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Alnylam Announces New RNAi Therapeutic Program for the Treatment of Hepatitis B Virus (HBV) Infection and Reports an Up to 2.3 Log10 Reduction of HBV Surface Antigen (HBsAg) in Chronically Infected Chimpanzees

May 12, 2014

– New ALN-HBV Program Stems from Alnylam’s Acquisition of Sirna Therapeutics from Merck –

– Alnylam Expects to Nominate ALN-HBV Development Candidate (DC) with Enhanced Stabilization Chemistry (ESC)-GalNAc-Conjugate Delivery Platform by End of 2014; File Investigational New Drug Application (IND) around Year-End 2015 -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics company, announced today that it has named a new program to its pipeline: ALN-HBV for the treatment of hepatitis B virus (HBV) infection. The new ALN-HBV program derives from the company’s January 2014 acquisition of Merck’s RNAi assets, including their Sirna Therapeutics subsidiary. HBV infection afflicts 400 million people worldwide, with 1 to 2 million people in the U.S., and is a leading cause of liver disease and hepatocellular carcinoma (HCC) worldwide. Despite the use of nucleoside analog inhibitors of viral DNA synthesis and interferon therapies, less than 10% of patients achieve a cure1. Reduction in HBV surface antigen (HBsAg) levels of over 0.5 log10 is the single best predictor of immunologic cure2. An RNAi therapeutic targeting the HBV genome could have the potential to achieve a “functional cure” by effectively decreasing expression of tolerogenic HBsAg, in addition to inhibiting all steps of the HBV life cycle. In the most comprehensive proof-of-concept pre-clinical study results presented to date with an RNAi therapeutic for the treatment of HBV, Alnylam reported significant, multi-log reductions in HBV surface antigen (HBsAg) and HBV viral titers, and showed evidence for an immune-mediated therapeutic effect in chronically infected chimpanzees.

“Alnylam’s new ALN-HBV program is a mature, pre-clinical asset acquired through the company’s acquisition of Sirna from Merck. We are very encouraged by the data we are presenting for the first time today, which we believe constitute the most robust proof-of-concept pre-clinical data to date with an RNAi therapeutic for the treatment of HBV,” said Laura Sepp-Lorenzino, Ph.D., Vice President, Entrepreneur-in-Residence at Alnylam, and Project Leader of the ALN-HBV program. “We believe our ALN-HBV RNAi therapeutic represents a powerful mechanism for inhibiting all steps of the HBV life cycle: replication, assembly, secretion of virus, and secretion of sub-viral antigens. The Development Candidate for our ALN-HBV program will employ our Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, enabling subcutaneous dose administration with improved potency and durability, and a wide therapeutic index. We believe that an ESC-GalNAc conjugate can emerge as the best-in-class approach for RNA therapeutics targeting HBV, and we expect to name our ALN-HBV Development Candidate by the end of this year and file an IND or IND equivalent around the end of 2015.”

The new data are being presented at the TIDES 2014 meeting, being held May 12 – 15 in Providence, Rhode Island. The results were from a model of chronically infected chimpanzees (N=4) showing that RNAi therapeutics targeting a conserved region of the HBV genome could have the potential of achieving a functional cure. First, potent siRNAs that target highly conserved regions of the HBV genome were designed and synthesized. When administered as a single 0.25 mg/kg dose in a lipid nanoparticle (LNP) formulation in chronically infected chimpanzees, the RNAi therapeutic showed an over 2 log10 reduction in circulating viral DNA in the highest titer animal and a mean 1.9 log10 decrease in viral DNA. These effects were confirmed to be RNAi specific by use of a control LNP-encapsulated siRNA, and to be mediated by an RNAi mechanism of action as detected by 5’RACE. In multi-dose, dose-escalation studies in the chronically infected animals, doses of 0.125 to 0.5 mg/kg achieved an over 4 log10 reduction of circulating viral DNA and an up to 2.3 log10 reduction in HBsAg; a mean 2.9 log10 reduction and a mean 2.0 log10 reduction were achieved in HBV DNA and HBsAg, respectively. In one animal with greater than five-fold elevated alanine aminotransferase (ALT) levels at baseline, administration of the RNAi therapeutic was associated with a complete normalization of elevated transaminase levels. Of interest, two of four animals showed mildly elevated liver transaminase levels of about two-to-three fold approximately one-to-two months post dosing that included increases in interferon-gamma and interleukin-6, suggestive of potential “therapeutic flares” related to immune clearance of infected hepatocytes.

“HBV infection is a major global health issue, affecting approximately 400 million people. As a leading cause of liver disease and liver cancer worldwide, significant unmet need exists for novel HBV therapies,” said Graham Foster, Ph.D., FRCP, Professor of Hepatology at Queen Mary University of London. “Because of its unique mechanism of action to inhibit key steps in the viral life cycle, an RNAi approach targeting the HBV genome could offer the potential for significant efficacy in the treatment of HBV, and a potential route to a functional cure.”

Alnylam plans to advance an ESC-GalNAc-siRNA conjugate targeting the HBV genome for its ALN-HBV program. An ESC-GalNAc-siRNA conjugate will enable subcutaneous dose administration with improved potency and durability, and a wide therapeutic index. The company expects to select a Development Candidate (DC) in late 2014 and plans to file an IND or IND equivalent around year end 2015.

About Hepatitis B Virus (HBV) Infection

Hepatitis B is the most common serious liver infection in the world. Worldwide, 2 billion people (1 out of 3 people) have been infected with hepatitis B and 400 million people have become chronically infected. An estimated 1 million people die each year from hepatitis B and its complications worldwide; about 5,000 of those are in the U.S. The clinical manifestations are severe. Worldwide, chronic infection with hepatitis causes 80% of all hepatocellular carcinoma (HCC) and more than 500,000 people die each year from this lethal cancer. About 5% of the population are chronic carriers of HBV, and nearly 25% of all carriers develop serious liver diseases such as chronic hepatitis, cirrhosis, and HCC. HBV infection causes more than 1 million deaths every year. With today’s medicines, the cure rate for chronic HBV infection is less than 10%. An RNAi therapeutic targeting the HBV genome has the potential to achieve a “functional cure” by inhibiting all steps of the HBV life cycle.

About GalNAc Conjugates and Enhanced Stabilization Chemistry (ESC)-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. Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology enables subcutaneous dosing with increased potency and durability, and a wide therapeutic index. This delivery platform is being employed in several of Alnylam’s genetic medicine programs, including programs in clinical development.

About LNP Technology

Alnylam has licenses to Tekmira LNP intellectual property for use in RNAi therapeutic products using LNP technology.

About 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 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 as genetic medicines, including programs as part of the company’s “Alnylam 5x15™” product strategy. Alnylam’s genetic medicine programs are RNAi therapeutics directed toward genetically defined targets for the treatment of serious, life-threatening diseases with limited treatment options for patients and their caregivers. These include: patisiran (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 TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3, an RNAi therapeutic targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia; and other programs yet to be disclosed. As part of its “Alnylam 5x15” strategy, as updated in early 2014, the company expects to have six to seven genetic medicine product candidates in clinical development - including at least two programs in Phase 3 and five to six programs with human proof of concept - by the end of 2015. Alnylam is also developing ALN-HBV, an RNAi therapeutic targeting the hepatitis B virus (HBV) genome for the treatment of HBV infection. The company’s demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and Genzyme, a Sanofi company. In March 2014, Alnylam acquired Sirna Therapeutics, a wholly owned subsidiary of Merck. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 200 peer-reviewed papers, including many in the world’s top scientific journals such as Nature, Nature Medicine, Nature Biotechnology, Cell, the New England Journal of Medicine, and The Lancet. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.

Alnylam Forward-Looking Statements

Various statements in this press release concerning Alnylam’s future expectations, plans and prospects, including without limitation, Alnylam’s views with respect to the potential for RNAi therapeutics, including ALN-HBV for treatment of HBV, its expectations with respect to further advancing ALN-HBV in development, the filing of an IND application for ALN-HBV, its expectations with respect to the timing and success of clinical trials with ALN-HBV, its expectations regarding the potential market opportunity for ALN-HBV, its expectations regarding its “Alnylam 5x15” product strategy, and its plans regarding commercialization of RNAi therapeutics, 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 manage operating expenses, Alnylam’s ability to discover and develop novel drug candidates and delivery approaches, successfully demonstrate the efficacy and safety of its drug candidates, 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 most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in other filings that Alnylam makes with the SEC. In addition, any forward-looking statements represent Alnylam’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation to update any forward-looking statements.

1 Perrillo, R., "The benefits and risks of interferon therapy for hepatitis B" Hepatology 49: S103-111 (2009)

2 Seto WK, Wong DK, Fung J, et al. A large case-control study on the predictability of hepatitis B surface antigen levels three years before hepatitis B surface antigen seroclearance. Hepatology 56: 812-819 (2012);



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