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

- 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.

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