Replies to post #125759 on Biotech Values

[DewDiligence]

More on the PCSK9 story:

http://www.reuters.com/article/2011/08/26/health-cholesterol-discovery-idUSN1E77O1IE20110826

[BTH]

I don't really follow this area at all but it sounds really promising. Pretty incredible stuff, thanks for the article.

Haven't considered ALNY as a stock to own for quite some time...but might be worth another look.

[exwannabe]

Steinberg, who has written extensively on PCSK9, said that patients with the protective mutation were shown to have an almost 90 percent reduced risk of coronary artery disease, compared with the general population.

"That's probably because their LDL has been low from birth," he said.

But he fails to mention OS.

There are certainly many genetic mutations that both reduce life expectancy and risk of coronary arterial disease.

PCKS9 might very well be real, but I would not trust this Steinberg guy for one second.

[mcbio]

Amgen Inc, Merck & Co, Alnylam Pharmaceuticals Inc and a partnership between Bristol-Myers Squibb Co and Isis Pharmaceuticals Inc are in hot pursuit, with rival drugs of their own.

If I were to play the PCSK9 field, I think I'd do that via ALNY given how we've talked in the past about how the shares seem to be really depressed. REGN has had a heck of a run and now sports over a $5B market cap. Maybe this news makes ALNY shares look a little more enticing?

[high_gear55]

Regeneron Pharmaceuticals - REGN - $55.81. doubled in the last eight months.

[mcbio]

ALNY - initiates Phase 1 for PCSK9 drug

http://finance.yahoo.com/news/Alnylam-Initiates-Phase-I-bw-2288306830.html?x=0&.v=1

Alnylam Initiates Phase I Clinical Study of ALN-PCS, an RNAi Therapeutic Targeting PCSK9 for the Treatment of Severe Hypercholesterolemia

– Study Provides Opportunity to Assess Human Proof of Concept with Second Generation Lipid Nanoparticles; Data Expected at Year’s End –

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY - News), a leading RNAi therapeutics company, announced today that it has initiated dosing in its Phase I clinical trial with ALN-PCS, an RNAi therapeutic targeting proprotein convertase subtilisin/kexin type 9, or PCSK9, for the treatment of severe hypercholesterolemia. The study is aimed at evaluating the safety and tolerability of ALN-PCS in subjects with elevated low-density lipoprotein cholesterol (LDLc, or “bad” cholesterol). In addition, the study will evaluate clinical activity of ALN-PCS based on measurements of plasma PCSK9 protein and serum LDLc levels. Alnylam expects to present data from this study at year’s end.

“We believe ALN-PCS has the potential to make a significant impact in the treatment of severe hypercholesterolemia, as this RNAi therapeutic targets both intracellular and extracellular PCSK9, a target validated by human genetics that is known to play a central role in LDLc metabolism. The primary objective of this Phase I study is to demonstrate safety and tolerability of ALN-PCS in subjects with elevated baseline LDLc. In addition, we also believe we have an opportunity to assess preliminary human proof of concept based on blood measurements of PCSK9 protein and LDLc levels,” said Akshay Vaishnaw, Ph.D., M.D., Senior Vice President, Chief Medical Officer of Alnylam. “The start of this trial also marks an important milestone in our Alnylam 5x15 product efforts, as it is the first program using our second generation lipid nanoparticle technology to enter clinical testing, where we aim to have important safety, tolerability, and clinical activity data by this year’s end.”

ALN-PCS is a systemically delivered RNAi therapeutic targeting PCSK9, a disease gene validated by human genetics that is involved in the metabolism of LDLc. By targeting the PCSK9 mRNA, ALN-PCS depletes both intracellular and extracellular PCSK9 protein, thereby phenocopying the human genetics observed in loss of function PCSK9 mutations (N. Engl. J. Med. (2006) 354:1264-1272; Am. J. Hum. Genet. (2006) 79: 514-523). An RNAi therapeutic targeting PCSK9 has the potential to lower tissue and circulating plasma PCSK9 protein levels resulting in higher LDL receptor levels in the liver, and subsequently lower LDLc levels, without any change in high-density lipoprotein (HDL, or “good” cholesterol) levels. Lower LDLc is associated with a decreased risk of cardiovascular disease, including myocardial infarction. Pre-clinical data from the ALN-PCS program have shown specific silencing of PCSK9 mRNA in the liver and reduced plasma PCSK9 protein levels of up to 90%, with an ED50 (the dose that provides a 50% silencing effect) estimated at approximately 0.06 mg/kg for both mRNA and protein reduction. These studies have also demonstrated a greater than 50% reduction in levels of LDLc, which is rapid and durable, lasting for weeks after a single dose.

“Cardiovascular disease is the leading cause of mortality worldwide, with elevated LDLc remaining the major risk factor. It is clear that new therapeutic options are needed for patients who cannot achieve target LDL levels with current drugs. As a key regulator of LDL receptor levels, PCSK9 is arguably one of the most important targets for development of molecular medicines for hypercholesterolemia,” said Jay Horton, M.D., Professor of Internal Medicine – Digestive and Liver Diseases, University of Texas Southwestern Medical Center. “An RNAi therapeutic targeting this genetically validated gene has the potential to rapidly and durably lower LDL cholesterol - while preserving HDL cholesterol - and may also function synergistically with statins.”

The Phase I trial of ALN-PCS is being conducted in the U.K. as a randomized, single-blind, placebo-controlled, single-ascending dose study, enrolling approximately 32 healthy volunteer subjects with elevated baseline LDLc (>116mg/dL). The primary objective of the study is to evaluate the safety and tolerability of a single dose of ALN-PCS, with patients being enrolled into five sequential cohorts of increasing doses ranging from 0.015 to 0.25 mg/kg. Secondary objectives include characterization of plasma and urine pharmacokinetics of ALN-PCS, and assessment of pharmacodynamic effects of the drug on plasma PCSK9 protein and LDLc levels measured from serial blood samples prior to and following dosing. ALN-PCS is an RNAi therapeutic that utilizes proprietary Alnylam second-generation lipid nanoparticle (LNP) technology, specifically the MC3 lipid.

“ALN-PCS is Alnylam’s fourth RNAi therapeutic to enter clinical development, highlighting our continued commitment and focus on advancement of breakthrough medicines to patients. This milestone also exemplifies our ongoing transition from ‘platform company’ to ‘product company’,” said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. “We look forward to results from this new Phase I study at year’s end as it defines an important data point for broader execution on our ‘Alnylam 5x15’ product strategy, including our programs in transthyretin-mediated amyloidosis, refractory anemia, and hemophilia.”

About Severe Hypercholesterolemia

Severe hypercholesterolemia affects more than 500,000 people worldwide and is characterized by very high levels of cholesterol in the blood which is known to increase the risk of coronary artery disease, the leading cause of death in the U.S. Most forms of hypercholesterolemia can be treated through dietary restrictions and medicines such as statins. However, a large proportion of patients with hypercholesterolemia are not achieving low-density lipoprotein cholesterol (LDLc, or “bad” cholesterol) goals by statin therapy including genetic familial hypercholesterolemia patients, acute coronary syndrome patients, high risk cardiovascular patients, and other patient populations that are statin intolerant or statin resistant. As a result, there is a significant need for novel therapeutics to treat patients with severe hypercholesterolemia whose disease is inadequately managed by existing therapies.

About ‘Alnylam 5x15’

The “Alnylam 5x15” strategy, launched in January 2011, establishes a path for development and commercialization of novel RNAi therapeutics to address genetically defined diseases with high unmet medical need. Products arising from this initiative share several key characteristics including: a genetically defined target and disease; the potential to have a major impact in a high unmet need population; the ability to leverage the existing Alnylam RNAi delivery platform; the opportunity to monitor an early biomarker in Phase I clinical trials for human proof of concept; and the existence of clinically relevant endpoints for the filing of a new drug application (NDA) with a focused patient database and possible accelerated paths for commercialization. This strategy leverages Alnylam’s clinical progress on siRNA delivery, including definitive human proof-of-concept data for systemic delivery. By the end of 2015, the company expects to have five such RNAi therapeutic programs in advanced clinical development. These include ALN-TTR for the treatment of transthyretin-mediated amyloidosis (ATTR), ALN-PCS for the treatment of severe hypercholesterolemia, ALN-HPN for the treatment of refractory anemia, ALN-APC for the treatment of hemophilia, and one additional program from the company’s ongoing discovery efforts that will be designated and advanced into development later in 2011. Alnylam intends to commercialize the products arising under the “Alnylam 5x15” strategy itself in the United States and potentially certain other countries; the company will seek development and commercial partners in other global territories.

About RNA Interference (RNAi)

RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNAs (siRNAs), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.

About Alnylam Pharmaceuticals

Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is leading the translation of RNAi as a new class of innovative medicines with a core focus on RNAi therapeutics for the treatment of genetically defined diseases, including ALN-TTR for the treatment of transthyretin-mediated amyloidosis (ATTR), ALN-PCS for the treatment of severe hypercholesterolemia, ALN-HPN for the treatment of refractory anemia, and ALN-APC for the treatment of hemophilia. As part of its “Alnylam 5x15TM” strategy, the company expects to have five RNAi therapeutic products for genetically defined diseases in advanced stages of clinical development by the end of 2015. Alnylam has additional partner-based programs in clinical or development stages, including ALN-RSV01 for the treatment of respiratory syncytial virus (RSV) infection, ALN-VSP for the treatment of liver cancers, and ALN-HTT for the treatment of Huntington’s disease. The company’s leadership position on RNAi therapeutics and intellectual property have enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, and Cubist. In addition, Alnylam and Isis co-founded Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics; Regulus has formed partnerships with GlaxoSmithKline and Sanofi. Alnylam has also formed Alnylam Biotherapeutics, a division of the company focused on the development of RNAi technologies for application in biologics manufacturing, including recombinant proteins and monoclonal antibodies. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 100 peer-reviewed papers, including many in the world’s top scientific journals such as Nature, Nature Medicine, Nature Biotechnology, and Cell. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.

[DewDiligence]

SNY/REGN Report Positive Phase-2 Data for REGN727 in Hypercholesterolemia

[REGN727 (a/k/a SAR236553) is the most advanced PCSK9 blocker, one of the hottest drug classes in development (#msg-66596860).]

http://en.sanofi.com/Images/29132_20111110_PCSK_EN.pdf

›Paris, France and Tarrytown, NY - November 10, 2011 - Sanofi (EURONEXT: SAN and NYSE: SNY) and Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced positive preliminary results from the Phase 2 study program in which patients with elevated low-density lipoprotein cholesterol (LDL-C) were treated with REGN727/SAR236553.

REGN727/SAR236553 is a novel, high-affinity, subcutaneously administered, fully-human antibody targeting PCSK9 (proprotein convertase subtilisin/kexin type 9). Blocking the PCSK9 pathway is a novel mechanism for lowering LDL-C, the leading known risk factor for coronary artery disease.

One Phase 2 trial studied patients with heterozygous familial hypercholesterolemia (heFH) with elevated cholesterol (LDL-C=100mg/dL) despite lipid lowering therapy (statins with or without ezetemibe). The objective of the study was to compare the effect of adding REGN727/ SAR236553 to the existing lipid lowering therapy in heFH patients. In the primary efficacy analysis of the study, after 12 weeks of treatment, patients who received different dosing regimens of REGN727/SAR236553 achieved mean LDL-C reductions from baseline ranging from approximately 30% to greater than 65% depending on dosing regimen of REGN727/SAR236553 compared to a mean reduction of 10% with placebo (p<0.05 for all dose groups). Patients in the study are being followed for a total of 20 weeks for safety.

In this trial, REGN727/SAR236553 was generally well tolerated over 12 weeks. There were no elevations in LFTs >3 times the upper limit of normal and no cases of elevated CPK reported. The most common adverse event was injection site reaction. There were no serious adverse events on active treatment. Full safety data from the 8-week post-treatment monitoring period will be presented at a future medical congress upon final analysis.

Another Phase 2 trial studied patients with primary hypercholesterolemia with elevated cholesterol (LDL-C= 100mg/dL) who were on a stable low dose of atorvastatin (10 mg). The primary objective of the study was to compare the effect of switching to a high dose of atorvastatin alone (80mg) versus a high dose of atorvastatin combined with REGN727/SAR236553. In the primary endpoint of the study, after eight weeks of treatment, patients who received REGN727/SAR236553 plus atorvastatin 80mg achieved a greater than 65% reduction in mean LDL-C compared to a mean reduction of 17% for atorvastatin 80mg only (p<0.001). The study also included a third arm in which REGN727/SAR236553 was added to the stable low dose of atorvastatin and the patients achieved a greater than 65% reduction in mean LDL-C. Patients in the study were followed for a total of 16 weeks for safety.

In this trial, REGN727/SAR236553 was generally well tolerated over 16 weeks. There was one serious adverse event of dehydration in the REGN727/SAR236553 + atorvastatin 80mg group that was deemed not treatment related. One patient in the REGN727/SAR236553 + atorvastatin 80mg group with mildly elevated AST prior to randomization (>ULN and = 3ULN) experienced an elevation of AST>3ULN and =5ULN and one patient discontinued therapy due to a hypersensitivity reaction (rash).

A third study of this Phase 2 program is still ongoing.

“The preliminary Phase 2 results with our anti-PCSK9 antibody are very encouraging,” said Elias Zerhouni, President, Global Research & Development, Sanofi. “We look forward to analyzing and presenting the complete data set and remain committed to advancing this program into Phase 3 development as soon as possible.”

“Despite the availability of statins, elevated cholesterol and coronary artery disease remain a leading cause of morbidity and mortality in the U.S. and the rest of the world,” said George D. Yancopoulos, M.D., Ph.D., Chief Scientific Officer of Regeneron and President of Regeneron Research Laboratories. “We are encouraged that blocking PCSK9 with our anti-PCSK9 antibody has the potential to offer a novel mechanism for lowering LDL-C in a broad range of patients. We look forward to further exploring the safety and efficacy of REGN727/SAR236553 in our Phase 3 clinical program.”

More detailed data from these Phase 2 trials, as well as from the third ongoing Phase 2 trial, will be submitted for presentation at an upcoming scientific conference.

About REGN727/SAR236553

REGN727/SAR236553 is the first fully human monoclonal antibody directed against proprotein convertase subtilisin/kexin type 9 (PCSK9). REGN727/SAR236553 is a high affinity, subcutaneously delivered, specific inhibitor of PCSK9. It blocks the binding of PCSK9 to the low density lipoprotein (LDL) receptor and interrupts the resultant internalization and degradation of the LDL receptor. In a 15-year retrospective epidemiological analysis from the Atherosclerosis Risk in Communities Study (ARIC) study, patients with nonsense mutations in PCSK9 had a 28% reduction in mean LDL cholesterol and an 88% reduction in the risk of coronary heart disease1. REGN727/SAR236553 was developed using Regeneron’s VelocImmune® antibody technology.

About the REGN727/SAR236553 Phase 2 Program

The REGN727/SAR236553 Phase 2 program consists of three Phase 2 clinical trials. These are:

1. A randomized, double-blind, multi-dose, placebo-controlled, 75-patient trial in patients with heterozygous familial hypercholesterolemia (heFH). In this trial, patients must meet the World Health Organization criteria for heFH, be on a stable daily statin regimen for at least 6-weeks before entering the trial, and have serum LDL-C levels = 100mg/dL. Patients could be taking ezetimibe in addition to a daily statin. Patients were randomized to one of four different dose regimens of REGN727/SAR236553 or placebo. The primary endpoint of the study is the change in LDL-C from baseline over the 12-week study period. Patients will be followed for a total of 20 weeks for safety.

2. A randomized, double-blind, single-dose, placebo-controlled, 90-patient trial in combination with atorvastatin in patients with primary hypercholesterolemia. In this trial, patients on a stable dose of atorvastatin 10mg for at least 6-weeks with LDL-C levels = 100mg/dL or who had LDL-C levels = 100mg/dL after a run-in period on atorvastatin 10mg, were randomized to either (a) titration from atorvastatin 10mg to atorvastatin 80mg plus REGN727/SAR236553, (b)titration from atorvastatin 10mg to atorvastatin 80mg plus placebo , or (c) continued atorvastatin 10mg plus REGN727/SAR236553. The primary endpoint of the study is the change in LDL-C from baseline over the 8-week study period. Patients were followed for a total of 16 weeks for safety.

3. A randomized, double-blind, multi-dose, placebo-controlled, 180-patient trial in combination with atorvastatin in patients with primary hypercholesterolemia and on stable doses of atorvastatin. In this trial, patients on a stable dose of atorvastatin 10mg, atorvastatin 20mg, or atorvastatin 40mg for at least 6-weeks with LDL-C levels = 100mg/dL or who had LDL-C levels = 100mg/dL after a run-in period on atorvastatin 10mg, atorvastatin 20mg, or atorvastatin 40mg were randomized to one of five different dose regimens of REGN727/SAR236553 plus continued atorvastatin or placebo plus continued atorvastatin. The primary endpoint of the study is the change in LDL-C from baseline over the 12-week study period. Patients will be followed for a total of 20 weeks for safety.

About Heterozygous Familial Hypercholesterolemia

Heterozygous Familial Hypercholesterolemia (heFH) is an inherited disease that is characterized by elevated LDL-C levels and family patterns of increased risk of premature coronary artery disease and heart disease-related death. The majority of these patients have inherited abnormalities in the gene for the LDL receptor. This results in a decreased ability to clear LDL-C from the blood and consequently, high levels of LDL-C. Because of the severe elevations in LDL-C, many of these patients cannot reach treatment goals with existing therapies. It is estimated that 1 in 500 people carries the genetic mutation that is responsible for heterozygous familiar hypercholesterolemia.

About Primary Hypercholesterolemia

Hypercholesterolemia, particularly an increase in LDL-C levels, is a major risk factor for the development of atherosclerosis and cardiovascular disease. It is estimated that there are approximately 63 million people in the US with elevated levels of LDL-C. LDL-C is identified as the primary target of cholesterol lowering therapies such as statins. Statins have significantly helped in managing the risk for cardiovascular disease. However, since guidelines have established more stringent goals for very high risk patients due to their CV profiles, more than 60% of this patient group does not reach goal and needs new therapeutic options.‹

[DewDiligence]

The “hottest” drug targets, according to Luke Timmerman, are PCSK9, P13 kinase, IL-17, and JAK:

http://www.xconomy.com/national/2012/04/23/what-are-the-hottest-targets-in-biotech-today/?single_page=true

[DewDiligence]

PCSK9—Lots of articles this week on the various programs from several companies/partnerships (but, oddly, no one has posted them). Perhaps it’s time for an iHub survey on which of these compounds will turn out to be best in class.

Comments?