Alnylam Expands Hepatic Infectious Disease Pipeline; Adds ALN-HDV For The Treatment Of Chronic Hepatitis Delta Virus Infection And ALN-PDL For The Treatment Of Chronic Liver Infections

Alnylam Pharmaceuticals, Inc.

, a leading RNAi therapeutics company, announced today that it has expanded its hepatic infectious disease pipeline. Specifically, in a presentation at the American Association for the Study of Liver Diseases (AASLD) meeting, the company announced it has added ALN-HDV, an RNAi therapeutic targeting the hepatitis delta viral (HDV) genome in development for the treatment of HDV infection. Further, it has added ALN-PDL, an RNAi therapeutic targeting hepatocyte-expressed programmed death ligand 1 (PD-L1) in development for the treatment of chronic liver infections. In addition, Alnylam continues to advance its ALN-HBV program, in development for the treatment of hepatitis B viral (HBV) infection; the company remains on track to select a Development Candidate (DC) by the end of the year and expects to file an investigational new drug (IND) application or IND equivalent around the end of 2015. “Hepatic infectious diseases, such as HBV and HDV infection, are major global health problems, affecting approximately 400 million and 15 million people worldwide, respectively. Significant unmet need exists for novel therapies to treat these infections, as they are the leading causes of fibrotic liver disease and liver cancer worldwide,” said Laura Sepp-Lorenzino, Ph.D., Vice President, Entrepreneur-in-Residence. “We believe that multiple opportunities exist for RNAi therapeutics for hepatic infectious diseases, and our initial focus on HBV will now be expanded to include programs for HDV and liver-specific immune checkpoint blockade by targeting hepatocyte-expressed PD-L1. In both cases, our approach will employ our Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, enabling subcutaneous dose administration with high potency and long durability, and a wide therapeutic index. Finally, we remain on track to select our DC for ALN-HBV by end of this year, with the goal of filing an IND or IND equivalent for this program around the end of 2015.” ALN-HDV, an investigational RNAi therapeutic targeting the HDV genome, is in development for the treatment of HDV infection. HDV is an RNA virus that infects hepatocytes and depends on a co-existing HBV infection to produce the envelope particle which holds its genome. HDV can be acquired at the same time or subsequent to infection with HBV, and is believed to infect between 15 and 20 million people worldwide. Chronic HDV infection results in more severe liver disease as compared to HBV infection alone, with higher risks of cirrhosis and hepatocellular carcinoma. Many chronic HDV patients progress to end-stage liver disease, where liver transplant is the only available treatment1. Alnylam plans to advance ALN-HDV as an ESC-GalNAc-siRNA conjugate combination with ALN-HBV targeting both the HBV and HDV genomes. In addition, Alnylam is expanding its hepatic infectious disease efforts with ALN-PDL, an investigational RNAi therapeutic targeting PD-L1 in development for the treatment of chronic liver infections. PD-L1 is a cell surface protein that is believed to play a major role in suppressing the immune system in cancer and infection. HBV and HCV infection of hepatocytes is known to lead to increased PD-L1 expression2 which could subdue the immune response against the virus. Further, monoclonal antibodies targeting PD-L1 and its T-cell ligand PD-1 have shown anti-viral effects in pre-clinical and early clinical studies3, but are also associated with systemic toxicities. ALN-PDL is aimed at knocking down liver-expressed PD-L1 to reactivate an immune response against liver viral infection without the systemic toxicities observed with monoclonal antibody therapy. In pre-clinical studies published previously4 by Alnylam and collaborators, an siRNA targeting PD-L1 was shown to increase the endogenous immune response and viral clearance in a mouse model of liver adenovirus infection. Alnylam plans to advance ALN-PDL as an ESC-GalNAc-siRNA conjugate. Finally, Alnylam is also continuing to advance ALN-HBV, an RNAi therapeutic targeting the HBV genome in development for the treatment of HBV infection. HBV infection afflicts 400 million people worldwide, with one to two million people in the U.S., and is a leading cause of liver disease and hepatocellular carcinoma (HCC) worldwide. An RNAi therapeutic targeting the HBV genome could have the potential to achieve a “functional cure” by effectively decreasing expression of tolerogenic hepatitis surface antigen (HBsAg), in addition to inhibiting all steps of the HBV life cycle. In pre-clinical study results presented at the TIDES 2014 meeting, Alnylam reported significant, multi-log reductions in HBsAg and HBV viral titers in chronically infected chimpanzees. Alnylam plans to advance ALN-HBV as an ESC-GalNAc-siRNA conjugate which should enable once monthly subcutaneous dose administration with potent and durable effects, and a wide therapeutic index. The company remains on track to select a DC in late 2014 and plans to file an IND or IND equivalent around year-end 2015.