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|Alnylam Reports Positive Preliminary Clinical Results for ALN-PCS, an RNAi Therapeutic Targeting PCSK9 for the Treatment of Severe Hypercholesterolemia|
– RNAi Therapeutic Achieves Robust Silencing of PCKS9 and Reductions of Over 50% in LDL Cholesterol, a Validated Clinical Endpoint –
– Results Highlight Major Potency Improvements of Second-Generation Lipid Nanoparticle Platform in Man –
– Alnylam to Host Conference Call Today,
“We are extremely pleased with these data from our ALN-PCS trial which represent what we believe is the first ever demonstration of efficacy for an RNAi therapeutic toward a clinically validated endpoint, namely LDL-C, a defined risk factor for coronary artery disease and acute myocardial infarction. Indeed, preliminary results from our ongoing study show robust, statistically significant, and dose-dependent lowering of both PCSK9 and LDL-C levels,” said Akshay Vaishnaw, M.D., Ph.D., Senior Vice President and Chief Medical Officer of Alnylam. “The RNAi effects were rapid and durable after a single dose, exemplifying a compelling profile for RNAi therapeutics that we have now established in man for two disease programs.”
This Phase I ALN-PCS study is being conducted as a randomized, single-blind, placebo-controlled, single-ascending dose study in healthy volunteer subjects with elevated baseline LDL-C (>116mg/dL). The primary objective of the study is to evaluate the safety and tolerability of a single dose of ALN-PCS, with subjects being enrolled into sequential cohorts of increasing doses. Secondary objectives of the study include characterization of plasma and urine pharmacokinetics of ALN-PCS, assessment of pharmacodynamic effects of the drug on plasma PCSK9 protein levels, and evaluation of clinical efficacy as measured by LDL-C levels. This trial is being performed in the absence of statins or other lipid lowering therapy. The findings presented today describe results from the initial 20 subjects enrolled in five sequential dose cohorts ranging from 0.015 to 0.250 mg/kg in a 3:1 randomization of drug to placebo.
In this study, administration of ALN-PCS resulted in a rapid, dose-dependent, and durable silencing of PCSK9 protein levels in plasma of up to 66% relative to baseline, with a statistically significant mean reduction of 60% at day four in the current high dose group of 0.250 mg/kg (p<0.001). In addition, administration of ALN-PCS resulted in dose-dependent reductions in LDL-C of up to 50% relative to baseline, with a statistically significant mean reduction of 39% at day four (p<0.05) at the 0.250 mg/kg dose level. Nadir effects on PCSK9 and LDL-C were achieved rapidly and occurred approximately four days after administration of a single dose. There was also a dose-dependent increase in the proportion of subjects who achieved “target” levels of LDL-C of less than 100 mg/dL (p<0.05), with 100% (6/6) of subjects in the two highest dose groups achieving target and a mean LDL-C of 84.0 mg/dL, as compared with 21.4% (3/14) of subjects achieving target in any other group. Moreover, the effects of a single dose were durable, supporting a once-monthly dose administration regimen expected in future studies. Further, there was no significant decrease in high-density lipoprotein (HDL), or “good” cholesterol levels, consistent with the phenotype observed in human loss-of-function mutations in PCSK9.
To date, ALN-PCS has been shown to be safe and well tolerated in this study and there have been no serious adverse events related to study drug administration. There have been no drug-related discontinuations from the study and no liver enzyme elevations. A mild, transient rash was observed in five subjects, including two who received placebo. The study is ongoing; based on the favorable safety profile and positive clinical activity to date, the company plans to continue dose escalation.
“Cardiovascular disease remains the leading cause of mortality
worldwide, with elevated LDL-C defining the major risk factor. It is
clear that new therapeutic options are needed for patients who cannot
achieve target LDL levels with current drugs,” said
ALN-PCS is an RNAi therapeutic that utilizes proprietary second-generation LNP technology with the MC3 lipid; this study represents the first human results with this delivery platform. The same RNAi delivery formulation is being used for Alnylam’s program on ALN-TTR02, an RNAi therapeutic for the treatment of transthyretin (TTR)-mediated amyloidosis (ATTR).
“These data mark an important milestone in our overall ‘Alnylam 5x15’
efforts, as they are the first to demonstrate safety, tolerability, and
clinical efficacy of an RNAi therapeutic utilizing our second generation
lipid nanoparticle delivery technology. In this regard, these data
strongly support advancement of our ALN-TTR02 program for the treatment
of transthyretin-mediated amyloidosis, where we expect to start clinical
studies shortly,” said
The presentation of these data can be found on Alnylam’s website at www.alnylam.com/capella.
Conference Call Information
Alnylam will host a conference call on
About Severe Hypercholesterolemia
Severe hypercholesterolemia is a condition 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, lifestyle modifications (e.g., exercise and smoking cessation) and medicines such as statins. However, a large proportion of patients with hypercholesterolemia are not achieving target LDL-C goals with statin therapy, including genetic familial hypercholesterolemia patients, acute coronary syndrome patients, high-risk patient populations (e.g. diabetics, symptomatic carotid artery disease, etc.) and other patients that are statin intolerant. Severe hypercholesterolemia is estimated to affect more than 500,000 patients worldwide, and 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.
ALN-PCS is a systemically delivered RNAi therapeutic targeting the gene proprotein convertase subtilisin/kexin type 9, or PCSK9, a target validated by human genetics that is involved in the metabolism of low-density lipoprotein cholesterol (LDL-C, or “bad” cholesterol). ALN-PCS targets both intracellular and extracellular PCSK9, thereby phenocopying the human genetics observed in loss of function or null human PCSK9 mutations (N. Engl. J. Med. (2006) 354:1264-1272; Am. J. Hum. Genet. (2006) 79: 514-523), without any adverse effects on high-density lipoprotein (HDL, or “good” cholesterol) levels. 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 LDL-C levels. Lower LDL-C is associated with a decreased risk of cardiovascular disease, including myocardial infarction and stroke. Pre-clinical data from the ALN-PCS program have shown specific silencing of PCSK9 messenger RNA (mRNA) in the liver, and plasma PCSK9 protein levels of up to 90%, with an ED50 (the dose that provides a 50% silencing effect) of approximately 0.06 mg/kg for both mRNA and protein reduction. These studies have also demonstrated a greater than 50% reduction in levels of LDL-C, which is rapid and durable, lasting for several weeks after a single dose.
About “Alnylam 5x15™”
The “Alnylam 5x15” strategy, launched in
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.
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
Alnylam Forward-Looking Statements
Various statements in this release concerning Alnylam’s future
expectations, plans and prospects, including without limitation,
statements regarding Alnylam’s views with respect to the potential for
RNAi therapeutics, including ALN-PCS and ALN-TTR02, the therapeutic
potential for its second-generation lipid nanoparticle delivery
technology, the expected timing of regulatory filings and clinical trial
initiation, including for ALN-TTR02, its expectations with respect to
the timing and success of its clinical and pre-clinical trials, its
expectation for a once-monthly dose administration regimen in future
clinical trials, its expectations regarding the reporting of additional
data from its ALN-PCS clinical trial, and Alnylam’s expectations
regarding its “Alnylam 5x15” product strategy, constitute
forward-looking statements for the purposes of the safe harbor
provisions under The Private Securities Litigation Reform Act of 1995.
Actual results may differ materially from those indicated by these
forward-looking statements as a result of various important factors,
including, without limitation, Alnylam’s ability to discover and develop
novel drug candidates, successfully demonstrate the efficacy and safety
of its drug candidates, including those formulated in its
second-generation lipid nanoparticle delivery technology, including
ALN-PCS and ALN-TTR02, the pre-clinical and clinical results for its
product candidates, which may not support further development of product
candidates, actions of regulatory agencies, which may affect the
initiation, timing and progress of clinical trials, obtaining,
maintaining and protecting intellectual property, obtaining regulatory
approval for products, competition from others using technology similar
to Alnylam’s and others developing products for similar uses, and
Alnylam’s ability to establish and maintain strategic business alliances
and new business initiatives, as well as those risks more fully
discussed in the “Risk Factors” section of its most recent quarterly
report on Form 10-Q on file with the
Alnylam Pharmaceuticals, Inc.