Oct 03, 2013 Press Release for Alnylam
Alnylam and Collaborators Publish Clinical Trial Results with ALN-PCS, an RNAi Therapeutic Targeting PCSK9 for the Treatment of Hypercholesterolemia, in The Lancet
Oct 03, 2013
— Results from Phase I Trial of ALN-PCS Demonstrate Rapid, Dose-Dependent, and Durable Reduction of Plasma PCSK9 of up to 84% and Serum LDL Cholesterol of up to 57% —
— New Paper Documents First Human Proof of Concept for an RNAi Therapeutic Toward a Clinically Validated Endpoint —
"Our data with ALN-PCS demonstrate that inhibition of PCSK9 synthesis by
an RNAi therapeutic may be a potentially safe and novel approach to
reduce LDL-C. The study also documents the first human proof of concept
for an RNAi therapeutic toward a clinically validated endpoint, namely
LDL-C," said
"Cardiovascular disease remains the leading cause of mortality
worldwide, with elevated LDL-C a well validated and modifiable risk
factor. A substantial number of patients, especially those at high risk
for cardiovascular disease, are unable to achieve target LDL levels with
current drugs, such as statins, and it is clear that new therapeutic
options are needed," said
ALN-PCS is a systemically delivered RNAi therapeutic targeting PCSK9, a target validated by human genetics that is involved in the metabolism of LDL-C, or "bad" cholesterol. ALN-PCS inhibits the synthesis of PCSK9, thereby reducing intracellular and extracellular levels of PCSK9, resulting in lowered levels of LDL-C.
The Phase I study was conducted as a randomized, single-blind, placebo-controlled, single-ascending dose study in healthy volunteer subjects with elevated baseline LDL-C (greater than 116mg/dL). The primary objective of the study was to evaluate the safety and tolerability of a single dose of ALN-PCS. Secondary objectives of the study included assessment of pharmacodynamic effects of ALN-PCS on plasma PCSK9 protein levels and evaluation of clinical activity as measured by LDL-C levels. A total of 32 subjects were enrolled into six sequential dose cohorts ranging from 0.015 to 0.400 mg/kg in a 3:1 randomization of drug to placebo.
Results of the Phase I study showed that single dose administration of ALN-PCS achieved rapid, dose-dependent, and durable knockdown of PCSK9 protein levels in plasma of up to 84% relative to baseline and placebo, with a statistically significant mean reduction of 70% (p < 0.0001) in the highest dose group of 0.400 mg/kg. In addition, ALN-PCS administration resulted in rapid, dose-dependent, and durable reductions in LDL-C of up to 57% relative to baseline and placebo, with a statistically significant mean reduction of 40% (p < 0.0001) at the 0.400 mg/kg dose level. Importantly, ALN-PCS demonstrated consistent clinical activity toward both PCSK9 and LDL-C in a manner that was independent of baseline levels of PCSK9, highlighting the unique mechanism of action for a PCSK9 synthesis inhibitor. In other words, subjects with high levels of PCSK9 at baseline achieved a comparable degree of knockdown of plasma PCSK9 and reductions in LDL-C as those with low levels of baseline PCSK9. Furthermore, there was no significant change in plasma levels of transthyretin (TTR), a liver-secreted protein that is not expected to change upon silencing PCSK9, thus confirming that the effects of ALN-PCS on plasma PCSK9 levels were specific to the target gene. In addition, data from pre-clinical studies in non-human primates were shown to be highly predictive of the clinical results, demonstrating that non-human primate data from studies with RNAi therapeutics translate to human data on a roughly equivalent mg/kg basis.
ALN-PCS was shown to be generally safe and well tolerated in this Phase I study and there were no serious adverse events related to study drug administration. There were no drug-related discontinuations and no liver enzyme elevations. In addition, there were no clinically significant, dose-dependent changes in any laboratory indices — including liver function tests, creatine phosphokinase, C-reactive protein, and hematological parameters — or cytokines. There was also no statistically significant change compared to baseline in levels of high-density lipoprotein (HDL), or "good" cholesterol, consistent with the phenotype observed in human PCSK9 loss-of-function mutations.
Alnylam is currently advancing ALN-PCSsc, an RNAi therapeutic targeting
PCSK9 that utilizes the company's proprietary GalNAc conjugate delivery
platform enabling subcutaneous dose administration with a wide
therapeutic index. At its R&D Day in
In
"We are very excited by the pre-clinical and early clinical data that our partner Alnylam has generated to date with ALN-PCS as reported in The Lancet, in addition to the more recent progress with ALN-PCSsc, which we believe has the potential to deliver a highly competitive profile with subcutaneous dose administration. We have seen that inhibition of PCSK9 by various therapeutic approaches, such as monoclonal antibodies and gene silencing, can substantially reduce LDL-C in patients. Epidemiological and disease mechanism studies suggest this reduction in LDL-C can further reduce the risks of the world's number one killer, coronary artery disease," said David Kallend MB.BS (Lon), Vice President and Global Medical Director for the lipid programs at The Medicines Company. "Our focus on acute and intensive care medicine has led us to a leadership position in the management of patients who are at extreme risk as a consequence of the rupture of their vulnerable coronary artery plaque at and around the time of acute coronary syndromes. We look forward to working with Alnylam in advancing ALN-PCSsc to patients."
About Hypercholesterolemia
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. Some 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., patients with coronary artery disease, diabetics, symptomatic carotid artery disease, etc.) and other patients that are statin intolerant. Severe forms of hypercholesterolemia are 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 hypercholesterolemia whose disease is inadequately managed by existing therapies.
About ALN-PCS
ALN-PCS is a systemically delivered RNAi therapeutic targeting the gene
proprotein convertase subtilisin/kexin type 9 (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 therapies are PCSK9 synthesis inhibitors that lower levels of
both intracellular and extracellular PCSK9, thereby phenocopying the
human genetics observed in loss of function or null human PCSK9
mutations (
About LNP Technology
Alnylam has licenses to Tekmira LNP intellectual property for use in RNAi therapeutic products using LNP technology.
About GalNAc Conjugates
GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Research findings demonstrate potent and durable target gene silencing, as well as a wide therapeutic index, with subcutaneously administered GalNAc-siRNAs from multiple "Alnylam 5x15" programs.
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 RNA (siRNA), 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 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 toward genetically defined targets for the
treatment of serious, life-threatening diseases with limited treatment
options for patients and their caregivers. These include: ALN-TTR02, an
intravenously delivered RNAi therapeutic targeting transthyretin (TTR)
for the treatment of TTR-mediated amyloidosis (ATTR) in patients with
familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously
delivered RNAi therapeutic targeting TTR for the treatment of ATTR in
patients with familial amyloidotic cardiomyopathy (FAC); ALN-AT3, an
RNAi therapeutic targeting antithrombin (AT) for the treatment of
hemophilia and rare bleeding disorders (RBD); ALN-AS1, an RNAi
therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the
treatment of porphyria including acute intermittent porphyria (AIP);
ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of
hypercholesterolemia; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for
the treatment of beta-thalassemia and iron-overload disorders; ALN-AAT,
an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the
treatment of AAT deficiency liver disease; and ALN-CC5, an RNAi
therapeutic targeting complement component C5 for the treatment of
complement-mediated diseases, amongst other programs. As part of its
"Alnylam 5x15TM" strategy, the company expects to have five
RNAi therapeutic products for genetically defined diseases in clinical
development, including programs in advanced stages, on its own or with a
partner by the end of 2015. Alnylam has additional partnered programs in
clinical or development stages, including ALN-RSV01 for the treatment of
respiratory syncytial virus (RSV) infection and ALN-VSP for the
treatment of liver cancers. 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,
About "Alnylam 5x15™"
The "Alnylam 5x15" strategy, launched in
Alnylam Forward-Looking Statements
Various statements in this press release concerning Alnylam's future
expectations, plans and prospects, including without limitation,
Alnylam's expectations regarding its "Alnylam 5x15" product strategy,
Alnylam's views with respect to the potential for RNAi therapeutics,
including ALN-PCS, its views regarding the predictive nature of
non-human primate data with RNAi therapeutics towards human data, its
expectations regarding the timing of nomination of an ALN-PCSsc
development candidate, its expectations with respect to the timing and
success of its clinical trials for the ALN-PCS program, including trials
with ALN-PCSsc, and its plans with respect to commercialization of the
ALN-PCS program, 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 and delivery approaches,
successfully demonstrate the efficacy and safety of its drug candidates,
including ALN-PCS and ALN-PCSsc, 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, Alnylam's ability to
enforce its patents against infringers and defend its patent portfolio
against challenges from third parties, obtaining regulatory approval for
products, competition from others using technology similar to Alnylam's
and others developing products for similar uses, Alnylam's ability to
obtain additional funding to support its business activities and
establish and maintain strategic business alliances and new business
initiatives, Alnylam's dependence on third parties for development,
manufacture, marketing, sales and distribution of products, the outcome
of litigation, and unexpected expenditures, as well as those risks more
fully discussed in the "Risk Factors" filed with Alnylam's Quarterly
Report on Form 10-Q filed with the
Vice
President, Investor Relations and Corporate Communications
or
Spectrum
Source:
News Provided by Acquire Media
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Christine Akinc
Chief Corporate Communications Officer media@alnylam.com 617-682-4340
For Investor Inquiries, please contact:
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VP, Investor Relations & Corporate Communications investors@alnylam.com 617-551-8276
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