 2000 estimates for the large cap biotech stocks, we view Genzyme as an inexpensive stock.



Genentech  (Profile, Yahoofin, forbes (1, 2,) )

Leader of the Biotech revolution. 


Genentech's mission is to be the leading biotechnology company, using human genetic information to discover, develop, manufacture and commercialize biotherapeutics that address significant unmet medical needs. We commit ourselves to high standards of integrity in contributing to the best interests of patients, the medical profession, our employees and our communities, and to seeking significant returns to our stockholders, based on the continual pursuit of scientific and operational excellence.

Founded in 1976 by venture capitalist Robert Swanson (1947-1999), and UCSF biochemistry professor Herb Boyer. 
Boyer's approach to developing biologics are drugs made in living cells.  Typically they are proteins developed using genetic engineering to develop the cellular host, and to customize animal source, DNA to produce human target proteins.  Biologics solve the problem of previous protein sources, extracted from animals or human sources, of contamination and immune responses.  The strategy is very effective for blood transported proteins such as antibodies, hormones and blood factors.  But intra-cellular proteins still demand delivery and accurate cell targeting.  This creates analogous problems to those of gene therapy. 
: was based on synthesizing the peptides from a peptide-coding gene, and individual peptides, based on Boyer, Stanley Cohen and Berg's discovery that genes from bacteria could be combined with genes from Eukaryotes.  In 1977 Boyer, Itakura and Riggs first described synthesis and expression of a peptide-coding gene in transgenic genetically modified bacteria.  The approach successfully generated synthetic: Insulin regulates the metabolism of carbohydrates, fats and protein by signalling the absorption of glucose by fat, liver and skeletal muscle cells.  It is a peptide hormone generated in the islets of Langerhans beta cells of the pancreas.  Peter Medawar explains it was an early drug therapy success.  As manufacturers have shifted from products developed by extraction to biologics: Humulin, Lantus, Levemir; safety has improved.  But the US list price has risen steeply (Feb 2016, Jan 2017)
, human growth hormone,


CEO Arthur Levinson (BW profiles 1, 2,) from 1995 has focused Genentech on cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).  , Immunology is indirect treatment of disease by stimulating the immune system.  Targeted diseases include cancers -- immuno-oncology.   and Vascular Biology. 
He invests about 20% of profit in Research. 
Investment fits Levinson's research based strategies, where he sustains programs that show high options from research model. 
He has avoided advertising spend, typical of big pharma, seeing it as low value investment from a customer perspective. 
Products have been typically focused on small patient groups.  That focus may come under stress from Xolair, which is a more general market treatment for Asthma is inflammation of the airways resulting in their narrowing, swelling and generating additional mucus which inhibits breathing.  Its prevalence doubled in the US between 1980 and 2000.  Diagnosis: Propeller Health; Treatments include: Xolair;

Levenson takes a high road position relative to industry structural challenges like Patent conflicts - arguing that Genentech has collaborated in alliances when patent issues occurred with Tanox (backed by Novartis).  With social medicine programs Levinson again argues the elderly should get help, but that it should be through a market based approach (Government assistance to the elderly) rather than social control of market pricing. 

Marketed products continue to drive performance.  Business week July 04 felt Rituxan revenues may be impacted by new government policies.  So far the case is not proven.  Avastin revenues were stronger than Wall Street expected. By Aug 04 damaging trial feedback was identified for Avastin.   In the long term BW see potential in Tarceva

Former chief scientific officer: Marc Tessier-Lavigne, 2016 president of Stanford University


Market Biotherapeutics.  

Genentech is using 23andMe's customer DNA/disease database to search for insights. 


Competitors:


Cell Genesis, Dyax corp (Phage display patents), MannKind corp, Nuvelo, Osiris therapeutics (Stem cell therapy), Sierra Biosource; Imclone, Pfizer, Novartis & GlaxoSK (with Avastin);

Main products:

Clinical trials:


Genentech are entering new molecular entities and product line extensions into our clinical development pipeline, including:
  1. a hedgehog pathway antagonist, licensed from Curis, Inc., for basal cell carcinoma;
  2. BR3-Fc, licensed from Biogen Idec Inc., as part of our B-cell franchise;
  3. our humanized anti-CD20 antibody is a y-shaped blood transported protein generated by the adaptive immune system's plasma cells, B lymphocytes, to accurately identify and neutralize pathogens such as bacteria and viruses that exhibit a matching antigen. 
    for hematological/oncology indications in collaboration with Biogen Idec and Roche; and
  4. A combination study of Avastin and Tarceva for patients with renal cell carcinoma.

Genentech Alzheimer's drugs
Genentech's crenezumab
Crenezumab is a fully humanized mab as a terminator in medication names indicates the drug is a monoclonal antibody biologic. 
that targets 1-40 and 1-42 Beta Amyloid. 
It failed a clinical trial in 2014, but there were improvements in the mildest alzheimer's cases. 



Genentech Operations

Manufacturing needs in both the short- and long-term, with the primary goal of ensuring that there is supply available to meet the needs of every patient who wishes to take a Genentech product.

COO until 1999 William Young (Bill) having joined Genentech in 1980 as director of manufacturing and Process Sciences.  

Genentech operations should be highly tailored to product with bulk, and possibly labile substances. 

  • Genentech purchased a 3rd factory from Glaxo SKB to ensure enough production capacity. 
  • Aug 04 Genentech enable capacity ramp of Avastin.  Vacaville site gets F.D.A. approval to bulk produce. 

IT

Like Apple products in research. 
HR has deployed peoplesoft. 
SAP will be deployed on IBM!  Genentech don't like Itanium. 

Alliances



Strategic environment:

Medicare is a social insurance program that guarantees access to health insurance for Americans aged 65 and over, and younger people with disabilities and end stage renal disease or ALS.  Medicare includes:
  • Benefits
    • Part A: Hospital inpatient insurance.  As of Dec 2013 Medicare pays for home care in only limited circumstances, such as when a person needs temporary nursing care after a hospitalization.  Part A covers 20 days of inpatient rehabilitation at a SNF after discharge from inpatient care at a hosptial. 
    • Part B: Medical insurance
    • Part C: Medicare Advantage 
    • Part D: Prescription drug coverage 
  • Eligibility
    • All persons 65 years of age or older who are legal residents for at least 5 years.  If they or a spouse have paid Medicare taxes for 10 years the Medicare part A payments are waived. 
    • Persons under 65 with disabilities who receive SSDI. 
    • Persons with specific medical conditions:
      • Have end stage renal disease or need a kidney transplant. 
      • They have ALS. 
    • Some beneficiaries are dual eligible. 
    • Part A requires the person has been admitted as an inpatient at a hospital.  This is constrained by a rule that they stay for three days after admission.  
  • Premiums
    • Part A premium
    • Part B insurance premium
    • Part C & D premiums are set by the commercial insurer. 
Modernization Act of 2003, follow-on biologics, and employee stock option expensing.

Officers:

Founder Herbert Boyer - was Professor of Biochemistry at University of Cal (San Fran) who showed potential of rDNA in low cost drug development.  (UCSF settled patent infringement & got Genentech to admit key contributions of UCSF scientists.  )
CEO & Chairman Arthur Levinson
Richard Scheller SVP of Research;
Vince Anicetti was promoted to vice president, Product Portfolio Management;
Martin Babler was promoted to vice president, Immunology Sales and Marketing;
Charlie Johnson was promoted to vice president, Clinical Bio therapeutics;
Karen McCormick was hired as vice president, Specialty therapeutic Sales and Marketing.
Susan Desmond-Hellman president of product development -> UCSF chancellor -> Gates Foundation CEO;
Myrtle S. Potter, president for commercial operations


Like Apple in Research - Co developed a new version of NCBI is the national center for biotech information.   Blast.  Not filling their job reqs.  Vault Job analysis argues they are low payers, but the environment is collegiate. 

From 1993 to 2000 Vice president of Research Discovery at Genentech Joffre Baker. 

Research Discovery includes departments:



Imclone Systems  (yahf )

1999 Imclone is a biotech company developing drugs to treat solid tumors, which is engaged in several Phase II/III studies. Their lead compound, the monoclonal antibody is a y-shaped blood transported protein generated by the adaptive immune system's plasma cells, B lymphocytes, to accurately identify and neutralize pathogens such as bacteria and viruses that exhibit a matching antigen. 
to the EGF receptor on tumor cells, C225, is similar to the approach taken by Genentech’s Herceptin.

We should have an excellent window into the compound’s efficacy during the next six months. Its $550 million market cap makes it quite attractive when compared to IDEC Pharmaceuticals’ $2.1 billion, assuming it lives up to its reputation. 

Aug 2004 Erbitux may benefit from Heart risks with Genentech Avastin

Devgen


Biochemical manufacturing

OSI Pharmaceutical

Research and development partner of Genentech.  Co-developed Tarceva(1, ). 

Lonza group

Lonza has agreements to manufacture for Genentech



Celgene Corporation

Head Quartered in Summit, NJ
CEO Robert J. Hugin
Dr. Thomas O. Daniel leads research and early development. 

1500 Owens St # 600, San Francisco, CA 94158
(415) 839-7000

Biotech that manufactures drug therapies for cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   and inflammatory disorders. 

Celgene's main revenue is from its blockbuster cancer drug Revlimid which treats multiple myeloma is a cancer of B lymphocytes.  The cause is unknown, but alcohol and obesity are risk factors.  Abnormal antibodies are generated which cause kidney problems and overly thick blood.  If the abnormal lymphocytes form a single mass the diagnosis is plasmacytoma.  If there are multiple masses the diagnosis is multple myeloma.  Treatments include: Revlimid, Velcade;

Price of $150,000 a year is a focus of regulators and states. 

Celgene is using the profits from Revlimid to enter the treatment of auto-immune diseases. 

It sells Otezla a treatment for psoriasis and psoriatic arthritis. 

Celgene is known for entering into generous deals with smaller companies for new drugs and technologies that give it access to a wide variety of potential approaches to treating cancer. 

In 2014 it invested in Nurix Inc

Celgene payed Juno Therapeutics $1 billion in June 2015 to collaborate on immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
  • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
  • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
  • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
  • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
drugs.  With the agreement Celgene has the option to be the commercialization partner outside North America for Juno's cancer drugs and any cell therapies Juno develops for autoimmune diseases include: celiac disease, eczema, IBD, lupus, multiple sclerosis, type-1-diabetes; are often debilitating and life long conditions.  Autoimmune diseases are increasing in prevelence rapidly over two or three generations in advanced societies.  One in thirteen Americans has an autoimmune condition.  Some are associated with gene alleles encoding the immune system.  .  Juno will be responsible for research, development and commercialization in North America.  Celgene would pay Juno a royalty. 

The $1 billion will purchase 9.1 million shares of Juno at $93 per share (2* market).  It can increase this 10% share to 30% towards the end of the 10 year collaboration.  It gets one seat on Juno's board.  Some analysts argue Celgene has overpaid because CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers.  But there are severe side effects.  -T and related approaches are not yet validated and it is not clear how the approach will apply to solid tumors such as breast is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013). 
, lung affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
  • Non-small-cell carcinomas are of three sub-types:
    • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
    • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
    • Large-cell carcinomas (5 to 10% of lung cancers).
  • Small-cell carcinomas.
and prostrate is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
  • Sarcomas
  • Small cell carcinomas
  • Neuroendocrine tumors
  • Transitional cell carcinomas
cancers, which represent a far larger market than blood cancers.  Celgene sees the deal as producing huge synergies. 

Jul 2015 Celgene payed $7.2 billion cash for Receptos of San Diego.  Receptos is developing ozanimod, an oral treatment for multiple-sclerosis and ulcerative cholitis that is in clinical trails with possible approval in 2018.  It licensed patents from the Scripps Research institute.  Oral treatment should be an advantage against Abbvie's Humira and J&J's Remicade that must be injected or infused.  Ozanimod has the same mechanism of action as Novartis's Gilyena, which has cardiac side effects, but Celgene argues Ozanimod could be safer. 
Celgene said that ozanimod could have peak annual sales of $4 - 6 billion.  They view it as a complement to GED-0301 and Otezla. 

Celgene's Revlimid

Revlimid is a blood cancer drug. 

Celgene's Revlimid patents are being threatened by the Coalition for Affordable drugs (Nov 2015).  It asked the patent board for sanctions against the coalition but the board ruled against Celgene. 


Cell Biotherapy

Cell Biotherapy is a cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   focused biotechnology company. 
President and founder is Dr. Scott Gottlieb



Cell Genesis   (yahoo fin, )

Was initially part of Novartis.  It's a relatively large company. 

It is the manufacturer of a custom cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   vaccine are a core strategy of public health and have significantly extended global wellbeing over 200 years.  Recent successes include: HPV vaccine.  They induce active acquired immunity to a particular disease.  But the development and deployment of vaccines is complex:
  • The business model for vaccine development has been failing (Aug 2015): 
    • No Zika vaccine was available as the epidemic grew (Mar 2016).  No vaccine for: CMV;
    • Major foundations: Michael J. Fox, Gates, Wellcome; are working to improve the situation including sponsorship of the GAVI alliance.  A geographic cluster is forming in Seattle including PATH (Apr 2016). 
    • Commercial developers include: Affiris, Cell Genesis, Chiron, CSL, Sanofi, Valeant;
  • Vaccine deployment traditionally benefited from centrally managed vertical health programs.  But political issues are now constraining success with less than 95-99% coverage required for herd immunity (Aug 2015, Sep 2015, Nov 2015, Nov 2016).  
    • Where clinics have been driven into local neighborhoods health improves (Apr 2016).  
    • Retail clinics (Mar 2016): CVS Minute Clinics focus on vaccination.  
  • Key vaccines include: BCG, C. difficile (May 2015), Cholera (El Tor), Dengvaxia (Mexico Dec 2015), Gvax, Malaria vaccine, Provenge;
  • Regulation involves: FDA (CBER), with CMS monitoring (star ratings, PACE (Aug 2016), Report cards (Sep 2015)) & CDC promoting vaccines: as a sepsis measure, To control C. difficile (May 2015);  
    • Coding : CVX, MVX;
  • Research on vaccines includes: 
    • NIH: AIDS vaccines (AVRC), Focus on using genetic analysis to improve vaccine response.  
      • NCI:
        • Roswell Park clinical trial of immuno-oncology vaccine cimavax. 
    • Geisinger: effective process leverage in treatment. 
    • Stanford Edge immuno-oncology for cancer vaccines.  
    • P53-driven-cancer focused, gene therapy (Jun 2015). 
(Gvax). 

Has a focus on the Gene therapy is the deployment of genes into patient's cells to treat or prevent diseases.  It can be performed outside the body (ex vivo) or in place (in vivo).  It requires a vector such as a: Virus, Ligandal style nanoparticle; to perform the deployment.  But viruses are: Difficult to sanitize (bringing in oncogenes etc.) and hard to target as needed,  Unable to target where the DNA is deployed into the target cell chromosomes, Key targets of the immune system.  The process is disease specific:
  • Blood cancers: NHL; can be treated with ex vivo CAR-T (Jul 2017, Oct 2017)
  • Cystic fibrosis requires a virus that infects the airways and then deploys a non-cystic fibrosis allele into the nucleus of the patient's cells.  The obstacles to this process have been challenging: 
    • The virus must not have any problematic effects.  In the case of cystic fibrosis one virus activated a cancer gene leaving several trial subjects with leukemia. 
    • Efficiency of delivery has to be very high and this has not proved possible as of 2015. 
    • The newly delivered DNA must remain intact and be replicated and transcribed.  This has not proved to be the case. 
    • The process has not been able to avoid an immune response.  Gene therapy has consequently been of limited value for cystic fibrosis. 
  • ADA based SCID was the first human treatment with gene therapy.  A normal ADA gene was inserted ex vivo into immune system cells.  Initially the updated cells did not live as long as needed. 
  • Sickle-cell anemia requires a non-sickle-cell trait allele of the hemoglobin gene to be vectored into the bone marrow of the affected person. 
area.  It merged with (somatix, ) in this area. 

Legal and Regulatory
Cell Genesys wins legal fight with Japan Tobacco for breaking contract. 

Partnerships
Medarex Human antibody is a y-shaped blood transported protein generated by the adaptive immune system's plasma cells, B lymphocytes, to accurately identify and neutralize pathogens such as bacteria and viruses that exhibit a matching antigen. 
being combined in trial with Gvax prostate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
  • Sarcomas
  • Small cell carcinomas
  • Neuroendocrine tumors
  • Transitional cell carcinomas
vaccine are a core strategy of public health and have significantly extended global wellbeing over 200 years.  Recent successes include: HPV vaccine.  They induce active acquired immunity to a particular disease.  But the development and deployment of vaccines is complex:
  • The business model for vaccine development has been failing (Aug 2015): 
    • No Zika vaccine was available as the epidemic grew (Mar 2016).  No vaccine for: CMV;
    • Major foundations: Michael J. Fox, Gates, Wellcome; are working to improve the situation including sponsorship of the GAVI alliance.  A geographic cluster is forming in Seattle including PATH (Apr 2016). 
    • Commercial developers include: Affiris, Cell Genesis, Chiron, CSL, Sanofi, Valeant;
  • Vaccine deployment traditionally benefited from centrally managed vertical health programs.  But political issues are now constraining success with less than 95-99% coverage required for herd immunity (Aug 2015, Sep 2015, Nov 2015, Nov 2016).  
    • Where clinics have been driven into local neighborhoods health improves (Apr 2016).  
    • Retail clinics (Mar 2016): CVS Minute Clinics focus on vaccination.  
  • Key vaccines include: BCG, C. difficile (May 2015), Cholera (El Tor), Dengvaxia (Mexico Dec 2015), Gvax, Malaria vaccine, Provenge;
  • Regulation involves: FDA (CBER), with CMS monitoring (star ratings, PACE (Aug 2016), Report cards (Sep 2015)) & CDC promoting vaccines: as a sepsis measure, To control C. difficile (May 2015);  
    • Coding : CVX, MVX;
  • Research on vaccines includes: 
    • NIH: AIDS vaccines (AVRC), Focus on using genetic analysis to improve vaccine response.  
      • NCI:
        • Roswell Park clinical trial of immuno-oncology vaccine cimavax. 
    • Geisinger: effective process leverage in treatment. 
    • Stanford Edge immuno-oncology for cancer vaccines.  
    • P53-driven-cancer focused, gene therapy (Jun 2015). 


Uses Strategic Decision Group 

Chiron Corporation

Chiron was a biotechnology focused on biopharmaceuticals, vaccines are a core strategy of public health and have significantly extended global wellbeing over 200 years.  Recent successes include: HPV vaccine.  They induce active acquired immunity to a particular disease.  But the development and deployment of vaccines is complex:
  • The business model for vaccine development has been failing (Aug 2015): 
    • No Zika vaccine was available as the epidemic grew (Mar 2016).  No vaccine for: CMV;
    • Major foundations: Michael J. Fox, Gates, Wellcome; are working to improve the situation including sponsorship of the GAVI alliance.  A geographic cluster is forming in Seattle including PATH (Apr 2016). 
    • Commercial developers include: Affiris, Cell Genesis, Chiron, CSL, Sanofi, Valeant;
  • Vaccine deployment traditionally benefited from centrally managed vertical health programs.  But political issues are now constraining success with less than 95-99% coverage required for herd immunity (Aug 2015, Sep 2015, Nov 2015, Nov 2016).  
    • Where clinics have been driven into local neighborhoods health improves (Apr 2016).  
    • Retail clinics (Mar 2016): CVS Minute Clinics focus on vaccination.  
  • Key vaccines include: BCG, C. difficile (May 2015), Cholera (El Tor), Dengvaxia (Mexico Dec 2015), Gvax, Malaria vaccine, Provenge;
  • Regulation involves: FDA (CBER), with CMS monitoring (star ratings, PACE (Aug 2016), Report cards (Sep 2015)) & CDC promoting vaccines: as a sepsis measure, To control C. difficile (May 2015);  
    • Coding : CVX, MVX;
  • Research on vaccines includes: 
    • NIH: AIDS vaccines (AVRC), Focus on using genetic analysis to improve vaccine response.  
      • NCI:
        • Roswell Park clinical trial of immuno-oncology vaccine cimavax. 
    • Geisinger: effective process leverage in treatment. 
    • Stanford Edge immuno-oncology for cancer vaccines.  
    • P53-driven-cancer focused, gene therapy (Jun 2015). 
and blood testing. 
Founded by:
Chairman William Rutter of UCSF,
CEO Edward Penhoet, of UC Berkeley. 
Vice President of research Pablo DT Valenzuela of UCSF

Chiron was purchased by Novartis in 2006 but parts were later sold or leased to Bayer and Novartis divested most of the remaining assets in 2013. 


CSL

CSL (originally Commonwealth Serum Laboratories) is an Australian pharmaceutical manufacturer.  It focuses on blood plasma derivatives, vaccines are a core strategy of public health and have significantly extended global wellbeing over 200 years.  Recent successes include: HPV vaccine.  They induce active acquired immunity to a particular disease.  But the development and deployment of vaccines is complex:
  • The business model for vaccine development has been failing (Aug 2015): 
    • No Zika vaccine was available as the epidemic grew (Mar 2016).  No vaccine for: CMV;
    • Major foundations: Michael J. Fox, Gates, Wellcome; are working to improve the situation including sponsorship of the GAVI alliance.  A geographic cluster is forming in Seattle including PATH (Apr 2016). 
    • Commercial developers include: Affiris, Cell Genesis, Chiron, CSL, Sanofi, Valeant;
  • Vaccine deployment traditionally benefited from centrally managed vertical health programs.  But political issues are now constraining success with less than 95-99% coverage required for herd immunity (Aug 2015, Sep 2015, Nov 2015, Nov 2016).  
    • Where clinics have been driven into local neighborhoods health improves (Apr 2016).  
    • Retail clinics (Mar 2016): CVS Minute Clinics focus on vaccination.  
  • Key vaccines include: BCG, C. difficile (May 2015), Cholera (El Tor), Dengvaxia (Mexico Dec 2015), Gvax, Malaria vaccine, Provenge;
  • Regulation involves: FDA (CBER), with CMS monitoring (star ratings, PACE (Aug 2016), Report cards (Sep 2015)) & CDC promoting vaccines: as a sepsis measure, To control C. difficile (May 2015);  
    • Coding : CVX, MVX;
  • Research on vaccines includes: 
    • NIH: AIDS vaccines (AVRC), Focus on using genetic analysis to improve vaccine response.  
      • NCI:
        • Roswell Park clinical trial of immuno-oncology vaccine cimavax. 
    • Geisinger: effective process leverage in treatment. 
    • Stanford Edge immuno-oncology for cancer vaccines.  
    • P53-driven-cancer focused, gene therapy (Jun 2015). 
, antivenoms and cell culture reagents.  It includes USA plasma maker CSL Behring. 

CSL Behring

CSL Behring manufactures plasma derived and recombinant therapys. 


Citius Pharmaceuticals

Citius's weight loss drug Suprenza

Suprenza is patented in 2013 and extended until 2029.  The patent is for an orally disintegrating tablet with a 'specled appearance'.  The patent is being challenged by the Coalition for Affordable drugs (Nov 2015). 


Clovis Oncology

Clovis Oncology in Boulder, Colorado is focused on personalized is a medical strategy where decisions, practices, and products are tailored to the individual patient.  Research is looking at the impact of providing potentially deleterious genomic testing information to people: The REVEAL study found no increased anxiety induced by hearing that one's genome implied increased risk of developing late onset Alzheimer's disease.  The take-up of personalized medicine benefits from the focus on genomics detailed by the NIH director Francis Collins and includes:
  • NCCN intensive cell therapies
  • Direct to consumer genomic testing
  • Direct to consumer diagnostics
  • Pharmacogenomics tailored drug treatments reducing the risk and cost of adverse drug reactions.  
cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   medicines. 

 

Curis

Curis initially born out of the merger of three cash-starved biotechs in 2000.  Unprofitable since it started. 

CEODaniel Passeri. 

Has targeted the Hedgehog signalling pathway, named after the furry-looking mutant fruit-flies in which it was first discovered.  The pathway is used for cell signalling.  They appear to act as a molecular switch, that may control tumor growth, hair follicle activity and reduce neuron degeneration in the brain.  The F.D.A. Food and Drug Administration. 
is likely to require heavy testing - especially for a quality of life treatment like hair restoration.  It's especially troubling since it seems to turn on to work in some cell situations and to turn off in others.  Modifiers in one treatment may have side effects in another cell type. 

In April 2005 Genentech licensed to start trials of a skin cancer drug based on Hedgehog signalling agonist. 


Denali Therapeutics

Denali is based in South San Francisco. 
Denali is a biotechnology company focused on discovery and development of therapies for neurodegenerative diseases. 
CEO Ryan Watts - former head of neuroscience at Genentech
It was founded by Marc Tessier-Lavigne, who later became president of Stanford University.  Initial funding round raised exceptional $200 million from Fidelity Bioscience, Flagship Ventures, Arch Venture

It focuses on Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form and set off the formation of tangled thread-like tau protein.
    • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
    • BACE inhibitors block an enzyme needed to form amyloid. 
  • The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
  • The brain becomes inflamed resulting in the killing of many more nerve cells. 
and other neurodegenerative diseases. 


DepoMed

DepoMed is a growth oriented specialty pharmaceutical company.  Its branded products treat pain amplifies the aggression response of people by interoceptive signalling of brain regions providing social emotions including the PAG projecting to the amygdala; making aggressive people more so and less aggressive people less so.  Pain is the main reason people visit the ED in the US.   and other conditions of the central nervous system. 


Depomed's Lazanda

Lazanda is a nasal spray formulation of fentanyl is a synthetic opioid pain medication that acts on micro-opioid receptors in the brain.  It is 50 times more potent than morphine.  It was originally manufactured by Janssen Pharmaceutica in 1959 which was acquired by Johnson & Johnson.  It is branded as: Sublimaze, Actiq, Durogesic, Duragesic, Fentora, Matrifen, Instanyl, Abstral, Lazanda; with a variety of deployment formulations.  It is often used, in a transdermal patch such as durogesic, to treat severe ongoing pain which can be induced by cancer.  It has followed heroin into the back-street opioid epidemic (Jun 2017). 


DepoMed has been a target of Horizon Pharma.  It fought off the acquisition by addopting a poison pill. 

Having been weakened by the Horizon fight it has been targeted by Starboard Value for its unfreindly policies to shareholders (Apr 2016). 


Dyax corp 


Dyax corp of Burlington Mass
Dyax develops treatments for HAE hereditary angioedema - is an autosomal dominant genetic disorder.  it induces symptoms including swelling, edema, in the hands, feet, face and airways.  While relatively rare it can be life threatening.  .  Its leading treatment is DX-2930. 

Oct 2015 Shire offers to acquire Dyax for $6.5 Billion. 

Exelixis

Exelixis is a biopharmaceutical company focused on small molecule therapies. 
They have a cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   platform on which they have developed cabozantinib and cobimetinib. 

Exelixis Cabozantinib

Cabozantinib (Cometriq) is a small molecule inhibitor of the tyrosine kinases are a class of phosporylating enzymes used to record state change by cells and hence in cell signalling, gene expression and metabolic control.  Due to this central role, cancer causing oncogenes often affect tyrosine kinases. 
c-MET and VEGFR2.  It has been shown to reduce tumor growth, metastasis and angiogenesis. 
It was F.D.A. Food and Drug Administration. 
approved in 2102 for treatment of medullary thyroid cancer. 
A year's treatment can cost $150,000. 

It has proved effective in reducing advanced kidney tumour - There are expected to be 61,560 new cases of kidney cancer in the US and 14,080 deaths in 2015.  Drug treatments have increased survival from 10 - 12 months to up to 30.  Exact causes are unknown but risk factors are: smoking, obesity, high blood pressure, genetic mutations and heredity.   progress. (Sep 2015) But it is not currently formulated for this treatment. 

Exelixis have world wide rights to cabozantinib. 

Exelixis Cobimetinib




Kaleo Pharma

Kaleo was the developer of the Auvi-Q. 
2016 CEO Spencer WIlliamson

Kaleo's Auvi-Q

Auvi-Q was invented by Dr. Eric Edwards and his twin brother, who grew up with food allergies and wanted an epinephrine injector that was easier to use than the EpiPen

It was seen as a clever alternative with:
  • Slim, rectangular, pocket-friendly design
  • Voice instructions for how to use it. 
It was initially marketed by Sanofi in 2013.  But was pulled from the market in 2015 when its list price was $500 for two injectors.  After the storm of bad publicity regarding EpiPen pricing Kaleo announced Auvi-Q would be re-released in 2017 (Oct 2016). 


The Auvi-Q, an epinephrine injector, competing with EpiPen, was initially marketed by Sanofi, who were sold the rights by Kaleo.  It was initially released in 2013 but Sanofi pulled it from the market in 2015 amid reports that it was failing to deliver the correct dose in some cases (Aug 2016). 

During the time it competed with EpiPen, Sanofi and Mylan fought hard, using discounts, to gain access to PBM is pharmacy benefit manager.  These companies, such as Caremark, were often originally PPMs.  PBMs are used by payers, such as insurance plans, to manage drug provision from pharmacies to the payer's plans subscribers. 
Express Scripts's formulary are lists of drugs that a health plan will cover.  The health plans control where and if the drug is listed in the plan.  A less expensive drug can be assigned a lower copayment to encourage patients to use it.  To counter this attack on their profits drug companies responded with coupons to help patients pay copayments removing the incentive to select the lower-priced drugs.  Health plans reacted to the copayment cards by dropping some drugs from the formulary altogether.  That encourages drug companies to bid for their drug to be the only one listed resulting in some downward price pressure.  

Kaleo, who once again owns the rights to Auvi-Q, said they were working to make it affordable.  Mylan argued in Sep 2016 that it had raised the price of EpiPen when it found in 2013 that Auvi-Q was 10% more expensive than their product. 





Loxo Oncology

Loxo is developing targeted therapies for genetically defined cancers is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).  

It has worked with Memorial Sloan Kettering Cancer Center (Aug 2017)


Mallinckrodt Pharmaceuticals

Mallinckrodt is based in Chesterfield, England.  It makes drugs and medical devices. 
Aug 2015 Agreed to purchase Therakos from Gores Group
Therakos makes the Cellex treatment system.  It provides immune cell therapies using ECP is extracorporeal photopheresis apheratically removes white blood cells and platelets from whole blood, treats them with a DNA crosslinking agent and ultraviolet light before returning them to the patient.  The goal is apoptosis of nucleated cells, subsequent induction of cytotoxic effects on T-cell formation producing antitumor action.  

Cadence of San Diego CA was purchased for $1.3 billion. 

Questcor Pharmaceuticals was purchased for $5.6 billion. 
Questcor makes H.P. Acthar Gel, an immune-modulating drug.  It is Mallinckrodt's biggest selling product but its growth is slowing. 

Ikaria a maker of treatments for critically ill infants was purchased for $2.3 billion. 


MannKind corp 


Meda

Meda is a Sweedish pharmaceutical manufacturer.  It includes:
Meda was acquired by Mylan in Aug 2016.  


Medivation Inc

Medivation is a San Francisco based biopharmaceutical company focused on oncology including prostate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
  • Sarcomas
  • Small cell carcinomas
  • Neuroendocrine tumors
  • Transitional cell carcinomas
.  It has a similar drug development process to Tesaro and Clovis

Medivation chairman Kim Blickenstaff

Medivation has two late-stage clinical testing oncology assets:


Medivation's Xtandi

Xtandi (Enzalutamide is an androgen competitive inhibitor with a very high binding affinity for the androgen receptor and an androgen receptor signalling inhibitor.  It is a general purpose androgen inhibitor and is used in androgen deprivation therapy to treat prostate cancer in men.  It is fully synthetic and was developed by Medivation, branded as Xtandi.  It can cross the blood-brain barrier and has mis-bound to GABA receptors causing seizures. 
) is F.D.A. Food and Drug Administration. 
approved.  It is targeted at prostate cancers is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
  • Sarcomas
  • Small cell carcinomas
  • Neuroendocrine tumors
  • Transitional cell carcinomas
which are metastatic and castration resistant.  There were 64,000 men treated in the US with Xtandi which has generated $2.2 billion in global sales in 12 months to Aug 2016.  Analysts predict annual sales reaching greater than $4 billion annually. 
Its US price of $129,000 for a year's treatment is two to four times the price paid in other developed countries.  As the ACA is the Patient Protection and Affordable Care Act amended by the Health Care and Education Reconciliation Act of 2010 (Obama care).  In part it is designed to make the health care system costs grow slower.  It aims to do this by: increasing competition between insurers and providers, offering free preventative services to limit the development of serious illnesses, constraining patients' use of expensive services, constraining the growth of payments to Medicare providers and piloting new ways for PCPs to manage patient care to keep patients away from costly E.D.s.  It funds these changes with increased taxes on the wealthy.  It follows an architecture developed by Heritage Action's Butler, Moffit, Haislmaier extended by White House OMB health policy advisor Ezekiel Emanuel & architect Jeanne Lambrew.  The Obama administration drafting team included: Bob Kocher; allowing it to integrate ideas from: Dartmouth Institute's Elliot Fischer (ACO).  The ACA did not include a Medicare buy in (May 2016).  The law includes:
  • Alterations, in title I, to how health care is paid for and who is covered.  This has been altered to ensure
    • Americans with preexisting conditions get health insurance cover - buttressed by mandating community rating and
    • That they are constrained by the individual mandate to have insurance but the requirement was supported by subsidies for the poor (those with incomes between 100 & 400% of the federal poverty line).  
    • Children, allowed to, stay on their parents insurance until 26 years of age. 
  • Medicare solvency improvements. 
  • Medicaid expansion, in title II: to poor with incomes below 138% of the federal poverty line; an expansion which was subsequently constrained by the Supreme Court's SCOTUS decision. 
  • Hospital Readmissions Reduction Program (HRRP) which was enforced by CMS mandated rules finalized in 2011 and effected starting Oct 2012.  
  • Medical home models.  
  • Community transformation grants support the transformation of low income stressed neighborhoods to improve their lifestyles and health. 
  • Qualifications for ACOs.  Organizations must:
    • Establish a formal legal structure with shared governance which allows the ACO to distribute shared savings payments to participating providers and suppliers. 
    • Participate in the MSSP for three or more years. 
    • Have a management structure. 
    • Have clinical and administrative systems. 
    • Include enough PCPs to care for Medicare FFS patient population (> 5000) assigned to the ACO. 
    • Be accountable for the quality and cost of care provided to the Medicare FFS patient population. 
    • Have defined processes to promote: Evidence-based medicine, Patient-centeredness, Quality reporting, Cost management, Coordination of care; 
    • Demonstrate it meets HHS patent-centeredness criteria including use of patient and caregiver assessments and individualized care plans.  
  • CMMI Medicare payment experimentation.  
  • Requirements that pharmaceutical companies must report payments made to physicians. 
  • A requirement that chain restaurants must report calorie counts on their menus. 
has driven patients to HDHP is a high-deductible health plan which has lower premiums and a higher deductable than traditional health insurance plan such as a HMO plan or PPO plan. 
s the high price has become a political issue. 

Sanofi bid for Medivation (Apr 2016), which rejected the acquisition. 

Pfizer bid $14 billion for Medivation (Aug 2016).  Blickenstaff, said the company had "significant scarecety value as one of the only profitable, commercial-stage oncology companies." 



Mylan Pharmaceuticals

Mylan is a large generic pharmaceutical manufacturer.  It sells over 2,700 products in over 160 countries.  But a significant amount of its profit comes from its EpiPen business. 
Chairman Robert Coury
CEO Heather Bresh, is daughter of Democratic Senator, and former governor Joe Manchin of West Virginia.  She chairs the Generic Pharmaceutical Association
By 2016 Bresh has worked at Mylan for 25 years.  She pushed for a law that requires more inspections of foreign manufacturers.  She helped get improved access to AIDS is acquired auto-immune deficiency syndrome, a pandemic disease caused by the HIV.  It also amplifies the threat of tuberculosis.   Initially deadly, infecting and destroying the T-lymphocytes of the immune system, it can now be treated with HAART to become a chronic disease.  And with an understanding of HIV's mode of entry into the T-cells, through its binding to CCR5 and CD4 encoded transmembrane proteins, AIDS may be susceptible to treatment with recombinant DNA to alter the CCR5 binding site, or with drugs that bind to the CCR5 cell surface protein preventing binding by the virus.  Future optimization of drug delivery may leverage nanoscale research (May 2016).   drugs. 

Mylan executive compensation

Mylan's business strategies appear to be associated with the companies executive compensation scheme (Sep 2016)


CEO Bresh has suggested Mylan had maintained a balance benefiting all its stakeholders.  But Proxy filings about executive pay indicate:



Mylan is a major producer of generic drugs. 

Mylan Inversion

Mylan moved its place of organization from Pennsylvania to the Netherlands to reduce its corporate tax rate.  Mylan inverted allows a U.S. company to move its tax domicile overseas by purchasing a foreign company.  In 2015 the U.S. Treasury department adjusted the inversion rules to require 40% of the combined company is owned by the shareholders of the purchased foreign entity.  In Apr 2016 they clamped down on the option to serially acquire American companies.  In section 7874 of the tax code, Congress defined statutory hurdles that must be cleared to gain tax benefits: Shareholders of foreign acquirers owning less than 20% of the combined entity the inversion fails, If less than 40% and the acquirer does substantial business in the foreign jurisdiction the inversion works but with some pain, If they own more than 40% there are few negative consequences.  Companies purchased serially within three years would be disregarded by the new rules.  Companies invert because of lower foreign tax rates and earnings stripping.  Once foreign, the parent loans the US subsidiary money.  The loan repayments offset the US income and the US tax bill is vastly reduced.   by acquiring a subsidiary of Abbott labs.  Shareholders were pleased.  But then Mylan invoked a 'just say never' defense against a purchase acquisition by Teva Pharmaceuticals based on its becoming a stakeholder company under Dutch law.  Shareholders were angered is an emotion which protects a person who has been cheated by a supposed friend.  When the exploitation of the altruism is discovered, Steven Pinker explains, the result is a drive for moralistic aggression to hurt the cheater. 


Mylan acquires Meda

Mylan acquires Meda, which specializes in women's health, respiratory, alergy, dermatology and pain management is an iterative process, overseen by a doctor, to limit a patient's pain.  The process is doctor prescribed, RN managed, pharmacist validated, and patient administered.  The process may be coordinated by pain management specialists.  Pain management is central to modern surgery where it is supported by hospital infrastructure.  It is central to the perioperative process.  It is a major aspect of ED operations.  It has been extended out to discharged patients with chronic long term pain where it can lead to opioid dependency.  Treatments include: Opioids including: Fentanyl, Morphine, OxyContin, Percocet; NSAIDs, Cannabinoids, Acupuncture, Massage, CBT, and Mindfulness.  


Mylan's rosuvastatin calcium generic. 

Mylan launched a generic crestor competitor in Jul 2016. 


Mylan's EpiPen

EpiPen is an injector for delivery of epinephrine to stop allergic attacks.  Mylan purchased EpiPen in 2007. 

Epipen is protected by patents on the device, such as the safety cap on the needle.  These patents are held by Pfizer's Meridian Medical Technologies. 

Mylan EpiPen pricing
Mylan has been criticized for the high price of EpiPen (Aug 2016). 


Mylan has raised the price of EpiPen ever since 2007, when it was $100, but the increases have become much larger in 2013 through 2016: 
  • With the threat of generic competition to EpiPen in 2012, Mylan started to raise prices aggressively (from $265 to $609 for two pens in Aug 2016). 
  • Then the F.D.A. Food and Drug Administration. 
    blocked the release of the Teva generic equivalent.  Teva says its product will not reach the market until 2017 at the earliest. 
  • After Sanofi's non-generic competitor product, Auvi-Q, was pulled from the market with dosing problems, Mylan was left with no competition to EpiPen in the US market. 
The price of 14 popular branded products under threat from entry of a generic rose 35% while unthreatened product prices rose 22% on average. 

HDHP is a high-deductible health plan which has lower premiums and a higher deductable than traditional health insurance plan such as a HMO plan or PPO plan. 
s make the EpiPen price an issue for voters who have raised the problem with their elected representatives. 

In response to the uproar about high prices Mylan is proposing to provide additional copayment is a fixed payment for a covered service after any deductible has been met.  It is a key strategy of the ACA to make subscribers aware of the costs of treatment and to put pressure on high cost health services.  As such suppliers and providers are keen to undermine the copayment: value based health insurance, Paying the copayment (Oct 2015), Place on the USPSTF list of preventative services (Sep 2016);
assistance.  That will undermine an ACA is the Patient Protection and Affordable Care Act amended by the Health Care and Education Reconciliation Act of 2010 (Obama care).  In part it is designed to make the health care system costs grow slower.  It aims to do this by: increasing competition between insurers and providers, offering free preventative services to limit the development of serious illnesses, constraining patients' use of expensive services, constraining the growth of payments to Medicare providers and piloting new ways for PCPs to manage patient care to keep patients away from costly E.D.s.  It funds these changes with increased taxes on the wealthy.  It follows an architecture developed by Heritage Action's Butler, Moffit, Haislmaier extended by White House OMB health policy advisor Ezekiel Emanuel & architect Jeanne Lambrew.  The Obama administration drafting team included: Bob Kocher; allowing it to integrate ideas from: Dartmouth Institute's Elliot Fischer (ACO).  The ACA did not include a Medicare buy in (May 2016).  The law includes:
  • Alterations, in title I, to how health care is paid for and who is covered.  This has been altered to ensure
    • Americans with preexisting conditions get health insurance cover - buttressed by mandating community rating and
    • That they are constrained by the individual mandate to have insurance but the requirement was supported by subsidies for the poor (those with incomes between 100 & 400% of the federal poverty line).  
    • Children, allowed to, stay on their parents insurance until 26 years of age. 
  • Medicare solvency improvements. 
  • Medicaid expansion, in title II: to poor with incomes below 138% of the federal poverty line; an expansion which was subsequently constrained by the Supreme Court's SCOTUS decision. 
  • Hospital Readmissions Reduction Program (HRRP) which was enforced by CMS mandated rules finalized in 2011 and effected starting Oct 2012.  
  • Medical home models.  
  • Community transformation grants support the transformation of low income stressed neighborhoods to improve their lifestyles and health. 
  • Qualifications for ACOs.  Organizations must:
    • Establish a formal legal structure with shared governance which allows the ACO to distribute shared savings payments to participating providers and suppliers. 
    • Participate in the MSSP for three or more years. 
    • Have a management structure. 
    • Have clinical and administrative systems. 
    • Include enough PCPs to care for Medicare FFS patient population (> 5000) assigned to the ACO. 
    • Be accountable for the quality and cost of care provided to the Medicare FFS patient population. 
    • Have defined processes to promote: Evidence-based medicine, Patient-centeredness, Quality reporting, Cost management, Coordination of care; 
    • Demonstrate it meets HHS patent-centeredness criteria including use of patient and caregiver assessments and individualized care plans.  
  • CMMI Medicare payment experimentation.  
  • Requirements that pharmaceutical companies must report payments made to physicians. 
  • A requirement that chain restaurants must report calorie counts on their menus. 
constraint on purchasing while allowing Mylan to continue benefiting from its monopoly pricing opportunity. 



Mylan attempted to shift blame to the insurers but this will likely backfire.  Given Mrs. Bresh's rising compensation, $19 million in 2016, and insider status she may get little sympathy is an emotion, the desire to help those in need.  Steven Pinker suggests it may develop into a sham emotion to earn gratitide.  Sapolsky adds that it can describe someone with the power to help, but who choses not to.  Alternately it can indicate feeling sorry for someone elses pain while not understanding it, in contrast with empathy.  Or it can mean the emotionally distanced sense of feeling for someone.  Or the state of feeling their pain as if it were happening to you where it may cause such distress as to focus you onto alleviating you own distress. 
for this positioning.


David Maris, an analyst at Wells Fargo commented on Mylan's pricing issue, to the NYT, "It's a real challenge to understand how a management team sits around a board table and makes a decision to raise the price of a lifesaving medication over and over and over, and when the P.R. storm hits, decides to blame someone else for that price increase."  Maris warned investors in June that Mylan's price increases on EpiPen and other drugs could soon draw unwanted media scrutiny. 



Mylan's PAC has given donations to the Clinton Foundation, and both the Republican (72%) and Democratic parties in the 2016 election season. 



NGM Biopharmaceuticals


NGM Biopharmaceuticals is based at 333 Oyster point blvd, South San Francisco

2016 NGM Chairman David Goeddel (managing partner at the column group) Was NGM CEO from 2008 to 2010.  Goeddel was the first scientist hired by Genentech specializing in gene cloning and expression of human proteins (human insulin regulates the metabolism of carbohydrates, fats and protein by signalling the absorption of glucose by fat, liver and skeletal muscle cells.  It is a peptide hormone generated in the islets of Langerhans beta cells of the pancreas.  Peter Medawar explains it was an early drug therapy success.  As manufacturers have shifted from products developed by extraction to biologics: Humulin, Lantus, Levemir; safety has improved.  But the US list price has risen steeply (Feb 2016, Jan 2017)
, human growth hormone, interferon-alpha, interferon-gamma, tissue plasminogen activator is tissue plasmogen activator.  It is an endothelial cell generated serine protease involved in the breakdown of blood clots. 
).  He cofounded Tularik in 1991 which was acquired by Amgen

2015 It has a $450 million collaboration with Merck


Nurix inc

Nurix Inc focuses on protein regulation, targeting E2 conjugating enzymes and E3 ligases which tag proteins with ubiquitin for degradation by the proteosome. 

Investments from Third Rock, The Column, and Celgene



Nuvelo



Ocata Therapeutics

Ocata is a pioneer in developing human embryonic stem cells.  It was initially called Advanced Cell Technology.  It is based in Marlborough Mass. 
Nov 2015 CEO Paul Wooton
Nov 2015 Chief scientific officer Dr. Robert Lanza is the driving force behind the company. 

Ocata pushes the frontiers of cloning and embryonic stem cell technologies. 
It tests medical treatments derived from human embryonic stem cells. 

It has reported early, encouraging results from clinical trials turning embryonic stem cells into a type of retinal support cell and implanting them into the eyes are major sensors in primates, based on opsins deployed in the retina & especially fovea, signalling the visual system: Superior colliculi, Thalamus (LGN), Primary visual cortex; and indirectly the amygdala.  They also signal [social] emotional state to other people.  And they have implicit censorious power with pictures of eyes encouraging people within their view to act more honorably.  Eyes are poor scanners and use a saccade to present detail slowly to the fovea.  The eye's optical structures and retina are supported by RPE.  Eyes do not connect to the brain through the brain stem and so still operate in locked-in syndrome.  Evo-devo shows eyes have deep homology.  High pressure within the eye can result in glaucoma.  Genetic inheritance can result in retinoblastoma.  Age is associated with AMD. 
of people suffering from two blinding diseases:
  1. Dry age-related macular degeneration (AMD is age related macular degeneration which is the leading cause of vision loss and blindness among Americans over 65.  It is associated with a damaging buildup of drusen pigments in the dry form and additionally, blood vessels in the wet form.  It is associated with a variety of genetic mutations.  Using HapMap data it was realized that two gene variations on separate chromosomes, both involved in inflammatory response carry high risk for this disease.  These two genetic factors along with smoking and obesity infer 80 percent of the risk.  Treatments can thus target the inflammatory response.  Ranibizumab blocks the VEGF stimulated growth of blood vessels that occur in the wet form.  )
  2. Stargardt disease

Nov 2015 Ocata acquired by Astellas.  Ocata sees the potential for injection of resources. 


Orexo pharma

Orexo is a Swedish pharmaceutical company formed with funding from Swedish VC HealthCap. 

Orexo's Abstral

Abstral is a formulation of fentanyl is a synthetic opioid pain medication that acts on micro-opioid receptors in the brain.  It is 50 times more potent than morphine.  It was originally manufactured by Janssen Pharmaceutica in 1959 which was acquired by Johnson & Johnson.  It is branded as: Sublimaze, Actiq, Durogesic, Duragesic, Fentora, Matrifen, Instanyl, Abstral, Lazanda; with a variety of deployment formulations.  It is often used, in a transdermal patch such as durogesic, to treat severe ongoing pain which can be induced by cancer.  It has followed heroin into the back-street opioid epidemic (Jun 2017). 



Otsuka Pharmaceutical


Otsuka's Abilify

Abilify (aripiprazole is a partial agonist of dopamine D2 receptors.  It is believed to lower transmission in the mesolimbic pathway and enhance transmission in the mesocortical pathway. 
) is a treatment for schizophrenia is a chronic, psychotic, brain disorder that affects 1.1 percent of the adult U.S. population.  It is characterized by hallucinations, delusions and disorganized and unusual thinking.  It seems to be caused by over pruning of prefrontal cortex neurons (Jan 2016).  There is evidence that some cases occur because of particular CNVs in the DNA of the sufferers: ZNF804A. 


Abilify is prescribed to people with schizophrenia is a chronic, psychotic, brain disorder that affects 1.1 percent of the adult U.S. population.  It is characterized by hallucinations, delusions and disorganized and unusual thinking.  It seems to be caused by over pruning of prefrontal cortex neurons (Jan 2016).  There is evidence that some cases occur because of particular CNVs in the DNA of the sufferers: ZNF804A. 
, bipolar disorder also termed manic-depression is a developmental disorder which can stimulate great creativity during the manic phase and suicide in the depressive phase.  GWAS implicate ANK3 and CACNA1C SNPs in bipolar disorder.  Lithium limits the extremes of the mood swings.  Anti-psychotic medications are prescribed.   or major depressive disorder (with an antidepressant).  It has just gone off patent. 

People suffering from these conditions often struggle with medication adherence is focused on improving how effectively patients take their medicines.  In the US in 2017 the problem is huge and costly (Apr 2017).  Chronic diseases such as Malaria illustrate the complexity of the task.  A coherent medical network with shared access to EHR should help.  So do blister packs with the days of the week marked.  M-health glow caps with a wireless transmitter that lights up if medication has not been taken as expected.  An improved prescription label is less open to confusion.  Codes on drugs can be scanned by smartphones to initiate download of an informational video.  Smart pillboxes control when pills are dispensed.  Measuring the contents of a medication bottle can alert for intervention if too much or too little is in the bottle.  Drug manufacturers see ways to get closer to the patient: Sanofi Toujeo deployment; Pharmacies are implementing VDS to support medication adherence: Connected Care;
.  But because these patients symptoms can include paranoia and delusions, they may not cooperate with any adherence scheme. 




Otsuka's Abilify MyCite

Abilify MyCite is a formulation of Abilify as a digital pill.  It is the first digital pill to gain F.D.A. Food and Drug Administration. 
approval (Nov 2017)



Abilify MyCite, was developed in a collaboration between Abilify's manufacturer Otsuka, and sensor platform developer Proteus

The sensor:
  • Contains copper, magnesium and silicon, in a formulation which
  • Generates an electrical signal when in contact with stomach acid. 
  • A patch worn above the left rib cage, that must be replaced weekly, detects the signals from the sensor via BlueTooth communications.  
  • The events are integrated in a mobile phone application with inputs from the patient and then the transaction is sent to a database that physicians may access.  
Proteus has raised $400 million from investors: Novartis, Medtronic; and invested years in the platforms development. 




Osiris therapeutics




Perrigo

Perrigo aims to offer afforable healthcare products

Perrigo's Tysabri

Tysabri (natalizumab is a used to treat MS and Crohn's disease.  It is a humanized MAB.  It is assumed to reduce immune cells' ability to pass through the cell layers lining the intestines and blood-brain barrier.  It is co-marketed by Biogen & Elan as Tysabri.  There is a worrying association with PML. 
) is a Crone's disease & MS is multiple sclerosis. 
mono-clonal antibody as a terminator in medication names indicates the drug is a monoclonal antibody biologic. 
which is co-marketed by Biogen & Elan.  It is deployed by intravenous infusion at monthly intervals. 


St. Jude Medical

St. Jude is based in Little Canada (Saint Paul) Minnesota.  It produces medical devices and related services focused on cardiac, neurological . 

Abbott has agreed to acquire St. Jude Medical (Apr 2016). 



Siemens

CEO Joe Kaeser
Chairman Gerhard Cromme
Siemens is a conglomerate based in Berlin & Munich.  It includes Divisions:
  • Process Industries and Drives
  • Digital Factory
  • Energy Management
  • Healthineers - producing medical technologies. 
  • Mobility
  • Power & Gas
  • Power generation services
  • Wind Power and Renewables
  • Building Technologies

Siemens Healthineers 

Siemens Healthineers is a medical technology company headquartered in Erlangen, Germany. 
CEO Bernd Montag



Sierra Biosource  


Shire


Shire is domiciled in Dublin Ireland. 
2015 CEO Flemming Ornshov

Shire's 2015 strategy is to become a global biotech leader focused on rare diseases and specialty conditions cost tens or hundreds of thousands of dollars a year when used to treat complex or rare diseases: cancer, rheumatoid arthritis, hemophilia, HIV.  By 2015 they account for one-third of all spending on drugs in the United States and should reach 50% by 2025.  With the MMA constraining Medicare drug price negotiations many old generic drugs appear to be being rebranded with controlled distribution as specialty drugs and re-priced with vast margins (Sep 2015). 


Oct 2015 Shire to acquire Dyax for $5.9 billion.  This is inline with Shire's 2015 strategy.  

Shire has invested in digital medicine (Nov 2015) with funding for Akili

2015 Shire has been on an acquisition spree focused on rare diseases which have consequently become 40% of its revenue stream and 65% by 2020:
Shire's Adderall
Adderall XR is used to treat ADHD is attention-deficit/hyperactivity disorder, a chronic condition including hyperactivity, impulsiveness and low attention.  Dopamine response profiles to temporal discounting tasks are abnormal for ADHD sufferers.  Imaging studies show differences in the brains of ADHD sufferers.  Stimulants have been found to have a calming effect on ADHD sufferers.  Causally associated factors include:
  • Family history
  • Genetics
    • May be influenced by high doses of Tylenol during pregnancy (Sep 2016). 
  • Environmental factors - a consistant daily schedule, praise for good behavior, clear bondaries, enough sleep and limiting distractions are all part of behavioral therapy for ADHD.  
  • CNS developmental problems.   
.  It represents one-third of Shire's sales in 2016. 


Shire has used a number of strategies to successfully protect the margins & market share of adderall:
The problem for Shire is that the proportion of the margin that is rebated has grown.  Shire recently announced it will sell off its attention-deficit drugs to focus on developing for rare-disease treatments. 


Shire's Gattex
Gattex is a treatment for short bowel syndrome. 
Shire's Lialda
Lialda is a therapy for ulcerative colitis. 

Shire's Gattex and Lialda patents are being threatened by the Coalition for Affordable drugs (Nov 2015). 

Stemcentrx

Stemcentrx is a South San Francisco oncology focused pharmaceutical company. 

Abbvie announced it will acquire Stemcentrx for $5.8 billion (Apr 2016). 


Synthetic Genomics 

Synthetic Genomics is using modified and synthesized microorganisms to produce products including fuels and biochemicals. 

Synthetic Genomics was co-founded by J. Craig Venter, president of the J. Craig Venter Institute, in 2005. 

ExxonMobil announced a $600 million collaboration in 2009 to research next-generation biofuels. 


Dr. J. Craig Venter has synthesized a full bacterial genome and deployed it successfully into a cell.  However, the initial synthesis was a near copy of an actual bacterium's DNA sequence.  Subsequently in 2016 he has developed a synthetic genome. 




Tesaro Inc

Tesaro is an oncology-focused biopharmaceutical company focused on small molecule treatments for ovarian cancer is a relatively uncommon disease but is often fatal.  It has been associated with use of talcum powder (May 2016).  

Tesaro's niraparib

Niraparib is a small molecule PARP inhibitor targeted at ovarian cancer.  It was developed by Tesaro. 
is being distributed by J&J


Tobira Therapeutics, inc. 

Tobira is a small therapeutics biopharma.  It focuses on therapies for liver diseases: NASH is non-alcoholic steatohepatitis. 
, PSC is either:
  • A Medicare benefit integrity Program Safeguard Contractor.   The PSC and ZPIC BI primary goal is to identify cases of suspected fraud to limit inappropriate payout from the Medicare trust fund.  Or
  • Primary sclerosing cholangitis which is suspected to be an autoimmune disease causing inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts.  

Its product pipeline includes:
  • Cenicriviroc (CVC) and
  • Evogliptin (EVO)

It is running a phase 2 study of CVC called CENTAUR on primary endpoints and a phase 2 study on metabolic parameters called ORION. 
Sep 2016 it is to be acquired by Allergan


Corgentech

Biospect

Novartis

Sandoz, a Swiss pharmaceutical company merged with Ciba Geigy to become Novartis. 

Novartis's Sandoz

Sandoz is now the generic division of Novartis.  It has developed a biosimilar are generic drugs made to copy biologics.  They could undermine the pharmaceutical industry's biologic profit model and so are subject to trade constraints: TRIPS, TPP. 
competing with Amgen's biologic are drugs made in living cells.  Typically they are proteins developed using genetic engineering to develop the cellular host, and to customize animal source, DNA to produce human target proteins.  Biologics solve the problem of previous protein sources, extracted from animals or human sources, of contamination and immune responses.  The strategy is very effective for blood transported proteins such as antibodies, hormones and blood factors.  But intra-cellular proteins still demand delivery and accurate cell targeting.  This creates analogous problems to those of gene therapy. 
Enbrel.  And it has obtained broad F.D.A. Food and Drug Administration. 
approval (Jul 2016). 

Novartis purchase Chiron

In 2006 Novartis moved to purchase Chiron Corporation integrating it into its gene therapy is the deployment of genes into patient's cells to treat or prevent diseases.  It can be performed outside the body (ex vivo) or in place (in vivo).  It requires a vector such as a: Virus, Ligandal style nanoparticle; to perform the deployment.  But viruses are: Difficult to sanitize (bringing in oncogenes etc.) and hard to target as needed,  Unable to target where the DNA is deployed into the target cell chromosomes, Key targets of the immune system.  The process is disease specific:
  • Blood cancers: NHL; can be treated with ex vivo CAR-T (Jul 2017, Oct 2017)
  • Cystic fibrosis requires a virus that infects the airways and then deploys a non-cystic fibrosis allele into the nucleus of the patient's cells.  The obstacles to this process have been challenging: 
    • The virus must not have any problematic effects.  In the case of cystic fibrosis one virus activated a cancer gene leaving several trial subjects with leukemia. 
    • Efficiency of delivery has to be very high and this has not proved possible as of 2015. 
    • The newly delivered DNA must remain intact and be replicated and transcribed.  This has not proved to be the case. 
    • The process has not been able to avoid an immune response.  Gene therapy has consequently been of limited value for cystic fibrosis. 
  • ADA based SCID was the first human treatment with gene therapy.  A normal ADA gene was inserted ex vivo into immune system cells.  Initially the updated cells did not live as long as needed. 
  • Sickle-cell anemia requires a non-sickle-cell trait allele of the hemoglobin gene to be vectored into the bone marrow of the affected person. 
businesses.  It partners with the University of Pennsylvania's Dr. June

Interested in gene therapy is the deployment of genes into patient's cells to treat or prevent diseases.  It can be performed outside the body (ex vivo) or in place (in vivo).  It requires a vector such as a: Virus, Ligandal style nanoparticle; to perform the deployment.  But viruses are: Difficult to sanitize (bringing in oncogenes etc.) and hard to target as needed,  Unable to target where the DNA is deployed into the target cell chromosomes, Key targets of the immune system.  The process is disease specific:
  • Blood cancers: NHL; can be treated with ex vivo CAR-T (Jul 2017, Oct 2017)
  • Cystic fibrosis requires a virus that infects the airways and then deploys a non-cystic fibrosis allele into the nucleus of the patient's cells.  The obstacles to this process have been challenging: 
    • The virus must not have any problematic effects.  In the case of cystic fibrosis one virus activated a cancer gene leaving several trial subjects with leukemia. 
    • Efficiency of delivery has to be very high and this has not proved possible as of 2015. 
    • The newly delivered DNA must remain intact and be replicated and transcribed.  This has not proved to be the case. 
    • The process has not been able to avoid an immune response.  Gene therapy has consequently been of limited value for cystic fibrosis. 
  • ADA based SCID was the first human treatment with gene therapy.  A normal ADA gene was inserted ex vivo into immune system cells.  Initially the updated cells did not live as long as needed. 
  • Sickle-cell anemia requires a non-sickle-cell trait allele of the hemoglobin gene to be vectored into the bone marrow of the affected person. 
where they purchased a number of companies (GTI, Systemix,) and are pursuing a CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers.  But there are severe side effects.  -T strategy.  They developed Gleevec is the Novartis trade name for Imatinib.  It is a tyrosine-kinase inhibitor that was designed to treat CML through a partnership between Dr. Brian Druker and Novartis who selected and productized it from a long list of potential small molecule inhibitors.  Due to the binding site that Gleevec targets being present in a variety of related cancer inducing proteins Gleevec is being used to successfully treat other types of cancers. 
(Imatinib is a tyrosine-kinase inhibitor that treats a set of cancers -- particularly CML -- where a tyrosine kinase becomes stuck turned on.  It is an early and well known targeted therapy.  It is marketed by Novartis as Gleevec.  It is taken orally and metabolised in the liver.  It has a benign side effect set allowing users to live a relatively normal life. 
) an early targeted therapy of CML is chronic myelogenous leukemia.  It is a leukemia characterized by the unregulated growth of myeloid cells in the bone marrow.  The growth is encouraged by the cellular signalling system (gene change that generates a faulty tyrosine kinase) being locked on.  Visual methods allowed Dr. Janet Rowley's team to recognize that most CML includes the Philadelphia chromosome.  It encodes the chimeric always on tyrosine kinase protein seen only in CML.  Targeted treatments such as Gleevec block the pathway for the tyrosine kinase. 
.  They later spun out Cell Genesis


Jul 2015 FDA approved Entresto from Novartis
After a large clinical trial indicated a 20% reduction in the death rate from cardiovascular causes or hospitalization from worsening heart failure is congestive heart failure which occurs when the heart is unable to generate enough blood flow to meet the body's demands.  There are two main types: failure due to left ventricular dysfunction and abnormal diastolic function increasing the stiffness of the left ventricle and decreasing its relaxation.  Treatments include: digoxin; the F.D.A. Food and Drug Administration. 
approved Entresto for patients with Class II to Class IV CHF is congestive heart failure which occurs when the heart is unable to generate enough blood flow to meet the body's demands.  There are two main types: failure due to left ventricular dysfunction and abnormal diastolic function increasing the stiffness of the left ventricle and decreasing its relaxation.  Treatments include: digoxin; - about 2.2 million Americans.  Novartis is sponsoring another trial to see if Entresto will help preseved ejection heart failure. 
Entresto is a combination of valsartan (Diovan) and sacubitril a neprilysin inhibitor. 
Novartis predicted Entresto will become the world's bestselling medication with $5 billion annual revenue.  It will be priced at $12.50 a day or $4,500 for a year's course. 
Entresto may replace ACE inhibitors is angiotensin-converting-enzyme inhibitor.  They help relax blood vessels and are used to treat hypertension and CHF.   and angiotensin II receptor blockers. 

Exjade
Exjade is used to treat iron overload in the blood. 

Novartis federal lawsuit - specialist pharmacies and Exjade
Novartis is being sued by Federal prosecutors seeking $3.3 billion in a whistle blower law suit claiming Novartis used financial incentives to influence specialty pharmacists including Accredo to promote its drugs: Exjade and ??. 

Novartis encouraged the pharmacists nurses to not tell customers about serious side-effects of Exjade. 

Novartis Ritalin
Ritalin (Methylphenidate) is a amphetamine style stimulent used to treat A.D.H.D. is attention-deficit/hyperactivity disorder, a chronic condition including hyperactivity, impulsiveness and low attention.  Dopamine response profiles to temporal discounting tasks are abnormal for ADHD sufferers.  Imaging studies show differences in the brains of ADHD sufferers.  Stimulants have been found to have a calming effect on ADHD sufferers.  Causally associated factors include:
  • Family history
  • Genetics
    • May be influenced by high doses of Tylenol during pregnancy (Sep 2016). 
  • Environmental factors - a consistant daily schedule, praise for good behavior, clear bondaries, enough sleep and limiting distractions are all part of behavioral therapy for ADHD.  
  • CNS developmental problems.   
 

Novartis's Femara
Femara (letrozole) is an aromatase inhibitor limit the synthesis of estrogen by aromatase.  Breast and ovarian cancers grow more stimulated by estrogen. 


  • Additional years of treatment with aromatase inhibitors limit the synthesis of estrogen by aromatase.  Breast and ovarian cancers grow more stimulated by estrogen. 
    reduced [re-]occurrence of breast cancer is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013). 
    but did not reduce mortality in postmenopausal women (Jun 2016). 
  • NCI is the national cancer institute. 
    's Rosenberg's TIL is tumor infiltrating lymphocyte, a class of lymphocyte that is considered to invade tumors and attack them.  TILs are isolated from the patient's tumors and cloned in large numbers.  Once the patient's native lymphocytes have been depleted with chemotherapy the TILs are infused in combination with interleukin-2 to attack the tumor. 
    therapy kills six KRAS is a gene that encodes the GTPase KRas, which is part of many signal transduction pathways that propagate growth factors.  Mutations in KRAS are essential for the development of many cancers. 
    tumors (Dec 2016)
  • Androgen deprivation therapy lowers the levels of male sex hormones.  These hormones stimulate the growth of prostrate cancer cells.  But the treatment: Bicalutamide, Lupron; is associated with increased rates of: Depression (Apr 2016), Dementia (Oct 2016) including Alzheimer's disease (Dec 2015). 
    after prostate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
    • Sarcomas
    • Small cell carcinomas
    • Neuroendocrine tumors
    • Transitional cell carcinomas
    surgery found in NCI is the national cancer institute. 
    study to save lives after reccurence (Feb 2017)



  • Novartis's Kymriah
    Kymriah was originally named tisagenlecleucel or CTL019. 
    Novartis's Tisagenlecleucel
    Tisagenlecleucel is a CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers.  But there are severe side effects.  -T biologic are drugs made in living cells.  Typically they are proteins developed using genetic engineering to develop the cellular host, and to customize animal source, DNA to produce human target proteins.  Biologics solve the problem of previous protein sources, extracted from animals or human sources, of contamination and immune responses.  The strategy is very effective for blood transported proteins such as antibodies, hormones and blood factors.  But intra-cellular proteins still demand delivery and accurate cell targeting.  This creates analogous problems to those of gene therapy. 


    Novartis plans to expand the approved market of Tisagenlecleucel, which targets CD19 signals on leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.   and lymphoma is when lymphocytes continue reproducing, and do not die - a blood cancer. 
    cell surfaces, from a few hundred a year, to add adults with diffuse large B-cell lymphoma is when lymphocytes continue reproducing, and do not die - a blood cancer. 
    in relapse. 

    Novartis is aiming to market other types of T-cell therapies targeted at: chronic lymphocytic leukemia, multiple myeloma is a cancer of B lymphocytes.  The cause is unknown, but alcohol and obesity are risk factors.  Abnormal antibodies are generated which cause kidney problems and overly thick blood.  If the abnormal lymphocytes form a single mass the diagnosis is plasmacytoma.  If there are multiple masses the diagnosis is multple myeloma.  Treatments include: Revlimid, Velcade;
    and glioblastoma are a fast growing form of glioma which usually strike older people and have an average survival time of 18 months in 2015.  The reason for the aggressive growth of glioblastomas is due to collapse of the barriers between two DNA islands which integrates a highly active loop with a low activation loop containing a growth promotor (Dec 2015). Researched by the TCGA project. 




    Novartis rheumatoid arthritis


    Novartis's Ilaris
    Ilaris (canakinumab is a human MAB that binds with interleukin-1 beta.  It is used to treat inflammation and problem immune system responses.  It is marketed by Novartis as Ilaris to treat: CAPS, rheumatoid arthritis, COPD, Gout, CAD, Schizophrenia. 
    ) is an immune system has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
    inhibitor.  It is marketed to treat rheumatoid arthritis and appears effective in treating lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
    • Non-small-cell carcinomas are of three sub-types:
      • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
      • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
      • Large-cell carcinomas (5 to 10% of lung cancers).
    • Small-cell carcinomas.
    & heart attacks is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
    • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    but its high price appears to limit its treatment base (Aug 2017). 


    Acerta Pharma

    Acerta was a privately held Netherlands/California company based in San Carlos established in 2012 and purchased by AstraZeneca in 2015.  It develops cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   drugs.  Series A funding led by BioGeneration Ventures

    It has two drug platforms which ensure rapid identification and optimization of high-quality drug candidates:
    1. Covalent Technology platform
    2. Multiparametric Phosphoflow Cytometry Platform
    An extensive development program for acalabrutinib, a BTK is Bruton's tyrosine kinase which supports the operation of the B cell antigen receptor.  When the B cell has become cancerous - a lymphoma, the signalling from the receptor will support the extended life of the cell.  BTK inhibitors are used to inhibit the signalling. 
    inhibitor, to treat blood cancer (CLL is chronic lymphocytic leukemia, a blood cancer which begins from an acquired mutation of the DNA of stem cells that generate lymphocytes in the bone marrow.  Some CLL grow fast, others grow slowly and may be responded to with watchful waiting.   
    and others) is in progress.  It is designed to improve on ibrutinib. 


    Agendia

    Agendia is a Dutch competitor of Genomic Health.  It has a US base in Irvine CA. 
    Founders: Laura Van't Veer

    Agendia's MammaPrint

    The genomic test uses genomic analysis to diagnose genetic disorders - for example Genomic Health's Oncotype DX & Agendia's MammaPrint.  The desire to see the genetic risk factors identified by such tests should depend on the risk * burden * Possibility of intervention.  Early tests look at only single gene mutations.  Genomic testing can be performed direct-to-consumer.  Data is being collated on the genetic components of most diseases to enable more sophisticated diagnosis in the future such as the OPHG (EGAPP initiative), USPSTF recommendations and NCBI (Genetic test registry).  While there is only limited identification of the significant mutations and limited patient bases misdiagnosis is a problem (Aug 2016). 
    MammaPrint, is a 70-gene assay, which was shown to indicate when breast cancer is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013). 
    patients can skip chemotherapy is the treatment of cancers by highly cytotoxic chemicals: Paclitaxel, Platinum, 6-mercaptopurine; assuming that cancer cells are unusually active and will be differentially poisoned.  It has been successful in offering treatments when no other course was available, but non-specificity means that healthy cells also get poisoned resulting in side effects which increase with age: Permanent nerve damage, heart failure (4-5%) and leukemia (0.5-1%). 
    (Aug 2016). 


    Array BioPharma

    Array BioPharma focuses at the clinical stage of drug development. 

    Array BioPharma's Selumetinib

    Selumetinib is a potential treatment for thyroid cancer are relatively rare.  They vary depending on the underlying cell type within the thyroid which generated them:
    • ATC
    • FTC
    • MTC
    • PTC 
    .  It is an inhibitor of MAPK kinase, an enzyme in the growth factor are chemical signals which stimulate cellular growth.  In the brain they induce plasticity. 
    initiated MAPK to ERK signalling, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
    pathway.  Problem mutations in the BRAF is a human gene that codes for the protein B-Raf. 
    gene & KRAS is a gene that encodes the GTPase KRas, which is part of many signal transduction pathways that propagate growth factors.  Mutations in KRAS are essential for the development of many cancers. 
    gene can activate the pathway enabling uncontrolled growth in papillary thyroid cancer. 

    Selumetinib has been licensed to AstraZeneca.  


    AstraZeneca

    AstraZeneca, a British-Swedish pharmaceutical company was formed from:
    ICI pharma divisions (Zeneca) and Sweden's Astra-AB. 


    In 2014 Pfizer attempted to buy AstraZeneca for $119 billion for its pipeline of cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   drugs. 
    Using the same strong pipeline logic Astrazeneca said no.  But with the Mystic failure both arguments are looking shaky. 



    AstraZeneca has since acquired:
    Cambridge antibody is a y-shaped blood transported protein generated by the adaptive immune system's plasma cells, B lymphocytes, to accurately identify and neutralize pathogens such as bacteria and viruses that exhibit a matching antigen. 
    Technology, MedImmune, Acerta pharma (for $4 billion obtaining acalabrutinib), ZS Pharma ($2.7 billion) which makes drugs for chronic kidney disease and heart failure is congestive heart failure which occurs when the heart is unable to generate enough blood flow to meet the body's demands.  There are two main types: failure due to left ventricular dysfunction and abnormal diastolic function increasing the stiffness of the left ventricle and decreasing its relaxation.  Treatments include: digoxin; , Takeda Pharmaceuticals respiratory business ($575 million) and Spirogen. 


    AstraZeneca has licensed Array BioPharma's potential thyroid cancer are relatively rare.  They vary depending on the underlying cell type within the thyroid which generated them:
    • ATC
    • FTC
    • MTC
    • PTC 
    drug Selumetinib.  


    AstraZeneca recently announced a collaboration with Merck to develop Lynparza and selumetinib



    AstraZeneca's Crestor cholesterol drug
    Crestor (Rosuvastatin are serum cholesterol lowering drugs established as safe and effective at reducing the risk of heart-attacks, hemorrhagic & Ischemic strokes and deaths from atherosclerotic heart disease.  They also reduce inflammation that can induce blood clots.  They appear to stabilize plaque.  About 5% of people, most with a specific allele of SLCO1B1, have muscle aches, and in some blood sugar increases.  Statins inhibit HMG-CoA reductase which produces cholesterol in the liver.  ) manages heart attack is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
    • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    and stroke is when brain cells are deprived of oxygen and begin to die.  There are two structural types: Ischemic and hemorrhagic. 
    risk, is an assessment of the likelihood of an independent problem occurring.  It can be assigned an accurate probability since it is independent of other variables in the system.  As such it is different from uncertainty. 
    .  It's market share and high price: $260 a month; place it under attack by generics, made by: Allergan, Apotex, Aurobindo, Glenmark, Mylan, Par, Sandoz, Sun, Teva; after its ODA is either
    • The orphan drug act of 1983 which aims to facilitate development of drugs for rare diseases.  The F.D.A. ensures that qualifying manufacturers obtain reduced costs of some parts of the testing process, and has tax incentives, enhanced patent protection, clinical research subsidies and support of a GSE to do research and development.  or
    • Official development assistance, funds donated by rich country governments to poor countries.  ODA is measured by the OECD's DAC. 
    market protection strategy failed (Jul 2016).  Its core patent expired on July 8th 2016. 

    Crestor was prescribed 20.3 million times in the US in 2015 and is AstraZeneca's best selling drug with a $5 billion contribution to the $23.6 billion total revenue. 


    Crestor, formerly AstraZeneca's bestselling drug has been undercut by sales of generics approved in 2016. 


    AstraZeneca's Farxiga diabetes includes type 1 and type 2.  Common side effects include: increased heart disease, hypertension, kidney disease, vision loss, nerve damage, and infections. 
    drug
    Farxiga (an SGLT2 is sodium glucose cotransporter 2 a low affinity sodium dependent glucose transporter reabsorbing glucose in the kidney.  So inhibition reduces blood glucose levels by excretion of glucose in the urine.  The inhibition has the side effect of increased urinary tract and genital infections.  The FDA has expressed concern that the inhibitors may cause bone fractures and a dangerous acid buildup in the blood. 
    inhibitor), will benefit from the reduced cardiovascular deaths reported in a Jardiance trial (Sep 2015). 


    AstraZeneca's Iressa lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
    • Non-small-cell carcinomas are of three sub-types:
      • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
      • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
      • Large-cell carcinomas (5 to 10% of lung cancers).
    • Small-cell carcinomas.
    drug
    Iressa (Gefitinib is an EGFR inhibitor, interupting signalling.  It has been used to successfully treat cancer's that are occuring because of uncontrolled EGFR activation. 
    ) was used to successfully treat Kate Robbins metastasized lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
    • Non-small-cell carcinomas are of three sub-types:
      • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
      • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
      • Large-cell carcinomas (5 to 10% of lung cancers).
    • Small-cell carcinomas.
    in 2002. 


    AstraZeneca's Tagrisso lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
    • Non-small-cell carcinomas are of three sub-types:
      • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
      • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
      • Large-cell carcinomas (5 to 10% of lung cancers).
    • Small-cell carcinomas.
    drug


    A separate trial for Tagrisso, showed it could help patients who had not yet received treatment for lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
    • Non-small-cell carcinomas are of three sub-types:
      • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
      • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
      • Large-cell carcinomas (5 to 10% of lung cancers).
    • Small-cell carcinomas.




    AstraZeneca's Mystic lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
    • Non-small-cell carcinomas are of three sub-types:
      • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
      • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
      • Large-cell carcinomas (5 to 10% of lung cancers).
    • Small-cell carcinomas.
    drug
    Mystic is a treatment combination of durvalumab is a human immunoglobulin G1 kappa MAB that blocks apoptosis through interactions with PD-L1 & PD-1.  It was developed by AstraZeneca's Medimmune marketed as Imfinzi. 
    & Tremelimumab is an immune checkpoint inhibitor, a human MAB against CTLA-4. 



    Mystic was estimated by analysts in 2014 to have a market of $6 billion annually.  But the drug trail failure will impact that projection. 



    AstraZeneca's Lynparza
    Lynparza (olaparib is a PARP inhibitor developed by KuDOS Pharmaceuticals and subsequently AstraZeneca, branded as Lynparza. 
    ) is the only F.D.A. Food and Drug Administration. 
    approved PARP inhibitor stops single stranded repair of DNA.  In cells with BRCA1/2 and PALB2 mutations this additional DNA repair inhibition will increase the likeliood that the cancer cells will die. 
    treatment for BRCA is breast cancer type 1 or 2 susceptibility gene.  The two types provide related cellular functions maintaining the validity of the cell.  If either gene product fails there is an increased likelihood of cancer.  Still individuals with mutations in BRCA1/2 genes account for only 5 to 10 percent of breast cancers.  The:  
    • Type 1 gene codes for a protein that supports DNA repair and where this is not possible can stimulate cell death.  Hence if the protein becomes defective one or both of these key caretaker functions may stop and increase the susceptibility to cancer.  The BRCA1 protein has multiple actions.  It:
      • Combines with other tumor suppressors, DNA damage sensors and cellular signal transducers to form the BASC surveillance complex monitoring the health of the cells DNA. 
      • Associates with RNA pol II to support transcription. 
      • Interacts with histone deacetylase to regulate transcription.  
      • It is a marker of high risk of breast and uterine cancer. 
      • It was collaboratively researched by Dr. Mary-Claire King and Francis Collins's labs studying chromosome 17 using genomics.  
        • In 1990 Dr. King had reported to ASHG evidence of 'this' single gene linked to a highly heritable form of breast cancer.  
        • Over the next two years the labs gathered details of BRCA1, allowing families with the mutation to understand their individual risk and plan for their futures.  
      • In 1993 BRCA1 was identified by Mark Skolnick of Myriad Genetics. 
    • Type 2 gene codes for a protein that binds both single stranded DNA and the recombinase RAD51 to facilitate homologous recombination.  
    • Advice from Dr. Collins, for families who have a history of breast or ovarian cancer includes:
      • Counselling women with the high risk BRCA mutations, about the risk of breast and ovarian cancer and the treatments available
      • Telling women who choose watchful waiting to have periodic MRIs.  And warn that watchful waiting is unreliable for ovarian cancer allowing metastasis before detection.  
      • Prophylactically removing the ovaries and Fallopian tubes on completion of childbearing.  
      • Teaching about breast reconstruction and recommending prophylactic mastectomy.  
      • Males with BRCA mutations should have careful surveillance for: Prostate, Pancreatic and breast cancer.  
      • No one being given the test without being fully counselled beforehand about the implications of the result.  Negative results may bring survivor guilt while positive results will need careful management.  
    1/2+ breast cancer is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013). 
    , as of Aug 2016. 


    AstraZeneca's Nexium
    Nexium (esomeprazole is a proton-pump inhibitor used to reduce stomach acid.  It inhibits a proton/potassium ATPase transporter in parietal cells of the stomach.  It is branded as Nexium. 
    ) is a proton pump inhibitor used to treat: GERD is gastroesophageal reflux disease where the acids from the stomach come into contact with the esophagus causing heartburn. 
    , Duodenal ulcers when combined with clarithromycin and amoxicillin, 


    Baxalta

    Baxalta is a biopharmaceutical company based in Bannockburn, Illinois; just outside Chicago. 
    Baxalta was spun off from Baxter International in July 2015 to streamline operations and focus on specialty drugs cost tens or hundreds of thousands of dollars a year when used to treat complex or rare diseases: cancer, rheumatoid arthritis, hemophilia, HIV.  By 2015 they account for one-third of all spending on drugs in the United States and should reach 50% by 2025.  With the MMA constraining Medicare drug price negotiations many old generic drugs appear to be being rebranded with controlled distribution as specialty drugs and re-priced with vast margins (Sep 2015). 


    Baxalta's Advate
    Key sales generated from Advate, a drug for hemophilia. 

    Jan 2016 Baxalta accepts Shire acquisition to create an inverted allows a U.S. company to move its tax domicile overseas by purchasing a foreign company.  In 2015 the U.S. Treasury department adjusted the inversion rules to require 40% of the combined company is owned by the shareholders of the purchased foreign entity.  In Apr 2016 they clamped down on the option to serially acquire American companies.  In section 7874 of the tax code, Congress defined statutory hurdles that must be cleared to gain tax benefits: Shareholders of foreign acquirers owning less than 20% of the combined entity the inversion fails, If less than 40% and the acquirer does substantial business in the foreign jurisdiction the inversion works but with some pain, If they own more than 40% there are few negative consequences.  Companies purchased serially within three years would be disregarded by the new rules.  Companies invert because of lower foreign tax rates and earnings stripping.  Once foreign, the parent loans the US subsidiary money.  The loan repayments offset the US income and the US tax bill is vastly reduced.   Irish giant in drugs for rare diseases. 


    Bellicum Pharmaceuticals


    Competitor to Juno Therapeutics


    Biogen

    99 strong product sales and earnings or major positive clinical events.

    We also expect increased visibility from Biogen’s pipeline as several products advance in clinical development.

    In fact, next year 2000 might be an important year for them from that regard, because it is possible that a slowdown in sales for their lead product, Avonex for multiple sclerosis is caused by collapse of the protective covering of certain neurons.  It may be due to problems with the Schwann cells that generate the myelin sheath or an autoimmune response where the myelin sheath covering of certain neurons are attacked.  Somatic DNA editing provides one direction for treatment adding surface signals which will tell the immune system cells to ignore the neurons.  Multipe sclerosis has been linked to Epstein-Barr virus which establishes a lifelong, mostly asymptomatic, infection in the majority of adults.  Harvard's Alberto Ascherio argues analogous to the late Polio infection induced paralysis model, that early infection with Epstein-Barr virus protects against M.S. while if infected in adolescence or adulthood the risk of M.S. doubles.   M.S. has been treated with Glatiramer acetate. 
    , may become more apparent later in the second half of next year.

    Consequently, from that perspective, the pipeline will become more important for Biogen in order to show what is going to be their encore product. Near term, I think they are still on pretty solid ground in terms of showing solid performance in both sales and earnings.

    Biogen's Avonex

    Avonex the multiple sclerosis is caused by collapse of the protective covering of certain neurons.  It may be due to problems with the Schwann cells that generate the myelin sheath or an autoimmune response where the myelin sheath covering of certain neurons are attacked.  Somatic DNA editing provides one direction for treatment adding surface signals which will tell the immune system cells to ignore the neurons.  Multipe sclerosis has been linked to Epstein-Barr virus which establishes a lifelong, mostly asymptomatic, infection in the majority of adults.  Harvard's Alberto Ascherio argues analogous to the late Polio infection induced paralysis model, that early infection with Epstein-Barr virus protects against M.S. while if infected in adolescence or adulthood the risk of M.S. doubles.   M.S. has been treated with Glatiramer acetate. 
    drug is Biogen's second biggest seller in 2015 with annual sales of $2.5 billion. 

    Biogen's aducanumab

    Aducanumab as a terminator in medication names indicates the drug is a monoclonal antibody biologic. 
    is designed to prevent or reduce the buildup of Amyloid plaques seen in Alzheimer's disease is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
    • Plaques form and set off the formation of tangled thread-like tau protein.
      • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
      • BACE inhibitors block an enzyme needed to form amyloid. 
    • The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    • The brain becomes inflamed resulting in the killing of many more nerve cells. 

    Biogen released trial results in March 2015 from an early-stage study showing sharply lowered decline in cognition is the ability to orchestrate thought and action in accordance with internal goals according to Princeton's Jonathan Cohen. 
    compared with a placebo.  Unfortunately there was localized brain swelling reported with the effective doses.  Lowered doses did not significantly reduce cognitive decline. 

    Biogen noted that they had started two late-stage trials to win approval for the drug in 2017 or 2018. 

    Biogen's Spinraza

    Biogen's Spinraza (nusinersen is an RNA based treatment for SMA converting the SMN2 gene to produce additional SMN protein.  It is an antisense oligonucleotide discovered by Adrian Krainer of Cold Spring Harbor Laboratory and Ionis Pharmaceuticals.  Preclinical studies at the University of Massachusetts were funded by Cure SMA.  It is marketed as Spinraza.  The F.D.A. identified side effects are respiratory infections, constipation, low blood platelet counts and poisoning of the kidneys. 
    ) is a treatment for SMA is spinal muscular atrophy, a recessive condition that typically results in paralysis and death by age two due to loss-of-function mutations in the SMN1 gene which codes for the SMN protein required by motor neurons.  One in 40 individuals is a carrier of the SMA allele.  400 babies are born with SMA in the US each year.  Treatments include: Spinraza (nusinersen). 
    .  Biogen licensed the drug from Ionis Pharmaceuticals

    Biogen's Spinraza pricing
    Biogen priced one dose of the drug at $125,000 list price.  For a years treatment the list cost will be $625,000 to $750,000 for 5 to 6 doses. 

    Biogen's Ligia Del Bianco commented to the NYT that is working with payers to ensure no patient will forgo treatment because of financial limitations or insurance status. 

    Biogen has also setup a program to help families gain insurance approval.  And advocates such as Cure SMA argue it is important that patients get access to Spinraza. 


    Amgen (yahoo fin,)

    99 The company has continued to post very good growth in their current franchises in terms of product sales that have impacted the bottom line very positively.

    The company beat earnings expectations by a comfortable margin last quarter. We continue to expect similar performance in the upcoming quarter. 

    In Amgen’s case, the company has done exceptionally well in turning around the outlook for their pipeline, where they were formerly criticized, and for good reasons, for not producing a major product from their pipeline for a prolonged period of time. The third product for the company was introduced nine years after Neupogen and represents a relatively small market to date.

    The company now has four products that are in late stages of development. One is NESP, a second-generation Epogen, which we believe will get filed later this year (99). It is a highly visible product with blockbuster potential.  Another product is a second-generation Neupogen, which we expect will receive increased visibility from data presented at an upcoming medical conference. In particular, we are expecting positive data to be presented from a Phase II study at the annual hematology meeting called ASH.

    Amgen also re-invented a product, called IL1ra, which they acquired when they bought Synergen, a product that previously failed for the treatment for sepsis is an infection triggered over-reaction by the immune system which causes general inflammation resulting in a cascade of problems: Blood clots, Leaky blood vessels; impeding blood flow to vital organs which can induce septic shock: Blood pressure drops, multiple organ failure, Heart damage and death.  For every hour without antibiotics the probability of death increases 8%.  Most cases start before people are hospitalized.  People over 65, infants under 1 year, people with chronic diseases such as diabetes, or weakened immune systems and healthy people with incorrectly treated infections are most likely to contract sepsis.  Most often the infections are of: lungs, urinary tract, skin, gut or intestines.  Typically such infections were the result of a previous visit to a clinic or hospital.  Symptoms of sepsis include: chills or fever, extreme pain or discomfort, clammy or sweaty skin, confusion or disorientation, shortness of breath and high heart rate.  The C.D.C. is concerned (Sep 2016) with antibiotic resistance supporting more sepsis. 
    .

    Amgen is planning on filing this product for the treatment of rheumatoid arthritis by the end of this year. Although we do not view this product as being as potent or as promising as other TNF is tumor necrosis factor.  It is a cytokine super-family which signals apoptosis.  Proteins in the family include:
    • TNF (cachectin) which can cause cytolysis of certain tumor lines.  It is produced in monocytes and macrophages.  It is processed and cleaved from a membrane-bound glycoprotein by the ADAM, TACE.  The cleaved chains associate into a soluble trimer.  It stimulates interleukin-1 secretion. 
    • Lymphotoxin-alpha & beta are produced by lymphocytes.   
    • CD40L
    • CD27L
    • CD30L
    • FASL
    • 4-1BBL
    • OX40L
    • TRAIL
    modulators, such as Immunex’s Enbrelor or Centocor’s Remicade, in the area of rheumatoidarthritis, I do expect the product will have a role to play in the market.

    The fourth late-stage product for Amgen is a product that the company licensed from a privately held company, Praecis Pharmaceuticals, called Abarelix. Abarelix is currently in pivotal Phase III studies for the treatment of advanced prostate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
    • Sarcomas
    • Small cell carcinomas
    • Neuroendocrine tumors
    • Transitional cell carcinomas
    and in Phase II studies for endometriosis. We expect Abarelix to be filed for prostate cancer later next year. With solid sales and earnings expected, coupled with a pipeline that is expected to generate plenty of news flow near term, we continue to like is an emotion which initiates and maintains an altruistic partnership.  It is a willingness to offer someone a favor.  It is directed to those who appear likely to return the favor.   Amgen. An issue for them is an upcoming patent infringement case,which is scheduled to come before the court system next spring. This is a case with a company called Transkaryotic Therapies (TKTX), which is partnered with Hoechst (HOE). Although we believe the odds favor Amgen given its past history in defending its Epogen patents, it is likely an event that is going to create volatility for both of those stocks. 

    Aug 2015 NYT Medicare, Reversing itself, Will Pay More for Blincyto, an Expensive New Cancer Drug
    Blincyto (blinatumomab as a terminator in medication names indicates the drug is a monoclonal antibody biologic. 
    ) is Amgen's mab as a terminator in medication names indicates the drug is a monoclonal antibody biologic. 
    for ALL is acute lymphocytic/lymphoblastic leukemia.  The cancer starts in the lymphocytes of the bone marrow.  Too many lymphocytes are produced instead of mature white blood cells.  In 2010 combination chemotherapy, including 6-mercaptopurine, cures 85 to 90% of children suffering from ALL. 
    , a particularly aggressive form of leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.  Medicare is a social insurance program that guarantees access to health insurance for Americans aged 65 and over, and younger people with disabilities and end stage renal disease or ALS.  Medicare includes:
    • Benefits
      • Part A: Hospital inpatient insurance.  As of Dec 2013 Medicare pays for home care in only limited circumstances, such as when a person needs temporary nursing care after a hospitalization.  Part A covers 20 days of inpatient rehabilitation at a SNF after discharge from inpatient care at a hosptial. 
      • Part B: Medical insurance
      • Part C: Medicare Advantage 
      • Part D: Prescription drug coverage 
    • Eligibility
      • All persons 65 years of age or older who are legal residents for at least 5 years.  If they or a spouse have paid Medicare taxes for 10 years the Medicare part A payments are waived. 
      • Persons under 65 with disabilities who receive SSDI. 
      • Persons with specific medical conditions:
        • Have end stage renal disease or need a kidney transplant. 
        • They have ALS. 
      • Some beneficiaries are dual eligible. 
      • Part A requires the person has been admitted as an inpatient at a hospital.  This is constrained by a rule that they stay for three days after admission.  
    • Premiums
      • Part A premium
      • Part B insurance premium
      • Part C & D premiums are set by the commercial insurer. 
    officials were initially dismissive, but after more scientific data they agreed the drug was a substantial improvement over existing treatments for some patients. 
    After the F.D.A. Food and Drug Administration. 
    approved Blincyto Amgen priced it at $178,000 for two 28 day cycles of treatment.  Medicare will allow a "new technology add-on payment" to hospitals for up to $27,000.  Patients typically start treatment at a hospital and then continue it at a doctor's office with specially trained nurses where Medicare will also help pay for the treatment. 

    The $178,000 price places Blincyto in the sites of President Obama, oncologists and Congress who are concerned that these useful drugs are unsustainably expensive. 

    Amgen paid $415 million in 2013 to acquire deCODE Genetics which had decoded the genomic sequences of 300,000 people in Iceland.  It is in a race with Sanofi + Regeneron (alirocumab branded as Praluent) to deliver the first PCSK9 is proprotein convertase subtilisin/kexin type 9 an enzyme activator.  It is encoded as zymogen and autocatalysed in the ER.  It plays a major role in cholesterol homeostasis.  It binds EGF-A domain of LDLR inducing LDLR degradation.  Academic researchers Dr. Helen Hobbs and Jonathan Cohen, studying large populations found reduced LDLR results in reduced metabolism of LDL which can lead to hypercholesterolemia.  Drugs that can inhibit PCSK9 can lower cholesterol much more than first generation cholesterol inhibitors. 
    inhibiting cholesterol drug with evolocumab


    Amgen's enbrel
    Etanercept branded as enbrel is a TNF is tumor necrosis factor.  It is a cytokine super-family which signals apoptosis.  Proteins in the family include:
    • TNF (cachectin) which can cause cytolysis of certain tumor lines.  It is produced in monocytes and macrophages.  It is processed and cleaved from a membrane-bound glycoprotein by the ADAM, TACE.  The cleaved chains associate into a soluble trimer.  It stimulates interleukin-1 secretion. 
    • Lymphotoxin-alpha & beta are produced by lymphocytes.   
    • CD40L
    • CD27L
    • CD30L
    • FASL
    • 4-1BBL
    • OX40L
    • TRAIL
    inhibitor.  It is the target of attacks by biosimilars are generic drugs made to copy biologics.  They could undermine the pharmaceutical industry's biologic profit model and so are subject to trade constraints: TRIPS, TPP. 
    (Jul 2016).  But Amgen is also developing a biosimilar to attack Humira whcih has obtained full F.D.A. Food and Drug Administration. 
    approval. 


    Enbrel's main patent has already expired.  But the drug is now protected by two "submarine patents are applied for and then progress very slowly through the patent office in an opaque process so that they apply to a product after the main patents have finished.  " with inventions made in the early 90s but with patents granted in 2011 and 2012. 
    If these patents hold Enbrel will have been on the market with no generic competition for 31 years. 



    Express Scripts is also restricting enbrel access and driving its deployment to Accredo (Sep 2016). 


    Amgen's Evolocumab. 

    Evolocumab as a terminator in medication names indicates the drug is a monoclonal antibody biologic. 
    branded as Repatha is a PCSK9 is proprotein convertase subtilisin/kexin type 9 an enzyme activator.  It is encoded as zymogen and autocatalysed in the ER.  It plays a major role in cholesterol homeostasis.  It binds EGF-A domain of LDLR inducing LDLR degradation.  Academic researchers Dr. Helen Hobbs and Jonathan Cohen, studying large populations found reduced LDLR results in reduced metabolism of LDL which can lead to hypercholesterolemia.  Drugs that can inhibit PCSK9 can lower cholesterol much more than first generation cholesterol inhibitors. 
    inhibitor targeted at controlling high cholesterol.  It costs $14,100 per year. 
    Aug 2015 evolocumab is F.D.A. Food and Drug Administration. 
    approved for people at high risk even while the main clinical trails of evolocumab are still proceeding.  Long term studies are needed to indicate the safety of PCSK9 inhibitors.  And the optimal level of LDL with age is not yet known (Jul 2015). 

    Express Scripts accepts Praluent and repatha (Oct 2015). 


    Amgen's Neupogen
    Neupogen (Filgrastim) is a G-CSF is granulocyte colony-stimulating factor (CSF-3) is a glycoprotein: part cytokine and part hormone; that stimulates the bone marrow to produce granulocytes and stem cells and to release them into the blood stream. 
    analog used as a bone marrow stimulant.  It can help the body make white blood cells after chemotherapy is the treatment of cancers by highly cytotoxic chemicals: Paclitaxel, Platinum, 6-mercaptopurine; assuming that cancer cells are unusually active and will be differentially poisoned.  It has been successful in offering treatments when no other course was available, but non-specificity means that healthy cells also get poisoned resulting in side effects which increase with age: Permanent nerve damage, heart failure (4-5%) and leukemia (0.5-1%). 




    Amgen atherosclerosis strategy
    Amgen announced in Sep 2015 it would pay $300 million to buy Dezima Pharma, a dutch private company developing a CETP is cholestrylester transfer protein facilitates the transfer of cholesteryl esters and triglycerides between very low density and high density lipoproteins. 
    inhibitor. 

    Amgen and osteoporosis
    Amgen's Prolia
    Prolia is similar to a bisphosphonate. 

    Amgen is partnering with UCB to trial romosozumab for osteoporosis is a set of diseases where the bones are being broken down faster than they are being renewed.  The effect is for bones to lose strength and become brittle.  The more bone mass developed the less likely osteoporosis becomes.  The risk increases with age and more often impacts women.  Certain hormone levels have an impact: Increased glucocorticoids and reduced sex hormone levels increase bone loss, over active: Thyroid, Parathyroid and Adrenal glands.  Some medical treatments can accelerate bone loss (prostate cancer treatments).  Osteoporosis treatments include:
    • Eli-Lilly's Forteo (teriparatide) a parathyroid hormone analog which encourages bone growth but is very expensive.  And it is only allowed to be taken for two years since it was associated with bone cancer in rats. 
    • Biphosphonates reduce the rate of bone loss but have frightening side effects in a small number of patients (Jun 2016). 
    .  But it was found to have the same low occurence side effects as earlier drugs (May 2016). 


    Amgen spun out the big data encompasses the IT systems and processes necessary to do population based data collection, management and analysis.  For the analysis to be useful it requires a hierarchy of supporting BI infrastructure:
    • Analytics utilization and integration delivered via SaaS and the Cloud to cope with the silos and data intensive nature. 
    • Analytics tools (BI) for PHM will be hard to develop.  
      • Complex data models must include clinical aspects of the patient specific data, including disease state population wide.  
      • A key aspect is providing clear signals about the nature of the data using data visualization. 
    • Data communication with the ability to exchange and transact.  HIEs and EMPI alliance approaches are all struggling to provide effective exchange. 
    • Data labeling and secure access and retreival.  While HIPAA was initially drafted as a secure MPI the index was removed from the legislation leaving the US without such a tool.  Silos imply that the security architecture will need to be robust. 
    • Raw data scrubbing, restructuring and standardization.  Even financial data is having to be restandarized shifting from ICD-9 to -10.  The intent is to transform the unstructured data via OCR and NLP to structured records to support the analytics process. 
    • Raw data warehousing is distributed across silos including PCP, Hospital system and network, cloud and SaaS for process, clinical and financial data. 
    • Data collection from the patient's proximate environment as well as provider CPOE, EHRs, workflow and process infrastructure.  The integration of the EHR into a big data collection tool is key. 
    analytics part of deCODE as NextCODE health

    Amgen's Josh Ofman 2015 interview at health evolution summit
    Josh Ofman talked at the health evolution summit on the evolving economics of drug pricing:

    Aurobindo Pharma Ltd.

    Aurobindo Pharma is a major generic manufacturer based in Hyderabad India. 
    It was founded by K. Nityananda Reddy and P.V. Ramprasad Reddy


    Bluebird Bio

    CEO Nick Leschly
    Bluebird has developed gene therapies is the deployment of genes into patient's cells to treat or prevent diseases.  It can be performed outside the body (ex vivo) or in place (in vivo).  It requires a vector such as a: Virus, Ligandal style nanoparticle; to perform the deployment.  But viruses are: Difficult to sanitize (bringing in oncogenes etc.) and hard to target as needed,  Unable to target where the DNA is deployed into the target cell chromosomes, Key targets of the immune system.  The process is disease specific:
    • Blood cancers: NHL; can be treated with ex vivo CAR-T (Jul 2017, Oct 2017)
    • Cystic fibrosis requires a virus that infects the airways and then deploys a non-cystic fibrosis allele into the nucleus of the patient's cells.  The obstacles to this process have been challenging: 
      • The virus must not have any problematic effects.  In the case of cystic fibrosis one virus activated a cancer gene leaving several trial subjects with leukemia. 
      • Efficiency of delivery has to be very high and this has not proved possible as of 2015. 
      • The newly delivered DNA must remain intact and be replicated and transcribed.  This has not proved to be the case. 
      • The process has not been able to avoid an immune response.  Gene therapy has consequently been of limited value for cystic fibrosis. 
    • ADA based SCID was the first human treatment with gene therapy.  A normal ADA gene was inserted ex vivo into immune system cells.  Initially the updated cells did not live as long as needed. 
    • Sickle-cell anemia requires a non-sickle-cell trait allele of the hemoglobin gene to be vectored into the bone marrow of the affected person. 
    for beta thalassemia and sickle cell anemia. 

    They have had strong results in early trials.  Nick Leschly noted that some of the patients treated were suffering from the most serious type of beta thalassemia. 
    2015 stock price exceeding $3 billion. 

    Cipla

    Cipla is a major generic manufacturer based in Mumbai India. 


    Dr. Reddy's Laboratories

    Dr. Reddy's Laboratories is a major generic manufacturer based in Hyderabad India. 


    Errant Gene Therapeutics

    CEO Mr. Girondi.  Mr. Girondi's son has beta thalassemia and so is likely to die in his mid 20s unless a treatment is developed for the mutation he carries. 
    Co-founder Norbert Wiech, a biochemist and pharmaceutical executive. 

    Errant Gene is focused on developing a gene therapy is the deployment of genes into patient's cells to treat or prevent diseases.  It can be performed outside the body (ex vivo) or in place (in vivo).  It requires a vector such as a: Virus, Ligandal style nanoparticle; to perform the deployment.  But viruses are: Difficult to sanitize (bringing in oncogenes etc.) and hard to target as needed,  Unable to target where the DNA is deployed into the target cell chromosomes, Key targets of the immune system.  The process is disease specific:
    • Blood cancers: NHL; can be treated with ex vivo CAR-T (Jul 2017, Oct 2017)
    • Cystic fibrosis requires a virus that infects the airways and then deploys a non-cystic fibrosis allele into the nucleus of the patient's cells.  The obstacles to this process have been challenging: 
      • The virus must not have any problematic effects.  In the case of cystic fibrosis one virus activated a cancer gene leaving several trial subjects with leukemia. 
      • Efficiency of delivery has to be very high and this has not proved possible as of 2015. 
      • The newly delivered DNA must remain intact and be replicated and transcribed.  This has not proved to be the case. 
      • The process has not been able to avoid an immune response.  Gene therapy has consequently been of limited value for cystic fibrosis. 
    • ADA based SCID was the first human treatment with gene therapy.  A normal ADA gene was inserted ex vivo into immune system cells.  Initially the updated cells did not live as long as needed. 
    • Sickle-cell anemia requires a non-sickle-cell trait allele of the hemoglobin gene to be vectored into the bone marrow of the affected person. 
    treatment for beta thalassemia.  The treatment was originally developed by Memorial Sloan-Kettering who licensed it to Errant Gene. 

    Mr Girondi was a successful commodities trader.  He discovered his young son had beta thalassemia in 1992.  During his search for treatments he contacted Dr. Michel Sadelian, a researcher at Sloan-Kettering, who had published a paper on his beta thalassemia gene therapy experiments. 

    Due to a death during treatment at the University of Pennsylvania with gene therapy in 1999 there was little commercial interest in developing new gene therapy treatments.  Girondi convinced Sloan-Kettering to license its treatment to Errant in 2005. 

    Errant had trouble raising finance for commercial development.  In part this was because Dr Sadelian was diverted to work on cancer and because the commercial environment was still negative. 

    To bring in more money Errant proposed sublicensing to Sigma Tau pharmaceuticals.  Sloan-Kettering refussed and in 2010 accused Errant of defaulting on the license agreement.  Errant has taken Sloan-Kettering to court. 

    Mr. Girondi argues that Bluebird is treating less sick patients and used a harsher regimen, one he would not want his son to undergo. 


    Genomic Health

    Genomic Health is based in Redwood City, California.  Founded in 2000.  IPO 2005.  
    Co-founder Dr. Steve Shak - chief scientific officer
    Co-founder Dr. Joffre Baker - senior biology fellow.  Joff and team are deploying next generation sequencing describes methods of DNA sequencing, that replace traditional Sanger sequencing, which have been implemented in commercial DNA sequencers after 2000.  The methods include:
    • Base-by-base is stepwise sequencing where there are 3' removable blockers on the DNA arrays. 
    • Pyrosequencing,  
    • Sequencing by synthesis,
    • Sequencing by ligation,
    • SMRT,
    • DNA colony sequencing,
    • DNA nanoball, 
    • Nanopore sequencing,
    • MPSS was the first of the next generation sequencing methods,
    • Polony sequencing.  
    technology to replace RT-PCR is reverse transcription polymerase chain reaction.   It uses reverse transcription of RNA to generate DNA which is then amplified by PCR.  , to all research initiatives to connect gene mutations or expression profiles to clinical outcomes (allowing examination of RNA-Seq expression and mutation analysis). 
    Joff was previously vice president for research discovery at Genentech
    CEO, president and board chair Kimberly Popovits

    Genomic Health has a 2014 pipeline for liquid Biopsy uses a tiny blood sample used for diagnostic testing.  Often the testing is based on using DNA sequencing to detect DNA in the blood from cancer cells.  By identifying the mutations in a patient's tumor accurate treatments can be selected, and recurrence can be detected.  But aging generates many similar mutations which could lead to false positives in a broad screening test.  Research and development is ongoing (Jun 2016). 

    Genomic Health provides genetic tests uses genomic analysis to diagnose genetic disorders - for example Genomic Health's Oncotype DX & Agendia's MammaPrint.  The desire to see the genetic risk factors identified by such tests should depend on the risk * burden * Possibility of intervention.  Early tests look at only single gene mutations.  Genomic testing can be performed direct-to-consumer.  Data is being collated on the genetic components of most diseases to enable more sophisticated diagnosis in the future such as the OPHG (EGAPP initiative), USPSTF recommendations and NCBI (Genetic test registry).  While there is only limited identification of the significant mutations and limited patient bases misdiagnosis is a problem (Aug 2016). 
    for active surveillance of cancers is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).  .  These include:
    Health care providers and their advocates argue that genomic tests are not well understood and could result in under treatment (Dec 2015).  The FDA Food and Drug Administration. 
    does not regulate one site testing but is asking to extend its authority. 

    Genomic health participated in the B-14 clinical trials supported by the NSABP is the national surgical adjuvant breast and bowel project.  

    They have worked hard to get Oncotype DX added to clinical guidelines. 


    Immunocore

    Targets T-cell receptors 
    Has a immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
    • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    platform technology ImmTACs.  ImmTACs are drugs based on TCR is T cell receptor. 
    'technology' targeted at Cancer, Viral infections and autoimmune diseases include: celiac disease, eczema, IBD, lupus, multiple sclerosis, type-1-diabetes; are often debilitating and life long conditions.  Autoimmune diseases are increasing in prevelence rapidly over two or three generations in advanced societies.  One in thirteen Americans has an autoimmune condition.  Some are associated with gene alleles encoding the immune system.  
    British company raised $320 million in the largest private funding round for a European life sciences company. 


    Impax Laboratories

    Impax is a specialty pharmaceutical cost tens or hundreds of thousands of dollars a year when used to treat complex or rare diseases: cancer, rheumatoid arthritis, hemophilia, HIV.  By 2015 they account for one-third of all spending on drugs in the United States and should reach 50% by 2025.  With the MMA constraining Medicare drug price negotiations many old generic drugs appear to be being rebranded with controlled distribution as specialty drugs and re-priced with vast margins (Sep 2015). 
    company based in Hayward California. 

    They purchased CorePharma and moved the distribution of generic drugs from drugstores to controlled distribution channels.  This makes it harder for other generics to compete with their products. 


    Ionis Pharmaceuticals

    Ionis is focused on RNA (RNA), a polymer composed of a chain of ribose sugars.  It does not naturally form into a paired double helix and so is far less stable than DNA.  Chains of DNA are converted by transcription into equivalently sequenced messenger m-RNA.  RNA also provides the associations that encode the genetic code.  Transfer t-RNAs have a site that maps to the codon and match the associated amino-acid.  Stuart Kauffman argues that RNA polymers may be the precursor to our current DNA based genome and protein based enzymes.  In the adaptive web framework's (AWF) Smiley we use a similar paradigm with no proteins. 
    -targeted drug discovery and development. 
    Ionis has an efficient and broadly applicable drug discovery platform.  As of 2016 Ionis has discovered three key drugs:

    Juno Therapeutics

    307 Westlake Avenue N., Suite 300, Seattle, WA 98109

    Hans Bishop CEO
    Board includes Marc Tessier-Lavigne - President of Stanford University (2016). 

    Specializes in clinical-stage cellular immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
    • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    platforms: CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers.  But there are severe side effects.  s and TCR is T cell receptor. 
    s.  They genetically engineer patients' immune system cells so they can recognize and attack tumors.  To do this they harvest cells from cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   patients and then reprogram them to fight the cancer. 

    Juno clinical trial of CAR-T therapy for adult ALL is acute lymphocytic/lymphoblastic leukemia.  The cancer starts in the lymphocytes of the bone marrow.  Too many lymphocytes are produced instead of mature white blood cells.  In 2010 combination chemotherapy, including 6-mercaptopurine, cures 85 to 90% of children suffering from ALL. 
    is halted after three deaths (Jul 2016). 

    Went public in Dec 2014 in a huge IPO for a biotech. 

    Juno partners with Sloan-Kettering, Fred Hutchinson Cancer Research Center and Seattle Children's Hospital

    Key competitors are Kite Pharma and Novartis/Bellicum Pharmaceuticals. 

    Has a 10 year collaboration with Celgene.  This should help Juno compete with Novartis which is developing similar CAR immuno therapies.  CEO Bishop commented "Celgene is the ideal partner for Juno to help us realize the full potential of our science and clinical research while maintaining the independence we, our employees, partners and investors believe is so critical for true innovation."  Juno has the option to codevelop and help commercialize certain Celgene drug candidates that are aimed at T-cells. 

    Kite Pharma


    Kite Pharma was cofounded by Arie Belldegrun and a group of colleagues in 2009.  Belldegrun qualified as a doctor in Israel, worked as a surgeon in the Israeli armed forces and went to Brigham & Women's for his residency is the apprenticeship of a medical or nursing graduate with a practitioner (attending), usually performed at a teaching hospital: Brigham & Women's, Cottage Health System, El Camino Hospital, Johns Hopkins, LSU Health Sciences Center, Rush University Medical Center, Stanford University Medical Center; skilled in the specialized techniques required for consistent success in diagnosis and treatment, or treatment execution, of medical conditions.  A first year resident is also called an intern.  Christensen, Grossman & Huang note the difficulty of presenting all the necessary case types to a resident during the limited period of the apprenticeship.  The difficulty of matching graduates with desired residency slots intrigued Al Roth who helped mitigate the problem with efficient market tools deployed by NRMP.  Docphin provides web access to categorized research information used during residency. 
    .  In 1985 he became a research fellow at the N.C.I. is the national cancer institute. 
    working for Dr. Steven Rosenberg extracting tumor fighting immune cells from cancer patients, multiplying then in the laboratory and returning them.  In 1988 he became a surgeon at UCLA Health.  He cofounded Agensys and helped start up Cougar Biotechnology (Zytiga) which was purchased by J&J in 2009 for $1 billion. 


    Kite was originally focused on cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   vaccines are a core strategy of public health and have significantly extended global wellbeing over 200 years.  Recent successes include: HPV vaccine.  They induce active acquired immunity to a particular disease.  But the development and deployment of vaccines is complex:
    • The business model for vaccine development has been failing (Aug 2015): 
      • No Zika vaccine was available as the epidemic grew (Mar 2016).  No vaccine for: CMV;
      • Major foundations: Michael J. Fox, Gates, Wellcome; are working to improve the situation including sponsorship of the GAVI alliance.  A geographic cluster is forming in Seattle including PATH (Apr 2016). 
      • Commercial developers include: Affiris, Cell Genesis, Chiron, CSL, Sanofi, Valeant;
    • Vaccine deployment traditionally benefited from centrally managed vertical health programs.  But political issues are now constraining success with less than 95-99% coverage required for herd immunity (Aug 2015, Sep 2015, Nov 2015, Nov 2016).  
      • Where clinics have been driven into local neighborhoods health improves (Apr 2016).  
      • Retail clinics (Mar 2016): CVS Minute Clinics focus on vaccination.  
    • Key vaccines include: BCG, C. difficile (May 2015), Cholera (El Tor), Dengvaxia (Mexico Dec 2015), Gvax, Malaria vaccine, Provenge;
    • Regulation involves: FDA (CBER), with CMS monitoring (star ratings, PACE (Aug 2016), Report cards (Sep 2015)) & CDC promoting vaccines: as a sepsis measure, To control C. difficile (May 2015);  
      • Coding : CVX, MVX;
    • Research on vaccines includes: 
      • NIH: AIDS vaccines (AVRC), Focus on using genetic analysis to improve vaccine response.  
        • NCI:
          • Roswell Park clinical trial of immuno-oncology vaccine cimavax. 
      • Geisinger: effective process leverage in treatment. 
      • Stanford Edge immuno-oncology for cancer vaccines.  
      • P53-driven-cancer focused, gene therapy (Jun 2015). 
    but Dr. Rosenberg convinced them to switch to CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers.  But there are severe side effects.  s.  The N.C.I. and Kite signed a contract in 2012.  It now has eight contracts with the government:
    • Kite licenses patented inventions and agreed to pay royalties of 5% of sales. 
    • Cooperative research and development agreement.  Kite provides money to the N.C.I. to support research.  Kite is paying $3million a year to Dr. Rosenberg's lab.  It pays $4 million a year to the N.C.I. and $3.8 million to academic and corporate partners. 

    Focus on novel cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   immunotherapy uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
    • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    products. 


    Kite's Yescarta


    Kite's KTE-C19
    Its first product is Yescarta (KTE-C19) targeted at blood cancers. 
    Wall Street analysts expect KTE-C19 will generate $1 billion to $2 billion a year. 


    3,500 people a year will be candidates for Yescarta.  It is created for each patient.  It will cost $373,000. 
    Ten to 15 authorized institutions will have been trained on Yescarta treatment at release. 

    Kite plans to seek approval for treatment of other blood cancers. 

    Approval leveraged a study of 111 patients at 22 hospitals with 101 patients using Yescarta.  The patients had: large B-cell lymphoma is when lymphocytes continue reproducing, and do not die - a blood cancer. 
    , primary B-cell lymphoma & transformed follicular lymphoma.  54% of the patients had complete remissions.  28% had partial remissions.  After six months 80% of the 101 were still alive. 

    Kite's cell-processing facility is in El Segundo, California.  It can support 4000 to 5000 patients a year. 



    Platform is eACT for CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers.  But there are severe side effects.  s and TCR is T cell receptor. 
    s. It partners with the NCI is the national cancer institute. 
    (Dr. Steven Rosenberg).  Kite pays several million a year to the government to support continuing research on CAR-T. 
    Kite has spent more than $200 million on R&D including funding large clinical trials. 
    Kite has invested $30 million in a factory for making treatments for 5,000 patients a year. 

    Competitor of Juno Therapeutics

    2017 Gilead purchases Kite to gain access to its cell based cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   drugs (Aug 2017)


    MDxHealth

    MDxHealth specialized in epigenetic prostate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
    • Sarcomas
    • Small cell carcinomas
    • Neuroendocrine tumors
    • Transitional cell carcinomas
    tests.  It is based in Irvine California.  
    Dr. Philip Ginsburg, executive vice president and chief medical officer argues the tests are aids to patient management. 

    MDxHealth's SelectMDx

    MDxHealth with DDL Diagnostic Laboratory have launched SelectMDx (Dec 2015).  The test aims to determine if a biopsy is necessary.  It measures messenger RNA levels of biomarkers associated with an increased probability of aggressive disease. 


    Myriad Genetics


    Myriad's Mark Skolnick
    Mark Skolnick's team at Myriad first identified the BRCA is breast cancer type 1 or 2 susceptibility gene.  The two types provide related cellular functions maintaining the validity of the cell.  If either gene product fails there is an increased likelihood of cancer.  Still individuals with mutations in BRCA1/2 genes account for only 5 to 10 percent of breast cancers.  The:  
    • Type 1 gene codes for a protein that supports DNA repair and where this is not possible can stimulate cell death.  Hence if the protein becomes defective one or both of these key caretaker functions may stop and increase the susceptibility to cancer.  The BRCA1 protein has multiple actions.  It:
      • Combines with other tumor suppressors, DNA damage sensors and cellular signal transducers to form the BASC surveillance complex monitoring the health of the cells DNA. 
      • Associates with RNA pol II to support transcription. 
      • Interacts with histone deacetylase to regulate transcription.  
      • It is a marker of high risk of breast and uterine cancer. 
      • It was collaboratively researched by Dr. Mary-Claire King and Francis Collins's labs studying chromosome 17 using genomics.  
        • In 1990 Dr. King had reported to ASHG evidence of 'this' single gene linked to a highly heritable form of breast cancer.  
        • Over the next two years the labs gathered details of BRCA1, allowing families with the mutation to understand their individual risk and plan for their futures.  
      • In 1993 BRCA1 was identified by Mark Skolnick of Myriad Genetics. 
    • Type 2 gene codes for a protein that binds both single stranded DNA and the recombinase RAD51 to facilitate homologous recombination.  
    • Advice from Dr. Collins, for families who have a history of breast or ovarian cancer includes:
      • Counselling women with the high risk BRCA mutations, about the risk of breast and ovarian cancer and the treatments available
      • Telling women who choose watchful waiting to have periodic MRIs.  And warn that watchful waiting is unreliable for ovarian cancer allowing metastasis before detection.  
      • Prophylactically removing the ovaries and Fallopian tubes on completion of childbearing.  
      • Teaching about breast reconstruction and recommending prophylactic mastectomy.  
      • Males with BRCA mutations should have careful surveillance for: Prostate, Pancreatic and breast cancer.  
      • No one being given the test without being fully counselled beforehand about the implications of the result.  Negative results may bring survivor guilt while positive results will need careful management.  
    1 gene in 1993. 
    Myriad requested 23 patents on BRCA1 and BRCA2.  Once granted they had a monopoly on diagonstic tests using these discoveries.  They had been able to maintain a monopolistic price on the tests. 

    In March 2010 the Supreme Court struck down seven of the patents.  In 2013 the Court struck down Myriad's BRCA1 and 2 patent monopoly on diagnostic testing. 

    Myriad's Prolaris

    Prolaris is a prostate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
    • Sarcomas
    • Small cell carcinomas
    • Neuroendocrine tumors
    • Transitional cell carcinomas
    biomarker test.  It has been criticised by the F.D.A. Food and Drug Administration. 
    in a Nov 2015 report saying it had not been studied adequauately for clinical use potentially leading to over and under treatment. 

    Myriad officials say the test has been validated and studied in thousands of patients, with 10 retrospective studies published in peer-reviewed journals (Dec 2015). 



    Oxitec

    Oxitec works on controlling insect pests. 
    Oxitec is developing a transgenic Mosquito which it is working with the F.D.A. Food and Drug Administration. 
    to release in the Florida Keys. 


    Regeneron pharmaceuticals

    Regeneron is a biotechnology company founded in 1989.  It partners with Sanofi


    Based in Tarrytown, N.Y.
    Founder and CEO Leonard Schleifer
    Regeneron President and Chief scientific officer George Yancopoulis. 

    Regeneron does DNA sequencing at its Tarrytown N.Y. facility. 

    It has agreed to sequence 100,000 volunteers among Geisinger's 3 million patients seeking variants linked to specific diseases. 

    Regeneron aims to use genetic discoveries to focus drug development onto key target medically significant enzymes.  Regeneron and Sanofi are already developing a PCSK9 is proprotein convertase subtilisin/kexin type 9 an enzyme activator.  It is encoded as zymogen and autocatalysed in the ER.  It plays a major role in cholesterol homeostasis.  It binds EGF-A domain of LDLR inducing LDLR degradation.  Academic researchers Dr. Helen Hobbs and Jonathan Cohen, studying large populations found reduced LDLR results in reduced metabolism of LDL which can lead to hypercholesterolemia.  Drugs that can inhibit PCSK9 can lower cholesterol much more than first generation cholesterol inhibitors. 
    inhibitor using this methodology. 

    They won regulatory approval on 24th July 2015, for Praluent a powerful but costly cholesterol lowering drug, the first result of the Sanofi partnership. 

    Praluent

    Praluent (Alirocumab as a terminator in medication names indicates the drug is a monoclonal antibody biologic. 
    ) sharply lowers Cholesterol offering a new option for sufferers of cardiovascular disease refers to:
    • Conditions where narrowed and blocked blood vessels result in angina, hypertension, CHD and heart attacks and hemorrhagic/ischemic strokes.  Mutations of the gene PCSK9 have been implicated in cardiovascular disease.  Rare families with dominant inheritence of the mutations have an overactive protein, very high levels of blood cholesterol and cardiac disease. Other rare PCSK9 mutations result in an 88% reduced risk from heart disease.  Inflammation is associated with cardiovascular disease (Aug 2017). 
    .  It is a PCSK9 is proprotein convertase subtilisin/kexin type 9 an enzyme activator.  It is encoded as zymogen and autocatalysed in the ER.  It plays a major role in cholesterol homeostasis.  It binds EGF-A domain of LDLR inducing LDLR degradation.  Academic researchers Dr. Helen Hobbs and Jonathan Cohen, studying large populations found reduced LDLR results in reduced metabolism of LDL which can lead to hypercholesterolemia.  Drugs that can inhibit PCSK9 can lower cholesterol much more than first generation cholesterol inhibitors. 
    inhibitor. 
    The F.D.A. Food and Drug Administration. 
    approved Praluent for patients who have had heart attack is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
    • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    s, strokes (Ischemic is a clot that occurs as a result of an Ischemia within a blood vessel supplying blood to the brain.  They account for 87% of all strokes.  There are two main types:
    1. Thrombotic - where cerebral arteries become diseased or damaged and then blocked by a blood clot within the brain. 
    2. Embolic - where a blood clot or plaque fragment forms outside the brain (usually the heart) and travels to the brain where it blocks a blood vessel. 
    & Hemorragic is the hemorrhage of a weakened blood vessel causing blood to leak into and around the brain creating swelling and pressure, damaging cells and tissue in the brain.  There are two main types:
    1. Intracerebral - where the hemorrhage is in small arteries or arterioles within the brain. 
    2. Subarachnoid - where the hemorrhage is in a blood vessel just outside the brain leading to the skull filling with blood. 
    ), chest pain amplifies the aggression response of people by interoceptive signalling of brain regions providing social emotions including the PAG projecting to the amygdala; making aggressive people more so and less aggressive people less so.  Pain is the main reason people visit the ED in the US.   or related conditions, or have a genetic condition that causes high cholesterol and who require additional lowering of LDL despite taking the highest dose of statins are serum cholesterol lowering drugs established as safe and effective at reducing the risk of heart-attacks, hemorrhagic & Ischemic strokes and deaths from atherosclerotic heart disease.  They also reduce inflammation that can induce blood clots.  They appear to stabilize plaque.  About 5% of people, most with a specific allele of SLCO1B1, have muscle aches, and in some blood sugar increases.  Statins inhibit HMG-CoA reductase which produces cholesterol in the liver.   they can tolerate.  Sanofi/Regeneron say this is 10 million Americans. 
    Regulators in Europe allow broader use (People may not have had a heart attack or stroke yet). 

    Praluent is injected under the skin once every two weeks. 

    Among the early users are likely to be the 600,000 American adults with heterozygous familial hypercholesterolemia (FH) which causes extremly high cholesterol and substantially increases the risk of heart attacks.  The current treatment - apheresis - requires sitting for hours while a machine cleans the blood of LDL cholesterol. 

    Clinical studies to show that Praluent and equivalent drugs: Amgen's Repatha; prevent heart attacks and strokes may complete in 2017.  Some doctors say they will limit prescriptions until then.   

    Praluent is viewed as costly.  The list price is $14,600 a year.  That is substantially higher than $7000 to $12000 that health plan and Wall Street analysts were expecting.  Health plans are expected to put in place strict measures to control which patients can use the drug.  Health plans are worried that so many patients might use the drugs that it would cost $[tens of] billions a year. 
    Sanofi and Regeneron argue that the saving in lower treatment costs for heart attacks and strokes. 

    Express Scripts accepts praluent and repatha (Oct 2015). 


    Regeneron & ANGPTL3

    Regeneron aims to leverage rare angiogenesis is the formation of new blood vessels from existing vessels.  It is important in growth, development and wound healing.  To become malignant many tumors stimulate angiogenesis. 
    mutations to develop a block buster CVD is cardiovascular disease which refers to:
    • Conditions where narrowed and blocked blood vessels result in angina, hypertension, CHD and heart attacks and hemorrhagic/ischemic strokes.  Mutations of the gene PCSK9 have been implicated in cardiovascular disease.  Rare families with dominant inheritence of the mutations have an overactive protein, very high levels of blood cholesterol and cardiac disease. Other rare PCSK9 mutations result in an 88% reduced risk from heart disease.  Inflammation is associated with cardiovascular disease (Aug 2017). 
    drug.  President Yancopoulis commented on the activity (May 2017)


    Regeneron's George Yancopoulos, said "The basic bottom line is that the reductions in triglycerides with these things is pretty unprecedented."





    Regeneron's Dupixent

    Dupixent (dupilumab is a monoclonal antibody which blocks two immune system pathways: interleukin 4 and interleukin 13; that are over produced in atopic dermatitis, by binding to the alpha subunit of the interleukin-4 receptor.  It was developed by Regeneron and marketed as Dupixent.  ) treats atopic diseases.  It is completing two trials for atopic dermatitis, is also called eczema is a long lasting inflammation of the skin.  It can be successfully treated with dupilumab.   (Oct 2016).  It is being marketed in partnership with Sanofi


    Regeneron's Dr. George Yancopoulos said he expects the F.D.A. Food and Drug Administration. 
    to rule on dupilumab is a monoclonal antibody which blocks two immune system pathways: interleukin 4 and interleukin 13; that are over produced in atopic dermatitis, by binding to the alpha subunit of the interleukin-4 receptor.  It was developed by Regeneron and marketed as Dupixent.   by March 29, 2017.  The agency has given the drug breakthrough status. 
    He declined to speculate on the drugs price, arguing it would be consistent with the value of the drug. 


    Dupixent is injected every two weeks. 


    Regeneron PD-1 inhibitor


    Sanofi will pay at least $1.7 billion to extend its collaboration to develop immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
    • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    drugs that leverage the immune system has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
    to fight cancers is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).  .  Sanofi has agreed to make an initial payment of $640 million.  The two companies will spend $650 million, with half coming from each company, to develop a monoclonal antibody is a y-shaped blood transported protein generated by the adaptive immune system's plasma cells, B lymphocytes, to accurately identify and neutralize pathogens such as bacteria and viruses that exhibit a matching antigen. 
    PD-1 is programmed cell death protein 1 (CD279) is encoded by the PDCD1 gene.  It is a cell surface receptor that belongs to the immunoglobulin superfamily. It is expressed on T-cells and pro-B cells.  It acts as an immune checkpoint preventing the activation of T-cells to help self-tolerance and reduce autoimmunity.  When it fails people can suffer from: Lupus, Crohn's disease, Rheumatoid arthritis.  PD-1 inhibitor drugs activate the immune system to attack tumors.   PD-1 inhibitors are being approved for Melanoma and squamous-cell form of lung cancer. 
    inhibitor.  They also agreed to reallocate $75 million from their previous partnership to the new one.  After successful proof of concept in a clinical trial, Sanofi has the right to opt in for further development and commercialization.  The two companies will share equally in worldwide profits. 

    They will also spend $1 billion on development of other drugs with $750 million coming from Sanofi. 

    Scientists appear to be succeeding in the strategy producing substantial remissions in certain patients.  Competitors, including Celgene in partnership with Juno Therapeutics, are investing heavily.  Immunocore just obtained $320 million funding. 

    Regeneron and Sanofi are lagging in immuno-oncology.  They are in early clinical trials of a PD-1 inhibitor.  Merck (Keytruda) and Bristol-Myers Squibb (Opdivo) already have PD-1 inhibitors on the market.  Roche and AstraZeneca are also further along in PD-1 development.  Schliefer argues that Regeneron will catch up by developing an array of immuno-oncology drugs that can be combined with one another to build far greater effectiveness.  Schliefer argued that they will be able to build bispecific antibodies that bind to both immune cells and tumor cells and can be deployed as off-the-shelf products.  In contrast other immuno-oncology strategies focus on developing patient specific treatments.  But the other companies are also working on combinations. 

    Regeneron argues that its technology to put human genes into mice is a key differentiator. 

    It may be hard to make this business model work given the competition from academic labs focused on this area of science. 


    Horizon Pharma


    CEO Timothy P. Walbert

    Horizon Pharma's Duexis

    Duexis is a combination of generics of Motrin and Pepcid.  It costs $1,500 a month.  Price has been increased 10 fold since initial introduction in 2011.  Generic Motrin and Pepcid cost between $20 and $40 a month combined. 
    In 2013 Horizon acquired Vimovo, the main competitor to Duexis for $35 million and raised its price 600%.  It has since doubled it again. 

    Sales of Duexis are growing due to a specialty drug channel program: 

    Horizon's Prescriptions Made Easy
    Horizon has developed a catalyst to propel sales of Duexis called "Prescriptions Made Easy".  Horizon recommends doctors submit prescriptions directly to a mail-order specialty pharmacy dispense specialty medications.  They aim to save health plans money by: teaching patients how to apply their medicines and deal with side effects, ensure they take the full course and limit waste.  These specialized channels can be used by drug companies to limit competition to their drugs since access in constrained.  Generic drugs rebranded as specialty medications may escape competition, remove copayment and formulary exclusion sales inhibitors and obtain considerable pricing power. 
    Linden Care, affiliated with the company. 
    The pharmacy mails the drug to the patient and deals with the insurance companies, relieving the doctor of the reimbursement is the payment process for much of US health care.  Reimbursement is the centralizing mechanism in the US Health care network.  It associates reward flows with central planning requirements such as HITECH.  Different payment methods apportion risk differently between the payer and the provider.  The payment methods include:
    • Fee-for-service,
    • Per Diem,
    • Episode of Care Payment, 
    • Multi-provider bundled EPC,
    • Condition-specific capitation,
    • Full capitation.  
    hassle otherwise associated with prescribing such an expensive drug. 

    Asked at Horizon's quarterly earnings call about the benefits of Prescriptions Made Easy Walbert replied "I think simply, the positive is we drove over $100 million in net revenue in the second quarter, rapidly increased prescriptions." 


    Rodelis Therapeutics

    Rodelis cycloserine

    Rodelis purchased cycloserine and increased its price from $500 for 30 pills to $10,800.  After an outcry (Sep 2015) they gave the drug back to the Purdue Research Foundation's Chao Center


    Savant Neglected Diseases

    Small privately held Californian specialty cost tens or hundreds of thousands of dollars a year when used to treat complex or rare diseases: cancer, rheumatoid arthritis, hemophilia, HIV.  By 2015 they account for one-third of all spending on drugs in the United States and should reach 50% by 2025.  With the MMA constraining Medicare drug price negotiations many old generic drugs appear to be being rebranded with controlled distribution as specialty drugs and re-priced with vast margins (Sep 2015). 
    pharmaceutical company. 


    Takeda Pharmaceuticals


    Takeda's Velcade

    Velcade (Bortezomib) is a proteasome inhibitor which treates multiple myeloma is a cancer of B lymphocytes.  The cause is unknown, but alcohol and obesity are risk factors.  Abnormal antibodies are generated which cause kidney problems and overly thick blood.  If the abnormal lymphocytes form a single mass the diagnosis is plasmacytoma.  If there are multiple masses the diagnosis is multple myeloma.  Treatments include: Revlimid, Velcade;
    and lymphoma is when lymphocytes continue reproducing, and do not die - a blood cancer. 
    .  In 2016 in the US it is only supplied in 3.5 milligram vials selling for $1,034 able to treat a 6'6" 250 pound person.  For a smaller patient the dose is reduced and the rest of the vial is discarded as waste (Mar 2016).  In the UK Velcade is sold in 1mg and 3.5 mg vials. 

    Takeda is trialing Actos (TOMORROW), as a method to delay the onset of Alzheimer's disease is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
    • Plaques form and set off the formation of tangled thread-like tau protein.
      • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
      • BACE inhibitors block an enzyme needed to form amyloid. 
    • The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    • The brain becomes inflamed resulting in the killing of many more nerve cells. 
    , in partnership with Zinfandel Pharmaceuticals.

    Takeda's Matrifen

    Matrifen is a fentanyl is a synthetic opioid pain medication that acts on micro-opioid receptors in the brain.  It is 50 times more potent than morphine.  It was originally manufactured by Janssen Pharmaceutica in 1959 which was acquired by Johnson & Johnson.  It is branded as: Sublimaze, Actiq, Durogesic, Duragesic, Fentora, Matrifen, Instanyl, Abstral, Lazanda; with a variety of deployment formulations.  It is often used, in a transdermal patch such as durogesic, to treat severe ongoing pain which can be induced by cancer.  It has followed heroin into the back-street opioid epidemic (Jun 2017). 
    patch. 

    Takeda's Instanyl

    Instanyl is a single dose nasal spray formulation of fentanyl is a synthetic opioid pain medication that acts on micro-opioid receptors in the brain.  It is 50 times more potent than morphine.  It was originally manufactured by Janssen Pharmaceutica in 1959 which was acquired by Johnson & Johnson.  It is branded as: Sublimaze, Actiq, Durogesic, Duragesic, Fentora, Matrifen, Instanyl, Abstral, Lazanda; with a variety of deployment formulations.  It is often used, in a transdermal patch such as durogesic, to treat severe ongoing pain which can be induced by cancer.  It has followed heroin into the back-street opioid epidemic (Jun 2017). 



    Takeda was acquired by AstraZeneca





    Teva Pharmaceuticals

    Teva is based in Isreal.  It is the largest generic pharmaceutical company.  But it also sells brand name drugs including: Copaxone; selling more than $6 billion in the USA in 2015.  It will offer 27 new speciality products in 2017. 
    It sees itself as a hybrid. 

    It reported in Jan 2016 that it marketed more than 315 new generic medicines in more then 60 countries in 2015.  It offers over 1000 new generic medicines in 2016 and plans for 1,500 in 2017. 

    It has offered $40.5 billion to acquire Allergan's world-wide generic operations. 

    2015 Teva Pharmaceuticals offered to acquire Mylan.  However, Mylan had inverted allows a U.S. company to move its tax domicile overseas by purchasing a foreign company.  In 2015 the U.S. Treasury department adjusted the inversion rules to require 40% of the combined company is owned by the shareholders of the purchased foreign entity.  In Apr 2016 they clamped down on the option to serially acquire American companies.  In section 7874 of the tax code, Congress defined statutory hurdles that must be cleared to gain tax benefits: Shareholders of foreign acquirers owning less than 20% of the combined entity the inversion fails, If less than 40% and the acquirer does substantial business in the foreign jurisdiction the inversion works but with some pain, If they own more than 40% there are few negative consequences.  Companies purchased serially within three years would be disregarded by the new rules.  Companies invert because of lower foreign tax rates and earnings stripping.  Once foreign, the parent loans the US subsidiary money.  The loan repayments offset the US income and the US tax bill is vastly reduced.   to the Netherlands and used Dutch law, where it has become a stakeholder company, to stop the purchase.  Many Mylan shareholders were angered is an emotion which protects a person who has been cheated by a supposed friend.  When the exploitation of the altruism is discovered, Steven Pinker explains, the result is a drive for moralistic aggression to hurt the cheater. 


    2016 Teva requests to join PhRMA (Jul 2016). 

    2017 Teva generic profits under pressure (Aug 2017)


    Teva Pharmaceuticals reported that it had missed analysts' earnings estimates in the second quarter [2017] and planned to lay off 7,000 workers.  Its share price plummeted 24 percent in one day as investors worried there was no end in sight. 




    Teva's Treanda

    Teva makes Treanda (Bendamustine a nitrogen mustard) is used to treat CLL is chronic lymphocytic leukemia, a blood cancer which begins from an acquired mutation of the DNA of stem cells that generate lymphocytes in the bone marrow.  Some CLL grow fast, others grow slowly and may be responded to with watchful waiting.   
    , NHL is non-Hodgkin lymphoma, It is:
    • A group of blood cancers that include all (> 60) types of lymphoma except HL.  
    • Risk factors include: poor immune function, autoimmune disease, Helicobacter pylori infection, hepatitis C, obesity, Epstein-Barr virus infection, HIV infection, radiation therapy, chemotherapy, PCBs, dioxin, phenoxy herbicides. 
    .  It is packaged in four seperate dosages and has about 1 percent wastage. 

    Teva's Copaxone

    Teva makes Copaxone (Glatiramer acetate is an immunomodulator.  It is a random polymer of four amino acids: glutamic acid, lysine, alanine, tyrosine; found in myelin.  It is used to treat multiple sclerosis.  ) to treat multiple sclerosis is caused by collapse of the protective covering of certain neurons.  It may be due to problems with the Schwann cells that generate the myelin sheath or an autoimmune response where the myelin sheath covering of certain neurons are attacked.  Somatic DNA editing provides one direction for treatment adding surface signals which will tell the immune system cells to ignore the neurons.  Multipe sclerosis has been linked to Epstein-Barr virus which establishes a lifelong, mostly asymptomatic, infection in the majority of adults.  Harvard's Alberto Ascherio argues analogous to the late Polio infection induced paralysis model, that early infection with Epstein-Barr virus protects against M.S. while if infected in adolescence or adulthood the risk of M.S. doubles.   M.S. has been treated with Glatiramer acetate. 



    Tolero Pharmaceuticals

    Tolero is based in Utah. 

    They assume life-threatening diseases are caused by accumulation of abnormalities: SNP is single nucleotide polymorphism where single base pairs have changed in two chromosomes of the same type.  There are 10 million common SNPs in the human genome.  There are a limited number of chromosomal types (Haplotypes).  This results in SNPs clustering into packs.  On average 30 to 40 SNPs travel together.  Knowing one or two SNPs in a local neighborhood predicts the others that are likely to be present. 
    ; in cell function over time. 

    Tolero was acquired by Sumitomo Dainippon Pharma for $780 million. 


    Gilead Sciences


    Gilead is based in Foster City CA.  It has emerged as the largest biotechnology company based on its targeting hepatitis C is a virus which destroys the liver during infection.  In 2016 it affects 185 million people worldwide.  Once the virus genome was sequenced in 1989 Dr. Bartenschlager and Dr. Rice worked to replicate the virus in the laboratory.  Rice realized the genome sequence was missing details that stopped the lab replication.  Bartenschlager was then successful at replicating the virus in cells in his laboratory.  The replication technique allowed Pharmasset's Dr. Sofia to develop a new hepatitis C drug, by enhancing an RNA-polymerase inhibitor with a coat that allowed the drug to enter the liver, where the coat was destroyed and the polymerase inhibitor was activated.  With high concentrations of the drug, sofosbuvir, in the liver it could eradicate the hepatitis C virus.   Sovaldi was the first sofosbuvir approved by the F.D.A. 
    and HIV/AIDS treatments

    2017 Gilead purchases Kite Pharma to gain access to its cell based cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   drugs (Aug 2017)


    The market has put pressure on Gilead to make a major acquistion. 

    Under the acquisition agreement:
    • Gilead will pay $180 a share in cash
    Gilead will acquire Kite's



    2011 Gilead purchases Pharmasset gaining access to its hepatitis-C drug now marketed by Gilead as Sovaldi is Gilead Sciences hepatitis-C drug.  It is the first effective cure with acceptable side effects.  In 2014 Sovaldi costs $84,000 for a typical course of treatment. 

    The strategy is seen as highly successful but is threatened by formulary are lists of drugs that a health plan will cover.  The health plans control where and if the drug is listed in the plan.  A less expensive drug can be assigned a lower copayment to encourage patients to use it.  To counter this attack on their profits drug companies responded with coupons to help patients pay copayments removing the incentive to select the lower-priced drugs.  Health plans reacted to the copayment cards by dropping some drugs from the formulary altogether.  That encourages drug companies to bid for their drug to be the only one listed resulting in some downward price pressure.   price constraint stategies and patients waiting for Harvoni to become available. 

    Gilead results

    Gilead Q3 2014
    Gilead reported Oct 2014 that Sovaldi is Gilead Sciences hepatitis-C drug.  It is the first effective cure with acceptable side effects.  In 2014 Sovaldi costs $84,000 for a typical course of treatment. 
    achieved Q3 sales of $2.8 billion, with $2.2 billion in U.S.  That was less than analysts predicted pushing shares 4% lower.  Q3 Sovaldi sales were down from Q3 $3.5 billion ($3 billion in U.S.).  The reduction is attributed to patients waiting for Harvoni, which was approved by the F.D.A. Food and Drug Administration. 
    in Oct 2014.  

    Gilead and legal fights

    Gilead has been criticised and attacked for its drug pricing and its patent strategies (Jan 2016). 

    Sovaldi

    Sovaldi is Gilead Sciences hepatitis-C drug.  It is the first effective cure with acceptable side effects.  In 2014 Sovaldi costs $84,000 for a typical course of treatment. 
    provides the first effective cure for hepatitis-C is a virus which destroys the liver during infection.  In 2016 it affects 185 million people worldwide.  Once the virus genome was sequenced in 1989 Dr. Bartenschlager and Dr. Rice worked to replicate the virus in the laboratory.  Rice realized the genome sequence was missing details that stopped the lab replication.  Bartenschlager was then successful at replicating the virus in cells in his laboratory.  The replication technique allowed Pharmasset's Dr. Sofia to develop a new hepatitis C drug, by enhancing an RNA-polymerase inhibitor with a coat that allowed the drug to enter the liver, where the coat was destroyed and the polymerase inhibitor was activated.  With high concentrations of the drug, sofosbuvir, in the liver it could eradicate the hepatitis C virus.   Sovaldi was the first sofosbuvir approved by the F.D.A. 
    .  Prior to Sovaldi there were drugs to manage the symptoms of hepatitis-C is a virus which destroys the liver during infection.  In 2016 it affects 185 million people worldwide.  Once the virus genome was sequenced in 1989 Dr. Bartenschlager and Dr. Rice worked to replicate the virus in the laboratory.  Rice realized the genome sequence was missing details that stopped the lab replication.  Bartenschlager was then successful at replicating the virus in cells in his laboratory.  The replication technique allowed Pharmasset's Dr. Sofia to develop a new hepatitis C drug, by enhancing an RNA-polymerase inhibitor with a coat that allowed the drug to enter the liver, where the coat was destroyed and the polymerase inhibitor was activated.  With high concentrations of the drug, sofosbuvir, in the liver it could eradicate the hepatitis C virus.   Sovaldi was the first sofosbuvir approved by the F.D.A. 
    and some treatments but with unacceptable side effects including fever, depression is a debilitating state which is facilitated by genetic predisposition - for example genes coding for relatively low serotonin levels; and an accumulation of traumatic events.  There is evidence of shifts in the sleep/wake cycle in affected individuals (Dec 2015).  The affected person will experience a pathological sense of loss of control, prolonged sadness, irritability, sleep disturbances, loss of appetite, and inability to experience pleasure.  It affects 12% of men and 20% of women.  It appears to be associated with androgen deprivation therapy treatment for prostate cancer (Apr 2016).  Chronic stress depletes the nucleus accumbens of dopamine, biasing humans towards depression.  Depression easily leads to following unhealthy pathways: drinking, overeating; which increase the risk of heart disease.   It has been associated with an aging related B12 deficiency (Sep 2016).  During depression, stress mediates inhibition of dopamine signalling.  There is an association between depression and particular brain regions: Hippocampal dendrite and spine number reductions, Dorsal raphe nucleus linked to loneliness, Abnormalities of the ACC.  Childhood adversity can increase depression risk by linking recollections of uncontrollable situations to overgeneralizations that life will always be terrible and uncontrollable.  Treatments include: CBT, UMHS depression management.  As of 2010 drug treatments take weeks to facilitate a response & many patients do not respond to the first drug applied, often prolonging the agony.   Genomic predictions of which treatment will be effective have not been possible because: Not all clinical depressions are the same, a standard definition of drug response is difficult; and anemia. 

    In 2014 there is pent up demand with a lot of people suffering from hepatitis-C.  3.2 million in the US alone.  So many people have been waiting for a cure like Sovaldi.  That is an issue to payers who are worried about being hit with huge immediate charges.  It is likely to disipate within a couple of years if the majority of sufferers are treated. 

    People used to get hepatitis-C from blood transfusions.  Now it is mostly contracted by intrvenous drug users who share needles. 

    The use of Sovaldi should be a significant benefit to overall national health.  Hepatitis-C slowly destroys the liver.  Over decades, many infected people end up with liver is an emergent cellular system providing metabolic: Dietary compound metabolism and signalling: After gorging on sugar-rich foods the liver releases FGF21 hormone to dampen further eating activity; Detoxification, Regulation of glucose through glycogen storage (asprosin signalling from white adipose tissue); clotting, immune, exocrine and endocrine functions.  It is supplied with oxygen-rich blood via the hepatic artery and blood rich in semi-processed foodstuffs from the intestines & spleen via the hepatic portal vein.  It is constructed from: Hepatocytes which swim in the blood to process it, BECs, Stromal cells, Hepatic stellate cells, Kupffer cells, and blood vessels.  The embryonic endoderm cells invade the mesoderm to form the liver bud.  Subsequently the liver bud vascularizes and is colonized by hematopoietic cells.  The liver operates on a daily cycle allowing it time to recover from the stress of processing toxic substances.  There are over 100 disorders of the liver.  Obesity and diabetes are associated with increased prevalence of these liver disorders worldwide. 
    damage and complications including joint pain amplifies the aggression response of people by interoceptive signalling of brain regions providing social emotions including the PAG projecting to the amygdala; making aggressive people more so and less aggressive people less so.  Pain is the main reason people visit the ED in the US.   and kidney provides multiple vital functions.  It: Produces renin which supports negative feedback, Removes excess organic molecules from the blood, Regulates electrolytes in the blood, Maintains pH homeostasis, Regulates fluid balance, Regulates blood pressure, Reabsorbs water, glucose (SGLT2) and amino acids.  Kidney function is monitored with the GFR.  Kidneys can fail acutely or chronically.  Kidneys are affected by a variety of cancers including: advanced kidney cancer, von Hippel Landau; some of which are induced by PFAS.    Multiple myeloma, type 2 diabetes, TB and drug treatments for MDR TB place a strain on the kidneys and can induce failure. 
    disease.  A smaller number get cirrhosis or liver cancer is the sixth most frequent cancer globally, and the second leading cause of cancer based death.  It is mainly associated with cirrhosis from hepatitis B, C,  or alcohol, but there is also a correlation with obesity (Aug 2016).  The most common liver cancer is HCC.  Immature hepatocytes can produce hepatoblastomas.  Some types of the fungus Aspergillus produce aflatoxins, which can be dangerous to children when ingested or to adults in chronic exposure causing cirrhosis and carcinoma of the liver.  Aflatoxin metabolites intercalate into DNA and alkylate the bases.  This causes mutations in p53. 
    .  A tiny group need liver transplants.  Early data from the CDC is the HHS's center for disease control and prevention based in Atlanta Georgia.  
    suggest that more than 60% of people with hepatitis-C end up with chronic liver disease.  20% get cirrhosis.  Treatment of those diseases is expensive.  And a liver transplant can cost over $600,000.  WIth a high cure rate Sovaldi is also likely to reduce the spread of disease to others. 

    Sovaldi pricing
    Pricing of $84,000 for a typical person's total treatment equates to $1000 a pill.  (This ignores the cost of the other drugs that must be taken along with Sovaldi -- alpha interferon and ribavirin or J&J's new Olysio $150,000).  Sovaldi can cure 90% of patients' hepatitis-C is a virus which destroys the liver during infection.  In 2016 it affects 185 million people worldwide.  Once the virus genome was sequenced in 1989 Dr. Bartenschlager and Dr. Rice worked to replicate the virus in the laboratory.  Rice realized the genome sequence was missing details that stopped the lab replication.  Bartenschlager was then successful at replicating the virus in cells in his laboratory.  The replication technique allowed Pharmasset's Dr. Sofia to develop a new hepatitis C drug, by enhancing an RNA-polymerase inhibitor with a coat that allowed the drug to enter the liver, where the coat was destroyed and the polymerase inhibitor was activated.  With high concentrations of the drug, sofosbuvir, in the liver it could eradicate the hepatitis C virus.   Sovaldi was the first sofosbuvir approved by the F.D.A. 
    in just a few weeks.  Compared to the treatment of chronic diseases like HIV is human immunodeficiency virus, an RNA retrovirus which causes AIDS.  It infects T-lymphocytes destroying the host's immune system. 
    ($380,000) or diabetes includes type 1 and type 2.  Common side effects include: increased heart disease, hypertension, kidney disease, vision loss, nerve damage, and infections. 
    the total treatment cost is low.  Similarly the previous treatments for hepatitis-C cost around $70,000 for a course of treatment.  Very few people chose to use these so there was little cost impact. 

    Analysts assume that as effective competitor drugs arrive in the market place the price of Sovaldi will drop.  formulary are lists of drugs that a health plan will cover.  The health plans control where and if the drug is listed in the plan.  A less expensive drug can be assigned a lower copayment to encourage patients to use it.  To counter this attack on their profits drug companies responded with coupons to help patients pay copayments removing the incentive to select the lower-priced drugs.  Health plans reacted to the copayment cards by dropping some drugs from the formulary altogether.  That encourages drug companies to bid for their drug to be the only one listed resulting in some downward price pressure.   constraints should encourgage that pricing impact. 

    But the discrete treatment timetable and per pill cost are not well aligned with Medicaid is the state-federal program for the poor.  Originally part of Lyndon Johnson's 1965 Bill, eligibility and services vary by state.  Less than 10 percent of Medicaid recipients, those in long-term care including nursing homes where 64% are dependent on Medicaid, use one-third of all Medicaid spending which is a problem.  The ACA's Medicaid expansion program made state optional by the SCOTUS decision was initially taken up by fifty percent of states.  As of 2016 it covers 70 million Americans at a federal cost of $350 billion a year.  In 2017 it pays for 40% of new US births. 
    's funding model or with the yearly structure of health insurance products

    In the first six months of 2014 Sovaldi sales were $6 billion.  That has Medicaid and insurers worried. 

    Harvoni

    Harvoni is the first complete treatment for hepatitis-C is a virus which destroys the liver during infection.  In 2016 it affects 185 million people worldwide.  Once the virus genome was sequenced in 1989 Dr. Bartenschlager and Dr. Rice worked to replicate the virus in the laboratory.  Rice realized the genome sequence was missing details that stopped the lab replication.  Bartenschlager was then successful at replicating the virus in cells in his laboratory.  The replication technique allowed Pharmasset's Dr. Sofia to develop a new hepatitis C drug, by enhancing an RNA-polymerase inhibitor with a coat that allowed the drug to enter the liver, where the coat was destroyed and the polymerase inhibitor was activated.  With high concentrations of the drug, sofosbuvir, in the liver it could eradicate the hepatitis C virus.   Sovaldi was the first sofosbuvir approved by the F.D.A. 
    in a once a day pill ($1,125).  It was approved by the F.D.A. Food and Drug Administration. 
    October 2014 for genotype I treatment.  It seems likely to be slightly less expensive per-treatment (max $94,500, but potentially only $63,000 for an eight week course) than Sovaldi is Gilead Sciences hepatitis-C drug.  It is the first effective cure with acceptable side effects.  In 2014 Sovaldi costs $84,000 for a typical course of treatment. 
    total treatment cost.  Harvoni is a combination of sofosbuvir and ledipasvir.  Gilead was successful with a combination pill Altripla for HIV is human immunodeficiency virus, an RNA retrovirus which causes AIDS.  It infects T-lymphocytes destroying the host's immune system. 


    As with Sovaldi payers (employers and insurers) are limiting access to Harvoni arguing their budgets can't cope with it.  They consider the patients able to use the eight week course the least in need of the treatment.  Patient advocates, such as the National Viral Hepatitis Roundtable - which gets some funding from drug companies, disagree.  "We're talking about a much lower cost to Medicaid is the state-federal program for the poor.  Originally part of Lyndon Johnson's 1965 Bill, eligibility and services vary by state.  Less than 10 percent of Medicaid recipients, those in long-term care including nursing homes where 64% are dependent on Medicaid, use one-third of all Medicaid spending which is a problem.  The ACA's Medicaid expansion program made state optional by the SCOTUS decision was initially taken up by fifty percent of states.  As of 2016 it covers 70 million Americans at a federal cost of $350 billion a year.  In 2017 it pays for 40% of new US births. 
    for a substantial number of people." 

    Gilead defends the price.  "we believe the price of Harvoni reflects the value of the medicine.  Unlike long-term or indefinite treatments for other chronic diseases, Harvoni offers a cure at a price that will significantly reduce Hepatitis-C costs now and deliver significant health care savings to the health care system over the long term." 

    Gilead have agreed to let poor countries use generic Sovaldi and Harvoni. 

    Abbvie is expected to get F.D.A. Food and Drug Administration. 
    approval for a competitive treatment by the end of 2014.  Insurers will then try to compete down the price. 

    Apr 2016 Gilead earnings tumbled on Harvoni. 


    Gilead's Truvada

    Truvada is used to prevent HIV is human immunodeficiency virus, an RNA retrovirus which causes AIDS.  It infects T-lymphocytes destroying the host's immune system. 
    infection.  It is a combination of two anti-retroviral drugs: Tenofovir disoproxil (reverse transcriptase inhibitor) and emtricitabine (nucleoside reverse transcriptase inhibitor).  It is used in pill form.  It was F.D.A. Food and Drug Administration. 
    approved in 2012. 


    Gilead HIV/AIDS treatments

    Gilead is the market leader in treatments for H.I.V. is human immunodeficiency virus, an RNA retrovirus which causes AIDS.  It infects T-lymphocytes destroying the host's immune system. 
    /AIDS is acquired auto-immune deficiency syndrome, a pandemic disease caused by the HIV.  It also amplifies the threat of tuberculosis.   Initially deadly, infecting and destroying the T-lymphocytes of the immune system, it can now be treated with HAART to become a chronic disease.  And with an understanding of HIV's mode of entry into the T-cells, through its binding to CCR5 and CD4 encoded transmembrane proteins, AIDS may be susceptible to treatment with recombinant DNA to alter the CCR5 binding site, or with drugs that bind to the CCR5 cell surface protein preventing binding by the virus.  Future optimization of drug delivery may leverage nanoscale research (May 2016).  
    It has followed a strategy of developing products based on combinations of three or four drugs bundled in a single pill taken once a day.  The core drug is tenofovir. 

    Gilead's Tenofovir

    Gilead sells Tenofovir as Viread, and also in drug bundles. 
    Tenofovir will lose patent protection in December 2017. 
    Gilead is moving to replace tenofovir in the combination pills with a modified version TAF. 

    Gilead's TAF

    TAF, tenofovir alafenamide, is more potent than basic tenofovir and it causes fewer side effects such as kidney provides multiple vital functions.  It: Produces renin which supports negative feedback, Removes excess organic molecules from the blood, Regulates electrolytes in the blood, Maintains pH homeostasis, Regulates fluid balance, Regulates blood pressure, Reabsorbs water, glucose (SGLT2) and amino acids.  Kidney function is monitored with the GFR.  Kidneys can fail acutely or chronically.  Kidneys are affected by a variety of cancers including: advanced kidney cancer, von Hippel Landau; some of which are induced by PFAS.    Multiple myeloma, type 2 diabetes, TB and drug treatments for MDR TB place a strain on the kidneys and can induce failure. 
    and bone damage.  The F.D.A. Food and Drug Administration. 
    approved a TAF based drug, Genvoya in November 2015. 
    The lack of a standalone version of TAF stops doctors prescribing it in combination with other non-Gilead drugs. 


    Imprimis Pharmaceuticals

    Imprimis is based in San Diego

    CEO Mark L. Baum

    Imprimis compounds a generic equivalent to Daraprim, using both pyrimethamine and leucovorin. 

    Baum commented Express scripts shift from Daraprim (Dec 2015) "From our perspective, it's a tremendous endorsement of the business model" of offering alternatives to high-priced drugs. 

    Imprimis is also developing competitors to Valeant drugs. 

    At least one of the compounding pharmacies make unique prescription drugs to order when doctors conclude that standard formulations are not effective treatments. 
    owned by Imprimis received a warning letter from the F.D.A. Food and Drug Administration. 
    in 2014 for deficiencies in manufacturing and other practices. 


    Kalobois

    Kalobois is a biotechnology company.  It is based in South San Francisco. 

    When a key clinical trial failed Kalobois was going to shut down, but Turing Pharmaceutical's Shkreli organized a private placement and was appointed CEO of Kalobois. 


    Kremers Urban

    Kremers Urban is a specialty generic pharmaceutical company.  It was part of UCB SA but was sold to Lannett

    Lannett


    Lannett was founded in 1942.  It is based in Philadelphia.  But it is seeking an inversion allows a U.S. company to move its tax domicile overseas by purchasing a foreign company.  In 2015 the U.S. Treasury department adjusted the inversion rules to require 40% of the combined company is owned by the shareholders of the purchased foreign entity.  In Apr 2016 they clamped down on the option to serially acquire American companies.  In section 7874 of the tax code, Congress defined statutory hurdles that must be cleared to gain tax benefits: Shareholders of foreign acquirers owning less than 20% of the combined entity the inversion fails, If less than 40% and the acquirer does substantial business in the foreign jurisdiction the inversion works but with some pain, If they own more than 40% there are few negative consequences.  Companies purchased serially within three years would be disregarded by the new rules.  Companies invert because of lower foreign tax rates and earnings stripping.  Once foreign, the parent loans the US subsidiary money.  The loan repayments offset the US income and the US tax bill is vastly reduced.  .  It makes generic drugs.  It is one of the fastest growing companies of 2015. 

    Lannett has acquired Kremers Urban for $1.23 billion with financing led by Morgan Stanley and RBC Capital Markets




    Turing Pharmaceuticals

    CEO/founder Martin Shkreli is a former hedge fund is an investment fund that accepts investments from a limited number of accredited individual or institutional investors.  Hedge funds are able to use investment methods that are not allowed for other types of fund. 
    (MSMB) manager
    He started MSMB Capital in his 20s and urged the F.D.A. Food and Drug Administration. 
    not to approve certain drugs made by companies he was shorting. 

    In 2011 he started Retrophin, which acquired old neglected drugs: Thiola; and sharply raised their prices.  Shkreli recognised that controlled distribution channels offered pharmaceutical companies a way to stop generic competition.  Retrophin's board fired Shkreli in 2014.  Retrophin filed a complaint in the Federal District Court in Manhattan, accusing Shkreli of using Retrophin as a personal piggybank to pay back angry investors in his hedge fund.  Mr Shkreli denies the accusations. 

    Shkreli led a group of investors that purchased 70% of KaloBois after the company announced it was shuting down.  Shkreli argues its drugs have promise (Benznidazole).  He and other Turing executives are now in key positions at the company. 

    KaloBois offers Turing the opportunity to gain access to an F.D.A. voucher that allows the holder an expedited review by the F.D.A. of another drug.  Shkreli's Retrophin similarly obtained a voucher which it subsequenty sold to Sanofi for $245 million.  Congress developed the voucher program in 2007 includes:
    • The priority review voucher allowing companies that get drugs approved for qualifying tropical diseases to be awarded a voucher that entitles the holder to an expedited (Priority) review by the F.D.A. of another drug, shaving four months off the process. These vouchers are traded between companies.  


    Shkreli was arrested in Dec 2015 for securities fraud during the time he ran a hedge fund.  Prosecutors argue that Shkreli ran a ponzi scheme using investments in subsequent companies to pay back the investors of prior failed schemes.  He resigned as CEO of Turing and KaloBois while on $5 million bail. 


    Turing's Daraprim

    Turing purchased Daraprim (pyrimethamine) a key generic treatment for toxoplasmosis.  It is also used to treat malaria (F.D.A. Food and Drug Administration. 
    approved in 1953).  It was produced in the USA by GSK who sold the rights to CorePharma in 2010.  They increased the price steadily from GSK's $1 a tablet.  Impax purchased CorePharma for $700 million.  Impax sold Daraprim to Turing for $55 million. 
    Overnight Turing increased the price from $13.50 to $750 a tablet.  Shkreli argued that the drug is rarely used and the impact on the health system would be miniscule.  He suggested Turing would use the extra revenue to develop better treatments for toxoplasmosis, with fewer side effects.  He claimed many patients use the drug for less than a year and that the price was now more in line with those of other drugs for rare diseases.  Shkreli suggested "This is still one of the smallest pharmaceutical products in the world.  It really doesn't make sense to get any criticism for this." 

    Medicaid is the state-federal program for the poor.  Originally part of Lyndon Johnson's 1965 Bill, eligibility and services vary by state.  Less than 10 percent of Medicaid recipients, those in long-term care including nursing homes where 64% are dependent on Medicaid, use one-third of all Medicaid spending which is a problem.  The ACA's Medicaid expansion program made state optional by the SCOTUS decision was initially taken up by fifty percent of states.  As of 2016 it covers 70 million Americans at a federal cost of $350 billion a year.  In 2017 it pays for 40% of new US births. 
    and certain hospitals get discounts under federal rules (MMA is the Medicare Modernization Act of 2003.  It includes Medicare part D the Medicare prescription drug benefit which constrains Medicare from negotiation its drug prices and created MAC and RAC.  IT was sponsored by Senator Bill Tauzin and implemented by Tom Scully. 
    ) for discounts and rebates.  Private insurers, Medicare is a social insurance program that guarantees access to health insurance for Americans aged 65 and over, and younger people with disabilities and end stage renal disease or ALS.  Medicare includes:
    • Benefits
      • Part A: Hospital inpatient insurance.  As of Dec 2013 Medicare pays for home care in only limited circumstances, such as when a person needs temporary nursing care after a hospitalization.  Part A covers 20 days of inpatient rehabilitation at a SNF after discharge from inpatient care at a hosptial. 
      • Part B: Medical insurance
      • Part C: Medicare Advantage 
      • Part D: Prescription drug coverage 
    • Eligibility
      • All persons 65 years of age or older who are legal residents for at least 5 years.  If they or a spouse have paid Medicare taxes for 10 years the Medicare part A payments are waived. 
      • Persons under 65 with disabilities who receive SSDI. 
      • Persons with specific medical conditions:
        • Have end stage renal disease or need a kidney transplant. 
        • They have ALS. 
      • Some beneficiaries are dual eligible. 
      • Part A requires the person has been admitted as an inpatient at a hospital.  This is constrained by a rule that they stay for three days after admission.  
    • Premiums
      • Part A premium
      • Part B insurance premium
      • Part C & D premiums are set by the commercial insurer. 
    and hospitalized patients have to pay closer to list price. 

    The New York Attorney General is examining if Turing violated anti-trust statutes with its restrictive competition strategies (Oct 2015). 

    By Nov 2015 Shkreli changed course and announced there would be no price decrease.  Turing said discounts to hospitals of up to 50% were more important than price decreases.  It also said it would help patients with co-payments ensuring patients paid no more than $10 per prescription instead. 

    Express Scripts has responded by announcing it will switch its customers using Daraprim to Imprimis drugs (Dec 2015).  Turing said that compounded drugs were not demonstrated to be safe and effective, while drugs like Daraprim were approved by the F.D.A. 

    The Obama Administration and the Senate are pushing for legislative changes to allow more competition with companies like Turing (Dec 2015).

    Turing's Benznidazole

    Turing agreed to licence the world wide distribution rights to KaloBois's Chagas is a parasitic infection, due to Trypanosoma cruzi, which can cause serious heart problems.   drug benznidazole.  Currently the drug is not F.D.A. Food and Drug Administration. 
    approved but is supplied for free to patients by the CDC is the HHS's center for disease control and prevention based in Atlanta Georgia.  
    .  But the paperwork required is troublesome for doctors who would prefer to write a prescription for an FDA approved version.  Martin Shkreli announced plans to get FDA approval and sharply increase prices of the drug. 

    Roche developed benznidazole in the 1970s but donated its remaining supply and rights to the Brazilian company Lafepe in 2003.  When there was a severe shortage of Lafepe's supply Argentina's Elea Laboratories also started to supply it.  KaloBois paid $2 million for the world wide rights to a version of benznidazole developed by Savant Neglected Diseases
    Elea would be a competitor as it is also working to get F.D.A. approval. 



    UCB

    UCB is a Belgian based global pharmaceutical company. 

    UCB's romosozumab

    UCB is partnering with Amgen in a phase 3 trial of romosozumab.  While they reported success for the treatment of osteoporosis is a set of diseases where the bones are being broken down faster than they are being renewed.  The effect is for bones to lose strength and become brittle.  The more bone mass developed the less likely osteoporosis becomes.  The risk increases with age and more often impacts women.  Certain hormone levels have an impact: Increased glucocorticoids and reduced sex hormone levels increase bone loss, over active: Thyroid, Parathyroid and Adrenal glands.  Some medical treatments can accelerate bone loss (prostate cancer treatments).  Osteoporosis treatments include:
    • Eli-Lilly's Forteo (teriparatide) a parathyroid hormone analog which encourages bone growth but is very expensive.  And it is only allowed to be taken for two years since it was associated with bone cancer in rats. 
    • Biphosphonates reduce the rate of bone loss but have frightening side effects in a small number of patients (Jun 2016). 
    , the drug exibited the same problematic side effects as earlier treatments (Jun 2016)


    Valeant Pharmaceuticals

    Quebec Canada
    CEO from May 2016 Joseph C. Papa was previously at the Perrigo Company. 
    Previous CEO Michael Pearson was formerly a McKinsey consultant.  With Valeant he has become a billionaire. 
    2016 Chief medical officer is Dr. Tage Ramakrishna. 

    Valeant generated $8.25 billion in revenue in 2014, up 43 percent from 2013. 

    Executive pay is heavily tied to shareholder returns.  It paid its five highest-paid executives 1.5% of sales. 
    Key shareholders include: William Ackman's Pershing Square Capital, John Paulson's Paulson & Company hedge fund, Sequoia fund, ValueAct, Lone Pine and Viking Global
    Ackman likened Valeant to Berkshire Hathaway!

    J. Michael Pearson's Valeant strategy
    Valeant invests insignificantly in R&D (3% of sales vs average greater than 10%). 

    Rather than developing drugs, Valeant acquires them.  It has spent $36 billion on purchasing companies since 2010.  It is the sixth-largest acquirer globally by deal size.  It has purchased over 100 companies. 

    Pearson's vision leveraged ACA is the Patient Protection and Affordable Care Act amended by the Health Care and Education Reconciliation Act of 2010 (Obama care).  In part it is designed to make the health care system costs grow slower.  It aims to do this by: increasing competition between insurers and providers, offering free preventative services to limit the development of serious illnesses, constraining patients' use of expensive services, constraining the growth of payments to Medicare providers and piloting new ways for PCPs to manage patient care to keep patients away from costly E.D.s.  It funds these changes with increased taxes on the wealthy.  It follows an architecture developed by Heritage Action's Butler, Moffit, Haislmaier extended by White House OMB health policy advisor Ezekiel Emanuel & architect Jeanne Lambrew.  The Obama administration drafting team included: Bob Kocher; allowing it to integrate ideas from: Dartmouth Institute's Elliot Fischer (ACO).  The ACA did not include a Medicare buy in (May 2016).  The law includes:
    • Alterations, in title I, to how health care is paid for and who is covered.  This has been altered to ensure
      • Americans with preexisting conditions get health insurance cover - buttressed by mandating community rating and
      • That they are constrained by the individual mandate to have insurance but the requirement was supported by subsidies for the poor (those with incomes between 100 & 400% of the federal poverty line).  
      • Children, allowed to, stay on their parents insurance until 26 years of age. 
    • Medicare solvency improvements. 
    • Medicaid expansion, in title II: to poor with incomes below 138% of the federal poverty line; an expansion which was subsequently constrained by the Supreme Court's SCOTUS decision. 
    • Hospital Readmissions Reduction Program (HRRP) which was enforced by CMS mandated rules finalized in 2011 and effected starting Oct 2012.  
    • Medical home models.  
    • Community transformation grants support the transformation of low income stressed neighborhoods to improve their lifestyles and health. 
    • Qualifications for ACOs.  Organizations must:
      • Establish a formal legal structure with shared governance which allows the ACO to distribute shared savings payments to participating providers and suppliers. 
      • Participate in the MSSP for three or more years. 
      • Have a management structure. 
      • Have clinical and administrative systems. 
      • Include enough PCPs to care for Medicare FFS patient population (> 5000) assigned to the ACO. 
      • Be accountable for the quality and cost of care provided to the Medicare FFS patient population. 
      • Have defined processes to promote: Evidence-based medicine, Patient-centeredness, Quality reporting, Cost management, Coordination of care; 
      • Demonstrate it meets HHS patent-centeredness criteria including use of patient and caregiver assessments and individualized care plans.  
    • CMMI Medicare payment experimentation.  
    • Requirements that pharmaceutical companies must report payments made to physicians. 
    • A requirement that chain restaurants must report calorie counts on their menus. 
    effects focusing on companies with elective spending products (consumer products and cosmetic dermatology). 

    Many of Valeant's drugs are low volume limiting the interest of generic drug makers. 

    In 2010 the predecessor company based in California was purchased by the Canadian Biovail.  It relocated to Canada which has a lower tax rate and the combined operations were renamed Valeant.  By moving to Canada Valeant lowered its statutory tax rate to 27% from 35%.  And Congress found its actual tax rate is far lower.  Its cash tax rate is now 3.3% vs 5.9% in 2010. 

    The rock-bottom tax rate turbocharged the company's acquisition strategy, Howard Schiller, a Valeant directory told Senate Investigators.  Citron reports of other reasons

    Valeant has typically laid off the US workers of company's it purchases:
    Valeant took over Dendreon Corporations assets in February 2015.  This included Provenge

    Valeant and Pershing Square attempted a hostile takeover of Allergan in 2014 but was unsuccessful.  Further Valeant and Pershing face an insider trading law suite for investments Mr. Ackman made in Allergan prior to the takeover bid being publicly disclosed. 

    Valeant was able to pay $1 billion for Sprout pharmaceuticals, a company setup by Cindy Whitehead, to force the FDA to approve Addyi which enhances female sex drive.  The acquisition occurred one day after Sprout obtained FDA approval.  Whitehead subsequently left Valeant. 


    Valeant reports two types of financial results:
    1. GAAP
    2. Pro forma, where certain costs are excluded.  There is a lot of freedom on which costs are excluded.  Valeant excludes expenses for stock-based compensation, legal settlements and restructuring/acquisition costs.  That makes company comparisons apples vs. pears.  
    The difference between the two book values is very large at Valeant.  Valeant uses pro forma numbers for forecasts.  Pro forma numbers make the market cap/earnings multiple less - 31 rather than 98 with GAAP. 

    Valeant's stock has grown six fold in price (800%) with its Canada tax/purchase of big drug portfolios/specialty US pricing strategy.  But in Oct 2015 after Citron Research wrote a report that likened the stock to Enron claiming that Valeant secretly controlled two little-known drug distribution companies (Philidor & R&O) that had resulted in phantom sales and false revenues in an effort to deceive auditors and investigators, shared fell 40%.  Valeant wrote that the Citron report was erroneous. 

    By 11 Nov 2015 the shares have fallen two thirds.  Pearson noted that the dermatology business would be impacted in the 4th quarter by the Philidor relationship termination.  Pearson suggested Valeant would seek relationships with other specialty pharmacies dispense specialty medications.  They aim to save health plans money by: teaching patients how to apply their medicines and deal with side effects, ensure they take the full course and limit waste.  These specialized channels can be used by drug companies to limit competition to their drugs since access in constrained.  Generic drugs rebranded as specialty medications may escape competition, remove copayment and formulary exclusion sales inhibitors and obtain considerable pricing power. 

    Pearson noted other businesses: contact lenses, gastrointestinal drugs and overseas businesses are not impacted and continue to grow. 

    Analysts note that the fall in share price has undermined Valeant's strategy:

    In Dec 2015 Valeant concluded a distribution deal with Walgreens, reducing its dependency on Philidor, agreeing to reduce the price of its dermatology (including: Jublia, Solodyn) and ophthalmology drugs by 10% over 6 to 9 months.  Valeant will ship drugs direct to Walgreens rather than to wholesalers. 

    J. Michael Pearson had to take medical leave at the end of 2015 to recover from bacterial pneumonia is an inflamed lung.  It can be caused by infection with viruses or bacteria, drugs and autoimmune diseases.  HAP, including VAP can be very troubling. .  Other company executives handled his role through the 'office of the CEO' with oversight from a specially formed board committee. 

    Valeant have responded to the Congressional pricing probe by reaching out to group purchasing supplies managers with 30% discounts on key heart drugs (May 2016). 

    Bill Ackman takes a seat on the Board of Valeant and pledges to Congress that the company would take a fair approach to drug pricing. 

    In June 2016 Valeant's new CEO Papa released their long awaited Q1 results which were poor. 


    Aid-in-dying is physician assisted termination of life by application of lethal medications.  It was legalized in Oregon by the Death with Dignity act and other states have followed that blue print (Jan 2017). 
    acts prescribe particular drugs for the termination procedure.  Valeant Pharmaceuticals took advantage of this new constraint by purchasing Seconal, the most prescribed aid-in-dying medication in 2015 and massively increasing the price. 



    Valeant's Addyi

    Addyi (flibanserin) is FDA approved as a female libido drug. 

    Addyi has not been selling well.  A study of its benefits concluded they were slight (Mar 2016).  Dr. Rage Ramkrishna commented the new study provided little additional context.  He said the way the analysis was done, combining data from a number of different studies, carried less statistical weight than randomized trials. 

    Valeant's Ativan

    Ativan is a major anxiety is manifested in the amygdala mediating inhibition of dopamine rewards.  Major anxiety results in elevated glucocorticoids and reduces hippocampal dendrite & spine density.  Some estrogen receptor variants are associated with anxiety in women. 
    medicine. 


    Valeant's Ecedrin

    Ecedrin is a diuretic.  Its US price has increased nine times between May 2014 price of $470 per vial and Oct. 2015 at $4,600 a vial. 


    Valeant's Glumetza

    Glumetza is a diabetes includes type 1 and type 2.  Common side effects include: increased heart disease, hypertension, kidney disease, vision loss, nerve damage, and infections. 
    drug (Salix).  Its dosage is typically 90 1,000 mg tablets.  Prior to 2015 its price was less than $900 for 90 tablets.  By August 2015 Valeant had increased the US price to $10,020 for 90 tablets.  Pearson argues that he raised prices because Glumetza is about to face generic competition. 


    Valeant's Syprine

    Syprine is a treatment for Wilson's disease.  Its dosage is typically 100 250 mg capsules.  From Feb. 2013 the US price of $1,395 has been increased in steps to $21,267 by 2015. 


    Valeant's Cuprimine

    Cuprimine is a treatment for Wilson's disease.  Its dosage is typically 100 250 mg capsules.  From Feb. 2013 the US price of $888 has been increased asymmetrically to $$26,189 in 2015. 
    The generic competitor sells for $1 a tablet. 


    Valeant's Demser

    Demser treats complications of adrenal gland tumors.  Its dosage is typically 100 250 mg capsules.  From Jan. 2104 the US price of $9,979 has increased stepwise to $32,794 in 2015. 

    Valeant's Jublia

    Jublia is a toenail fungus ointment.  In 2015 it is one of Valeant's fastest growing products.  It costs $500 for a small bottle. 


    Valeant's Mephyton

    Mephyton is vitamin K1, a WHO is World Health Organization a United Nations organization.   essential medicine.  It is a blood clotting or coagulation is formation of a clot:
    • Platlets become activated, adhere and aggregate supported by
    • Fibrin polymerization, deposition and maturation.  
    agent.  From 2014 its US price of $9.37 per tablet has increased 8 times to %58.76 per tablet. 


    ValEAnt's Isuprel

    Isuprel is a treatment for slow or irregular heart rate.  Its dosage is typically twenty-five 0.2 ml. ampules.  Isuprel US price increased 525% as it was rebranded as a specialty medicine cost tens or hundreds of thousands of dollars a year when used to treat complex or rare diseases: cancer, rheumatoid arthritis, hemophilia, HIV.  By 2015 they account for one-third of all spending on drugs in the United States and should reach 50% by 2025.  With the MMA constraining Medicare drug price negotiations many old generic drugs appear to be being rebranded with controlled distribution as specialty drugs and re-priced with vast margins (Sep 2015). 



    ValEAnt's Nitropress

    Nitropress US price increased 212% as it was rebranded as a specialty medicine cost tens or hundreds of thousands of dollars a year when used to treat complex or rare diseases: cancer, rheumatoid arthritis, hemophilia, HIV.  By 2015 they account for one-third of all spending on drugs in the United States and should reach 50% by 2025.  With the MMA constraining Medicare drug price negotiations many old generic drugs appear to be being rebranded with controlled distribution as specialty drugs and re-priced with vast margins (Sep 2015). 


    Both Isuprel and Nitropress were purchased from Marathon Pharmaceuticals. 

    After Congressional democrats asked for documents on Valeant's pricing and proposed subpoenaing them the share price fell (Oct 2015) and CEO Pearson responded by writing to employees.  He rejected investor concerns that the company's strategy relied on big price increases.  He noted that half the company's sales came from domestic and international businesses in which it had realized small or no net price increases. 

    Valeant's Provenge

    Provenge (Sipuleucel-T is a cell based cancer therapy that is marketed by Valeant Pharmaceuticals as Provenge.  ) is a cell-based vaccine are a core strategy of public health and have significantly extended global wellbeing over 200 years.  Recent successes include: HPV vaccine.  They induce active acquired immunity to a particular disease.  But the development and deployment of vaccines is complex:
    • The business model for vaccine development has been failing (Aug 2015): 
      • No Zika vaccine was available as the epidemic grew (Mar 2016).  No vaccine for: CMV;
      • Major foundations: Michael J. Fox, Gates, Wellcome; are working to improve the situation including sponsorship of the GAVI alliance.  A geographic cluster is forming in Seattle including PATH (Apr 2016). 
      • Commercial developers include: Affiris, Cell Genesis, Chiron, CSL, Sanofi, Valeant;
    • Vaccine deployment traditionally benefited from centrally managed vertical health programs.  But political issues are now constraining success with less than 95-99% coverage required for herd immunity (Aug 2015, Sep 2015, Nov 2015, Nov 2016).  
      • Where clinics have been driven into local neighborhoods health improves (Apr 2016).  
      • Retail clinics (Mar 2016): CVS Minute Clinics focus on vaccination.  
    • Key vaccines include: BCG, C. difficile (May 2015), Cholera (El Tor), Dengvaxia (Mexico Dec 2015), Gvax, Malaria vaccine, Provenge;
    • Regulation involves: FDA (CBER), with CMS monitoring (star ratings, PACE (Aug 2016), Report cards (Sep 2015)) & CDC promoting vaccines: as a sepsis measure, To control C. difficile (May 2015);  
      • Coding : CVX, MVX;
    • Research on vaccines includes: 
      • NIH: AIDS vaccines (AVRC), Focus on using genetic analysis to improve vaccine response.  
        • NCI:
          • Roswell Park clinical trial of immuno-oncology vaccine cimavax. 
      • Geisinger: effective process leverage in treatment. 
      • Stanford Edge immuno-oncology for cancer vaccines.  
      • P53-driven-cancer focused, gene therapy (Jun 2015). 
    for prostate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
    • Sarcomas
    • Small cell carcinomas
    • Neuroendocrine tumors
    • Transitional cell carcinomas


    It costs $93,000 at FDA Food and Drug Administration. 
    approval and rose to $100,000 in 2014. 

    Valeant's Solodyn

    Solodyn is an acne tablet.  It costs $1000 a month. 


    Valeant's Xifaxan

    Xifaxan is a gastrointestinal drug acquired with Salix in 2015.  It is Valeant's top product in 2016. 


    Valeant and Philidor Rx


    J. Michael Pearson revealed at the Oct 2015 quarterly earnings call that Valeant had purchased on option to acquire Philidor Rx Services late in 2014.  He said Philidor's results were consolidated into Valeant's financials. 

    Valeant and Walgreens

    Valeant has moved to replace the prescription deal with Philidor with a Walgreens prescription drug deal. 
    But there have been problems:
    • Some patients had been receiving drugs before it was learned whether the patients' insurer would pay for them, resulting in a loss. 

    Pearson noted at that earnings call that the pricing environment had changed, and that the industry was "being aggressively sort of attacked for past pricing actions."   He said Valeant was considering divesting the the division selling neurological drugs where, he said, the biggest price increases (36% on average for the U.S.) had occurred.  He said that in the future, price increases would be "more modest," probably not more than 10 percent per year. 

    PBM is pharmacy benefit manager.  These companies, such as Caremark, were often originally PPMs.  PBMs are used by payers, such as insurance plans, to manage drug provision from pharmacies to the payer's plans subscribers. 
    s Express scripts, CVS Health and OptumRx stopped reimbursing Philidor in Oct 2015. 



    Questcor pharmaceuticals

    Questcor is based in Anaheim, California.  It is owned by Mallinckrodt

    Questcor's H.P. Acthar Gel

    H.P. Acthar Gel is used to treat severe autoimmune conditions include: celiac disease, eczema, IBD, lupus, multiple sclerosis, type-1-diabetes; are often debilitating and life long conditions.  Autoimmune diseases are increasing in prevelence rapidly over two or three generations in advanced societies.  One in thirteen Americans has an autoimmune condition.  Some are associated with gene alleles encoding the immune system.  : spasms in infants, nephrotic syndrome occurs when to much protein is excreted in the urine.  It can occur for many reasons but often indicates damage to the small blood vessels in the kidneys which filter waste and excess water from the blood. 
    ;

    Questcor's Acthar Gel is priced at $38,000 per vial. 

    It has supported this high price by acquiring the rival drug Synacthen Depot the NYT reports.  The F.T.C. reviewed the situation and concluded there was an issue.  Malinckrodt / Questcor agreed to pay $100 million and license Synthacthen Depot to a competitor.  Synthacthen is sold oversees for a tiny fraction of the price of Acthar. 

    The NYT views Questcor's strategy as similar to Valeant, and a model for Turing's



    ViiV Healthcare

    ViiV is based in research Triangle Park, NC

    ViiV's Ziagen

    Ziagen (abacavir is a nucleoside reverse transcriptase inhibitor, an ARV medication, branded as Ziagen, which is used in the prevention and constraint of AIDS.  It is a WHO essential medicine.  Its use is problematic in about 6% of the patient base.  Pharmacogenomics allows these patients to be identified and treated with an alternative ARV. 
    ) is an AIDS is acquired auto-immune deficiency syndrome, a pandemic disease caused by the HIV.  It also amplifies the threat of tuberculosis.   Initially deadly, infecting and destroying the T-lymphocytes of the immune system, it can now be treated with HAART to become a chronic disease.  And with an understanding of HIV's mode of entry into the T-cells, through its binding to CCR5 and CD4 encoded transmembrane proteins, AIDS may be susceptible to treatment with recombinant DNA to alter the CCR5 binding site, or with drugs that bind to the CCR5 cell surface protein preventing binding by the virus.  Future optimization of drug delivery may leverage nanoscale research (May 2016).   medication manufactured for ViiV by GSK



    Zinfandel Pharmaceuticals

    Zinfandel is owned and was founded by Duke University neurologist Allen Roses.  It is based in Durham, North Carolina. 
    Zinfandel is trialing Actos (TOMORROW), as a method to delay the onset of Alzheimer's disease is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
    • Plaques form and set off the formation of tangled thread-like tau protein.
      • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
      • BACE inhibitors block an enzyme needed to form amyloid. 
    • The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    • The brain becomes inflamed resulting in the killing of many more nerve cells. 
    , in partnership with Takeda.  The trial strategy is in line with Dr. Roses theory of Alzheimer's disease




    Biotech supplies and infrastructure


    Pall Corporation

    Pall makes filtration, separation and purification products.  They supply them to life science and industrial companies. 

    2009 Pall purchased Micro Reactor Technologies, a startup based around Michel Maharbiz's Ph. D research. 




    Eco-Web owners




    General Electric Healthcare

    Includes Amersham International whose leader aims to develop plans and strategies which ensure effective coordination to improve the common good of the in-group.  John Adair developed a leadership methodology based on the three-circles model. 
    Sir William Castell became a GE vice chairman and head of healthcare until the reorganization when he retired in 2006. 

    GE Healthcare offers financial and administrative, clinical and service IT solutions to a range of organizations from small to large hospital groups via Centricity product line. 

    GE Centricity
    2013 GE has 4% HER/EMR refers to electronic medical records which are a synonym of EHR.  EMRs have strengths and weaknesses:
    • The EHR provides an integrated record of the health systems notes on a patient including: Diagnosis and Treatment plans and protocols followed, Prescribed drugs with doses, Adverse drug reactions;
    • The EHR does not necessarily reflect the patient's situation accurately. 
    • The EHR often acts as a catch-all.  There is often little time for a doctor, newly attending the patient, to review and validate the historic details. 
    • The meaningful use requirements of HITECH and Medicare/Medicaid specify compliance of an EHR system or EHR module for specific environments such as an ambulatory or hospital in-patent setting. 
    • As of 2016 interfacing with the EHR is cumbersome and undermines face-to-face time between doctor and patient.  
    system market. 


    2013 GE Healthcare has 12% of the Radiology Information Systems market. 


    GE Healthcare has spent more than $1.3 billion on HCIT since 1992.  Acquisitions include:




    Accuray of Sunnyvale California

    Accuray manufactures Cyberknife.  The system was invented by Stanford neurosurgery and radiation oncology professor John Adler & Schonberg Research Corporation's Peter & Russell Schonberg. 

    Accuray Cyberknife

    Cyberknife:


    Becton, Dickinson and Company

    BD makes medical supplies, devices and technology; laboratory products and antibodies is a y-shaped blood transported protein generated by the adaptive immune system's plasma cells, B lymphocytes, to accurately identify and neutralize pathogens such as bacteria and viruses that exhibit a matching antigen. 



    Boehringer Ingelheim

    German drug maker
    Swaped assets with Sanofi (Dec 2015) gaining animal health business Merial (Frontline & Heartguard). 


    Boehringer's Aggrenox

    Aggrenox is a stroke is when brain cells are deprived of oxygen and begin to die.  There are two structural types: Ischemic and hemorrhagic. 
    medication containing aspirin & dipyridamole is a cAMP phosphodiesterase inhibitor, increasing the volume of cellular cAMP and blocking platelet aggregation response.  It is used to treat strokes. 



    Intuitive Surgical 

    Intuitive Surgical make the da Vinci Surgical System 

    Intuitive Surgical's da Vinci Surgical System

    The da Vinci robotic surgical system aims to perform MIS is minimally invasive surgery, which aims to replace open surgery with techniques that reduce pain and recovery time by use robots or laparoscopes. 
    controlled by a surgeon at a console. 


    Johnson & Johnson

    CEO Alex Gorsky criticized for strategy of selling Risperdal off label to children by NYT (Sep 2015)
    2014 Salary $25 million. 


    Most pharmaceutical companies are limiting acquisitions in 2017 to process the ones executed in recent years, except for Johnson & Johnson's $30 billion takeover of Actelion. 


    J & J purchase hair care consumer product maker Vogue for $3.3 billion. 

    1989 - 2002 Chairman & CEO Ralph Larson.  Larson served on the boards of: Xerox, RWJ Foundation, AT&T, AT&T Wireless and GE
    Larson started at J&J as a manufacturing trainee in 1962.  He rose through consumer and hospital supply division. 
    Larson left J&J in 1981 to become president of consumer products at Becton, Dickinson and company
    He returned in 1983 to run the J&J subsidiary that manufactured bandage fabrics. 
    In 1998 J&J's LifeScan unit was raided by Federal agents after it failed to notify the FDA Food and Drug Administration. 
    of a software glitch in a diabetes includes type 1 and type 2.  Common side effects include: increased heart disease, hypertension, kidney disease, vision loss, nerve damage, and infections. 
    diagnostic device.  LifeScan pleaded guilty to criminal charges in 2000 and agreed to pay $60 million in fines for selling defective devices.  Larson wrote a statement of apology noting "Mistake and misjudgments were made." 

    Larson carried out a number of acquisitions that turned J&J into a multinational giant:
    • Consumer products - Neutragena.  Larsen turned Tylenol into a blockbuster by shifting its promotion from doctor focused to consumer focused. 
    • Drugs
    • Medical devices - Centocor, Cordis, Kodak clinical diagnostics;
    • Russia & Eastern Europe


    19xx - 1989 Chairman & CEO James Burke oversaw a vast expansion of J&J. 

    J&J's Tylenol

    Tylenol is a consumer brand of pain killer acetaminophen is a generic analgesic (pain killer) marketed by many companies including J&J's Tylenol, Paracetamol; discovered in 1877.  At high doses there is risk of liver failure.  Acetaminophen is the most common cause of acute liver failure in the US in 2017. 


    J&J's Biosense Webster

    Biosense Webster specializes in the diagnosis and treatment of cardiac arrythmia is irregular heartbeat, a very common problem where the heart's electrical cells malfunction.  It can be diagnosed and treated by electrophysiology.  

    Will Webster developed an early deflectable tip catheter.  Biosense Webster followed that lead in design and manufacture of diagnostic and therapeutic catheters for use by cardiologists is the diagnosis and treatment of: Congenital heart defects, CAD, Heart failure, Valvular heart disease; by cardiologists.   and electrophysiologists is the study of the heart's electical circuits.  Electrophysiologists diagnose and treating the electrical arrhythmias of the heart. 



    Johnson & Johnson's Centocor

    Dec 2004 Buys Guidant to build its market opportunity in the Medical Devices Markets.  J&J gains:
    • expanded line of blood vessel blockage clearing systems
    • Implanted defibrillators
    Centocor's Remicade
    Centocor makes the immunosuppressant monoclonal antibody is a y-shaped blood transported protein generated by the adaptive immune system's plasma cells, B lymphocytes, to accurately identify and neutralize pathogens such as bacteria and viruses that exhibit a matching antigen. 
    Remicade (infliximab as a terminator in medication names indicates the drug is a monoclonal antibody biologic. 
    ) used to treat arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, plaque psoriasis and ulcerative colitis.  It is considered to generate considerable costly waste (Mar 2016). 


    Johnson & Johnson's Ethicon


    A division of J. & J.  that makes surgical products. 
    It has announced a partnership with Google's life sciences division to develop new robot-assisted surgery technologies



    J&J Invokna

    Invokna is a (SGLT2 is sodium glucose cotransporter 2 a low affinity sodium dependent glucose transporter reabsorbing glucose in the kidney.  So inhibition reduces blood glucose levels by excretion of glucose in the urine.  The inhibition has the side effect of increased urinary tract and genital infections.  The FDA has expressed concern that the inhibitors may cause bone fractures and a dangerous acid buildup in the blood. 
    inhibitor) drug that treats diabetes includes type 1 and type 2.  Common side effects include: increased heart disease, hypertension, kidney disease, vision loss, nerve damage, and infections. 
    .  Along with Invokamet it has sales of $318 million in Q2 2015. 

    J&J Risperdal

    Risperdal (Risperidone) is an antipsychotic are diseases of the brain which impact the patient's models of reality and their ability to differentiate illusion from reality.  Anti-psychotic medications are prescribed: Risperdal; medicine used in the treatment of schizophrenia is a chronic, psychotic, brain disorder that affects 1.1 percent of the adult U.S. population.  It is characterized by hallucinations, delusions and disorganized and unusual thinking.  It seems to be caused by over pruning of prefrontal cortex neurons (Jan 2016).  There is evidence that some cases occur because of particular CNVs in the DNA of the sufferers: ZNF804A. 
    , Bipolar disorder also termed manic-depression is a developmental disorder which can stimulate great creativity during the manic phase and suicide in the depressive phase.  GWAS implicate ANK3 and CACNA1C SNPs in bipolar disorder.  Lithium limits the extremes of the mood swings.  Anti-psychotic medications are prescribed.   and Autism is a major hereditary mental disorder that starts before age three.  Autistics do not attribute minds to other people.  They almost never pretend.  They can't explain the difference between an instance of an object and a memory of it.  Autism occurs in every country and social class.  It lasts a lifetime.  It has genetic and neurological causes.  The genes: SHANK3, CDH10; are involved but account for a very small percentage of the risk.  Facial gaze studies indicate a high genetic influence and an opportunity to identify more genes associated with autism (Jul 2017).  ASD is associated with a reduced fusiform face area response.  Tests [in development] for autism include: SynapDx's blood test. 
    .  It is a dopamine antagonist (D1, D5, D2, D3, D4), with anti-serotonergic, anti-adrenergic (alpha 1 and 2) and anti-histaminergic (H1) properties. 
    It was approved by the F.D.A. Food and Drug Administration. 
    in 1994 just for schizophrenia which is a relatively small market. 
    It is classed as an essential medicine by the WHO. 

    Sep 2015 NYT Nicholas Kristof editorial Drug Crime That Paid Billions
    Kristof notes J&J wanted to expand Risperdal into a larger market than just schizophrenia is a chronic, psychotic, brain disorder that affects 1.1 percent of the adult U.S. population.  It is characterized by hallucinations, delusions and disorganized and unusual thinking.  It seems to be caused by over pruning of prefrontal cortex neurons (Jan 2016).  There is evidence that some cases occur because of particular CNVs in the DNA of the sufferers: ZNF804A. 
    .  But Risperdal can cause stroke is when brain cells are deprived of oxygen and begin to die.  There are two structural types: Ischemic and hemorrhagic. 
    s among the elderly.  It can cause boys to grow large pendulous breasts.  J&J proposed Risperdal could treat a broader range of conditions.  They also paid doctors consulting fees.  They lobbied Texas to replace generics with Risperdal increasing the Medicaid bill from $250 a year to $3,000 per person treated. 
    They built a sales force to sell Risperdal to the elderly.  And they provided an incentive for Omnicare to prescribe Risperdal at nursing homes it serviced. 
    They targeted pediatricians is a doctor who specializes in the treatment of infants, children and adolescents.  They are represented by the American Academy of Pediatrics. 
    resulting in one fifth of sales going to children and adolescents. 
    J&J was found to have marketed Risperdal to the elderly and to boys while changing/hiding the data about breast development according to Steven Brill in the Huffington Post.  They were caught and pleaded guilty but Kristoff notes paid a $2 billion fine on global revenues of $30 billion and profits of $18 billion.  Alex Gorsky who was in charge of the marketing strategy was promoted to J&J CEO.  Kristoff argues this sends the message that crime pays. 

    Sep 2015 NYT Responses Re"Drug Crime That Paid Billions" Henry Greenspan writes
    Henry Greenspan an ethics, policy and the pharmaceutical industry teacher at the University of Michigan notes that essentially identical stories can be told about every company that makes a drug in this class: AstraZeneca's Seroquel, Pfizer's Geodon, Lilly's Zyprexa.  They have all been prosecuted by the DOJ - U.S. Department of Justice. 
    for the same kind of activity. 
    But Greenspan argues the important detail is that off label promotion of drugs may gain First Amendment protection (Aug 2015).  In part that seems to be because academics have been nudged for years to argue that this makes sense reorienting the court system towards this idea. 

    J&J's Sylvant

    Sylvant (Siltuximab is a monoclonal antibody built with human and mouse proteins, which binds interleukin-6.  In 2017 it is being investigated as a treatment for neoplastic diseases: metastatic renal cell cancer, prostate cancer, Castleman disease. 
    ) is being investigated for treating neoplastic diseases. 


    J&J's Janssen

    Johnson & Johnson acquired Janssen pharmaceutica which produced a variety of opioid pain amplifies the aggression response of people by interoceptive signalling of brain regions providing social emotions including the PAG projecting to the amygdala; making aggressive people more so and less aggressive people less so.  Pain is the main reason people visit the ED in the US.  killers. 

    J&J Janssen's Sublimaze
    Sublimaze is a branded formulation of fentanyl is a synthetic opioid pain medication that acts on micro-opioid receptors in the brain.  It is 50 times more potent than morphine.  It was originally manufactured by Janssen Pharmaceutica in 1959 which was acquired by Johnson & Johnson.  It is branded as: Sublimaze, Actiq, Durogesic, Duragesic, Fentora, Matrifen, Instanyl, Abstral, Lazanda; with a variety of deployment formulations.  It is often used, in a transdermal patch such as durogesic, to treat severe ongoing pain which can be induced by cancer.  It has followed heroin into the back-street opioid epidemic (Jun 2017). 


    J&J Janssen's Durogesic
    Durogesic is a fentanyl is a synthetic opioid pain medication that acts on micro-opioid receptors in the brain.  It is 50 times more potent than morphine.  It was originally manufactured by Janssen Pharmaceutica in 1959 which was acquired by Johnson & Johnson.  It is branded as: Sublimaze, Actiq, Durogesic, Duragesic, Fentora, Matrifen, Instanyl, Abstral, Lazanda; with a variety of deployment formulations.  It is often used, in a transdermal patch such as durogesic, to treat severe ongoing pain which can be induced by cancer.  It has followed heroin into the back-street opioid epidemic (Jun 2017). 
    transdermal patch. 

    J&J Janssen's Duragesic
    Duragesic is an extended release formulation of fentanyl is a synthetic opioid pain medication that acts on micro-opioid receptors in the brain.  It is 50 times more potent than morphine.  It was originally manufactured by Janssen Pharmaceutica in 1959 which was acquired by Johnson & Johnson.  It is branded as: Sublimaze, Actiq, Durogesic, Duragesic, Fentora, Matrifen, Instanyl, Abstral, Lazanda; with a variety of deployment formulations.  It is often used, in a transdermal patch such as durogesic, to treat severe ongoing pain which can be induced by cancer.  It has followed heroin into the back-street opioid epidemic (Jun 2017). 
    .

    J&J Janssen's Invega
    Invega (paliperidone is a dopamine antagonist used as an antipsychotic.  It can be used to treat schizophrenia, mania and at low doses to maintain bipolar disorder.  It is marketed by Janssen as Invega. 
    ) is an extended release treatment for schizophrenia is a chronic, psychotic, brain disorder that affects 1.1 percent of the adult U.S. population.  It is characterized by hallucinations, delusions and disorganized and unusual thinking.  It seems to be caused by over pruning of prefrontal cortex neurons (Jan 2016).  There is evidence that some cases occur because of particular CNVs in the DNA of the sufferers: ZNF804A. 


    J&J Janssen's Xarelto
    Xarelto is a pill form of Rivaroxaban is an anticoagulant pill used to prevent blood clots.  It is a factor Xa inhibitor inhibiting thrombosis & preventing stroke.  It was developed by Bayer.  It is marketed in the US by Janssen as Xarelto. 
    used to treat clots or coagulation is formation of a clot:
    • Platlets become activated, adhere and aggregate supported by
    • Fibrin polymerization, deposition and maturation.  
    and thrombosis is the formation of a blood clot inside a blood vessel.  .  It was patented in 2007, approved by the F.D.A. Food and Drug Administration. 
    in 2011 & loses protection in 2020. 

    J&J Janssen's Prezista
    Prezista (darunavir is an HIV medication taken once a day.  It is marketed in the US as Prezista. 
    ) is a once daily HIV medication.  

    Johnson & Johnson and IBM's Watson

    Johnson & Johnson are using Watson to improve care for knee and hip replacements. 



    J&J and Prostate Cancer

    J&J's Zytiga
    Zytiga (abiraterone is a steroidal androgen synthesis inhibitor used in androgen deprivation therapy for prostate cancer. 
    ) is the leading androgen deprivation therapy lowers the levels of male sex hormones.  These hormones stimulate the growth of prostrate cancer cells.  But the treatment: Bicalutamide, Lupron; is associated with increased rates of: Depression (Apr 2016), Dementia (Oct 2016) including Alzheimer's disease (Dec 2015). 
    drug for treating prostate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
    • Sarcomas
    • Small cell carcinomas
    • Neuroendocrine tumors
    • Transitional cell carcinomas
    as of Aug 2016. 

    J&J is also developing apalutamide is a non-steroidal androgen receptor competitive inhibitor developed to treat prostate cancer.  It is structurally similar to enzalutamide.  , a close mechanistic competitor of Xtandi


    J&J has agreed to distribute Tesaro's Niraparib is a small molecule PARP inhibitor targeted at ovarian cancer.  It was developed by Tesaro. 



    J&J and tuberculosis

    J&J Sirturo
    J&J manufacture and market Sirturo (bedaquiline is an oral prescription treatment for tuberculosis, discovered by Koen Andries at Janssen Pharmaceutica.  It affects an ATP synthase proton pump.  It is specifically approved by the F.D.A. to treat MDR TB and is a WHO essential medicine. 
    ). 
    In Dec 2012 the F.D.A. Food and Drug Administration. 
    granted accelerated approval allows a drug treating serious conditions or unmet medical needs be approved based on a surrogate endpoint. 
    for bedaquiline to treat drug-resistant tuberculosis, consumption or otherwise TB, is mostly an airborn bacterial lung infection, but it can also infect the brain, kidneys and other parts of the body.  The only vaccine is still the BCG.  The deployment of antibiotics during the 1940s allowed effective treatment: Streptomycin.  Diagnostic tools for TB are insufficient.  And because TB grows slowly in walled off pockets in the lungs it takes many months of treatment for antibiotics to eradicate the infection.  TB benefits from compromised hosts and has benefited from HIV/AIDS.  TB is also leveraging the plasmids that now carry immunity to all current antibiotics.  In 2016 it is estimated to latently infect two billion people.  9.6 million worldwide became infected in 2014.  1.5 million people will die from TB in 2016.  Deaths from the disease have fallen drastically since 2000.  TB has been halted or reversed in 16 of the 22 countries: India (Sep 2016, Infection base estimate increased Oct 2016), Vietnam, Indonesia; that have the majority of cases.  But it is still the infectious disease causing the most deaths world-wide.  Nano scale drug delivery has the potential to push back on TB and is being actively researched (May 2016).   .   But the tests only showed that TB infected sputum fell to zero rather than less patient's died.  So it is stated on the label that other treatments should be used first. 


    Duchesnay Inc.

    Duchesnay is a Canadian pharmaceutical company. 

    Duchesnay makes:

    Duchesnay's Diclegis

    diclegis is the leading prescription morning sickness is pregnancy sickness, a universal part of pregnancy.  Evolutionary psychology explains:
    • It as a beneficial response to toxins that would harm a developing fetus.  Margie Profet developed this hypothesis and collated hundreds of studies that supported it. 
    • It is protecting a differentiating embryo from teratogens.  Women with more extreme pregnancy sickness are less likely to bear babies with birth defects. 
    • Women with pregnancy sickness avoid bitter, pungent, highly flavored and novel foods which are likely to contain toxins.  Their sense of smell becomes hypersensitive during the period of pregnancy sickness.  
      • Hunter gatherers are particularly at risk from teratogens since much of their diet is from wild plants gathered as they travel. 
    • Differentiating embryos, while laying down organ systems are growing slowly with limited need for nutrients.  
    • Once organ systems are nearly complete pregnancy sickness reduces. 
    • Pregnancy sickness treatments include: Duchesnay's Diclegis.  
    medicine in 2015. 


    Pfizer


    2010 CEO Ian Read is a Scot. 

    2006-2010 CEO Jeff Kindler, is a lawyer, and a Democrat.  He was appointed by Pfizer as part of the strategy to increase health insurance drug coverage by Americans based on backing the ACA is the Patient Protection and Affordable Care Act amended by the Health Care and Education Reconciliation Act of 2010 (Obama care).  In part it is designed to make the health care system costs grow slower.  It aims to do this by: increasing competition between insurers and providers, offering free preventative services to limit the development of serious illnesses, constraining patients' use of expensive services, constraining the growth of payments to Medicare providers and piloting new ways for PCPs to manage patient care to keep patients away from costly E.D.s.  It funds these changes with increased taxes on the wealthy.  It follows an architecture developed by Heritage Action's Butler, Moffit, Haislmaier extended by White House OMB health policy advisor Ezekiel Emanuel & architect Jeanne Lambrew.  The Obama administration drafting team included: Bob Kocher; allowing it to integrate ideas from: Dartmouth Institute's Elliot Fischer (ACO).  The ACA did not include a Medicare buy in (May 2016).  The law includes:
    • Alterations, in title I, to how health care is paid for and who is covered.  This has been altered to ensure
      • Americans with preexisting conditions get health insurance cover - buttressed by mandating community rating and
      • That they are constrained by the individual mandate to have insurance but the requirement was supported by subsidies for the poor (those with incomes between 100 & 400% of the federal poverty line).  
      • Children, allowed to, stay on their parents insurance until 26 years of age. 
    • Medicare solvency improvements. 
    • Medicaid expansion, in title II: to poor with incomes below 138% of the federal poverty line; an expansion which was subsequently constrained by the Supreme Court's SCOTUS decision. 
    • Hospital Readmissions Reduction Program (HRRP) which was enforced by CMS mandated rules finalized in 2011 and effected starting Oct 2012.  
    • Medical home models.  
    • Community transformation grants support the transformation of low income stressed neighborhoods to improve their lifestyles and health. 
    • Qualifications for ACOs.  Organizations must:
      • Establish a formal legal structure with shared governance which allows the ACO to distribute shared savings payments to participating providers and suppliers. 
      • Participate in the MSSP for three or more years. 
      • Have a management structure. 
      • Have clinical and administrative systems. 
      • Include enough PCPs to care for Medicare FFS patient population (> 5000) assigned to the ACO. 
      • Be accountable for the quality and cost of care provided to the Medicare FFS patient population. 
      • Have defined processes to promote: Evidence-based medicine, Patient-centeredness, Quality reporting, Cost management, Coordination of care; 
      • Demonstrate it meets HHS patent-centeredness criteria including use of patient and caregiver assessments and individualized care plans.  
    • CMMI Medicare payment experimentation.  
    • Requirements that pharmaceutical companies must report payments made to physicians. 
    • A requirement that chain restaurants must report calorie counts on their menus. 
    .  He became chairman of the PhRMA in 2010.  Kindler directed a majority of the company's political donations to Democrats and hired top Democrats to lead the company's lobbying efforts.  Sally Susman was hired from Estee Lauder. 

    2008 Executive VP for policy, external affairs and communications is Sally Susman.  She is Pfizer's chief lobbyist.  Her father is Louis Susman, a major bundler for the Clintons and Clinton appointed U.S. Ambassador to GB.  Ms. Susman is a former Clinton administration staff member and a major fund raiser for President Obama and Secretary of State Clinton. 
    In 2010 Read asked Susman to improve the company's image with the public.  Susman was frustrated at the public's lack of excitement about the scientific advances delivered by the pharmaceutical industry. 


    Pfizer was founded by German immigrants in Brooklyn in 1849.  It provided pain amplifies the aggression response of people by interoceptive signalling of brain regions providing social emotions including the PAG projecting to the amygdala; making aggressive people more so and less aggressive people less so.  Pain is the main reason people visit the ED in the US.   killers during the American civil war and manufactured penicillin during world war 2.  In 2015 it is based in New York. 

    It is structured into businesses including:

    Pfizer's biggest challenge from 1995 to 2015 has been its laboratories' lack of productivity.  To continue growing, the company has been forced to merge acquiring:
    • Warner-Lambert
    • Pharmacia
    • Wyeth
    In Aug 2016 it bid $14 billion to acquire Medivation and gain access to Xtandi

    Ian Read, an accountant, is frustrated at the tax 26% he is levied with Pfizer being a US company.  He views it as a competitive disadvantage.  Allergan paid 5% in Ireland.  International competitors GSK, AstraZeneca and Novartis also pay lower tax rates than Pfizer. 
    Read commented "The problem is our tax code is hugely disadvantageous to American high-tech multinational companies.  I personally have been to Washington for the last two years .  I have tried to get this as an urgent issue that we need to fix, and I have been totally unsuccessful."

    Pharmaceutical companies, including Pfizer, have used tax credits to limit their tax bills.  They moved operations to Puerto Rico to leverage the 1976 Section 936 IRC is the Internal Revenue Code Congressional statute codifying the tax laws in one place.  The IRC was setup in 1939 but restructured in 1954.  Subsequent updates have kept the 1954 structure. 
    tax credits (Dec 2015). 
    Pfizer is estimated to have received over $50 billion in U.S. subsidies between 2000 and 2015. 

    Pfizer's Greenstone
    Pfizer has a generic drug business including Greenstone, a wholly owned subsidiary. 

    Pfizer attempted to purchase AstraZeneca, based in Britain so that Pfizer could invert allows a U.S. company to move its tax domicile overseas by purchasing a foreign company.  In 2015 the U.S. Treasury department adjusted the inversion rules to require 40% of the combined company is owned by the shareholders of the purchased foreign entity.  In Apr 2016 they clamped down on the option to serially acquire American companies.  In section 7874 of the tax code, Congress defined statutory hurdles that must be cleared to gain tax benefits: Shareholders of foreign acquirers owning less than 20% of the combined entity the inversion fails, If less than 40% and the acquirer does substantial business in the foreign jurisdiction the inversion works but with some pain, If they own more than 40% there are few negative consequences.  Companies purchased serially within three years would be disregarded by the new rules.  Companies invert because of lower foreign tax rates and earnings stripping.  Once foreign, the parent loans the US subsidiary money.  The loan repayments offset the US income and the US tax bill is vastly reduced.  .  The outcry resulted in the U.S. is the United States of America.   Treasury is the department of the treasury.  it is a federal government executive department created by Act of Congress in 1789 to manage government revenue.  The Secretary of the Treasury is a Cabinet officer.  To support funding of high cost investments: Disaster recovery, Wars, Famines; the treasury can issue debt instruments and manage the national debt. 
    tightening rules on inversions scuttling this merger and a number of others: Abbvie with Shire

    Oct 2015 NYT Pfizer Bid For Allergan Has Its Eyes On Ireland
    In line with this issue Oct 2015 Pfizer proposed buying the $120 billion market cap Allergan which is now domiciled in Ireland.  Read has concluded that this merger will pass the updated Treasury is the department of the treasury.  it is a federal government executive department created by Act of Congress in 1789 to manage government revenue.  The Secretary of the Treasury is a Cabinet officer.  To support funding of high cost investments: Disaster recovery, Wars, Famines; the treasury can issue debt instruments and manage the national debt. 
    rules on inversion.  The deal would also allow Pfizer to restructure as two companies: A generics company which would leverage the Irish domicile and a high growth branded product company. 
    US congressmen are frustrated at the deal which they see as aiming to leverage Pfizer's access to Medicare is a social insurance program that guarantees access to health insurance for Americans aged 65 and over, and younger people with disabilities and end stage renal disease or ALS.  Medicare includes:
    • Benefits
      • Part A: Hospital inpatient insurance.  As of Dec 2013 Medicare pays for home care in only limited circumstances, such as when a person needs temporary nursing care after a hospitalization.  Part A covers 20 days of inpatient rehabilitation at a SNF after discharge from inpatient care at a hosptial. 
      • Part B: Medical insurance
      • Part C: Medicare Advantage 
      • Part D: Prescription drug coverage 
    • Eligibility
      • All persons 65 years of age or older who are legal residents for at least 5 years.  If they or a spouse have paid Medicare taxes for 10 years the Medicare part A payments are waived. 
      • Persons under 65 with disabilities who receive SSDI. 
      • Persons with specific medical conditions:
        • Have end stage renal disease or need a kidney transplant. 
        • They have ALS. 
      • Some beneficiaries are dual eligible. 
      • Part A requires the person has been admitted as an inpatient at a hospital.  This is constrained by a rule that they stay for three days after admission.  
    • Premiums
      • Part A premium
      • Part B insurance premium
      • Part C & D premiums are set by the commercial insurer. 
    , the VA - Department of Veterans Affairs.  Includes the Veterans Health Administration.   and US trained scientists while lowering the taxes it pays. 

    Nov 2015 Pfizer purchases Allergan for $152 billion
    Ian Read says the merger with Allergan is good for the U.S.  He called Washington Lawmakers and Obama Administration officials, telling them:
    • A deal that would allow the company to move its headquarters to Irelandwas good for the United States. 
    • A merger with Allergan, would significantly cut Pfizer's tax bill and give it more cash that it could invest in the United States and ultimately add jobs.  
    • He argues that the deal will be good for Pfizer shareholders and patients who use its drugs.  Investors did not appear impressed with shares of both Pfizer and Allergan down.  
    Sally Susman must advocate Read's strategy to the Obama administration and Congressional leaders aims to develop plans and strategies which ensure effective coordination to improve the common good of the in-group.  John Adair developed a leadership methodology based on the three-circles model. 
    who are discussing tax-code changes to stop the merger.  Ms. Susman noted "Ironically, an inversion makes it easier for an American company to invest in the U.S. and less likely that it will be encumbered by competitive tax disadvantages -- or acquired by a foreign competitor," in an e-mail.  Other lobbyists lament that Pfizer's actions ensure all Pharmaceutical lobbyists will have to start getting used to losing (Nov 2015). 

    Susman noted in the e-mail "The purpose of this combination of Pfizer and Allergan is to create a global R&D leader with an expanded ability to make investments in the U.S., find cures and treatments for conditions ranging from Alzheimer's disease is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
    • Plaques form and set off the formation of tangled thread-like tau protein.
      • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
      • BACE inhibitors block an enzyme needed to form amyloid. 
    • The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    • The brain becomes inflamed resulting in the killing of many more nerve cells. 
    and Parkinson's disease corresponds to the breakdown of certain interneurons in the brain.  It is not fully understood why this occurs.  Dopamine system neuron breakdown generates the classical symptoms of tremors and rigidity.  In some instances an uncommon LRRK2 gene mutation confers a high risk of Parkinson's disease.  In rare cases Italian and Greek families are impacted in their early forties and fifties resulting from a single letter mutation in alpha-synuclein which alters the alpha-synuclein protein causing degeneration in the substantia nigra.  But poisoning from MPTP has also been shown to destroy dopamine system neurons.  Paraquat has also been linked to Parkinson's disease.  Parkinson's disease does not directly kill many sufferers.  But it impacts swallowing which encourages development of pneumonia through inhaling or aspirating food.  And it undermines balance which can increase the possibility of falls.  Dememtia can also develop. 
    to cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   and rare genetic disorders." 

    Allergan and Pfizer are betting the Treasury is the department of the treasury.  it is a federal government executive department created by Act of Congress in 1789 to manage government revenue.  The Secretary of the Treasury is a Cabinet officer.  To support funding of high cost investments: Disaster recovery, Wars, Famines; the treasury can issue debt instruments and manage the national debt. 
    Department will not be able to implement new rules to block the union in time (Apr 2016), and that Congress will fail to revamp the tax code before the merger's close late 2016.  Instead of an inversion Allergan is technically buying Pfizer.  To manage political issues they retained Moelis & Company whose vice chair is Eric Cantor.  He has advised the merger partners on political strategy.  The FTC - is either:
    • Federal Trade Commission.  Setup during the Wilson administration.  Its powers include blocking mergers due to antitrust concerns using the powers of the Clayton act. 
    • Follicular thyroid cancer. 
    is not likely to resist the deal.  Orrin Hatch argued for a full restructuring of the tax code. 

    2015 Pfizer buys Hospira for $15 billion. 

    May 2016 Pfizer acquires Anacor for $4.5 billion (5.2 billion including debt). 


    2005 Major products are:
    Bextra was forced to withdraw Apr 2005.  With Celebrex awareness issues this is a $4.5B impact in yearly revenue.  Celebrex has not been forced from the market but the stigma attached to COX-2 inhibitors has impacted its sales. 

    Pfizer's Rapamune

    Rapamune (Sirolimus is a macrolide compound which inhibits mTOR signalling pathway cellular regulator's activation of T cells and B cells by reducing production of interleukin-2. 
    ) was marketed by Wyeth. 

    Pfizer's Ibrance

    Ibrance (palbociclib) is used to treat ER-positive and HER2 is a gene encoding the protein 'human epidermal growth factor receptor 2', which is similar in structure to the native receptor HER1. 
    -negative advanced breast cancer is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013). 
    .  It is an inhibitor of cyclin, four enzymes A, B, C, D which cooperate to enforce the four phases of the eukaryotic cell cycle. 
    partner kinases CDK4 and CDK6.  It is considered extreemly expensive at $9,850 a month and is sold through specialty pharmacies dispense specialty medications.  They aim to save health plans money by: teaching patients how to apply their medicines and deal with side effects, ensure they take the full course and limit waste.  These specialized channels can be used by drug companies to limit competition to their drugs since access in constrained.  Generic drugs rebranded as specialty medications may escape competition, remove copayment and formulary exclusion sales inhibitors and obtain considerable pricing power. 
    .  The Wall Street Journal has analysed the pricing and sees no relation to manufacturing or research costs.  Typical health plan discounts were around 20% of list (Dec 2015). 

    While it slowed progression of advanced cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).   it did not alter the patient survival rate in the phase 2 PALOMA-1 trial. 


    Pfizer's torcetrapib

    Pfizer halted late-stage trials of CETP is cho