Alnylam Pharmaceuticals, Inc. Presents New Pre-Clinical Data on RNAi Therapeutic Programs for Cardio-Metabolic Diseases at American Heart Association Scientific Sessions 2014
Nov 17 14
Alnylam Pharmaceuticals, Inc. announced that it has presented new pre-clinical data from its investigational RNAi therapeutic programs toward genetically validated targets in development for the treatment of cardiovascular metabolic diseases, including: ALN-PCSsc targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AC3 targeting apolipoprotein C3 for the treatment of hypertriglyceridemia; and ALN-ANG targeting angiopoietin-like 3 for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia. These new data are being presented at the American Heart Association Scientific Sessions 2014 in a poster presentation titled Development of Monthly to Quarterly Subcutaneous Administration of RNAi Therapeutics Targeting the Metabolic Disease Genes PCSK9, ApoC3 and ANGPTL3. Among other data, Alnylam presented new pre-clinical multi-dose data in non-human primates with over six months of dosing for ALN-PCSsc showing robust and clamped knockdown of PCSK9 of up to 92% and reductions in LDL-C of up to 77% with a once-monthly subcutaneous dosing regimen. Recently, Alnylam filed and received approval for a Clinical Trial Application for ALN-PCSsc, and now expects to start the Phase 1 trial before year's end with initial clinical data expected in mid-2015. ALN-PCSsc is a subcutaneously administered RNAi therapeutic that utilizes Alnylam's proprietary Enhanced Stabilization Chemistry (ESC)-GalNAc-siRNA conjugate delivery platform. ESC-GalNAc-siRNA conjugates are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor, and enable subcutaneous dosing with increased potency and durability and a wide therapeutic index. The new pre-clinical NHP studies showed that monthly subcutaneous administration of ALN-PCSsc resulted in PCSK9 knockdown of up to 92% and LDL-C lowering, in the absence of statin co-administration, of up to 77%; mean maximum knockdown of PCSK9 was 83.2% +/- 7.2%, and mean maximum LDL-C reduction was 59.0% +/- 13.3%. As a PCSK9 synthesis inhibitor, ALN-PCSsc showed rapid, durable, and clamped knockdown of PCSK9 and reduction of LDL-C, which contrasts with the cyclical variation in LDL-C observed with monthly dose regimens of anti-PCSK9 monoclonal antibodies. Based on current human translational data with ESC-GalNAC-conjugates, the projected human dose levels are expected to be less than 1 mg/kg at a subcutaneous injection volume of less than 1 mL administered once-monthly. In aggregate, these pre-clinical data are supportive of a once-monthly, and possibly once-quarterly, dosing regimen for ALN-PCSsc, which the company believes could represent a highly competitive target product profile. Alnylam's CTA for a Phase 1 trial with ALN-PCSsc has been approved and the company now expects to initiate this study before the end of this year, with initial data expected to be reported in mid-2015. The Phase 1 trial of ALN-PCSsc will be conducted as a randomized, single-blind, placebo-controlled, single- and multi-dose, dose-escalation study. The study is designed to enroll up to 76 healthy volunteer subjects with elevated baseline LDL-C, with subjects randomized 3:1, drug:placebo. The study will be performed in two phases: a single ascending dose phase and a multiple dose phase. In the MD phase, subjects will receive two doses of either ALN-PCSsc or placebo administered four weeks apart. The MD phase will also include subjects both on and off statin co-medication. The primary objective of the Phase 1 study is to evaluate the safety and tolerability of ALN-PCSsc. Secondary objectives include assessment of clinical activity as determined by knockdown of plasma PCSK9 levels and serum LDL-C levels, as well as pharmacokinetics of ALN-PCSsc. In support of the approved CTA, Alnylam has completed toxicology studies in rodents and NHPs. In both species, the no observed adverse effect level (NOAEL) was determined to exceed 250 mg/kg, the top dose in both studies, with no adverse findings in clinical, hematology, laboratory chemistry, and histopathology assessments. Alnylam is collaborating with The Medicines Company on the advancement of ALN-PCSsc. Alnylam also presented data from its ALN-AC3 program at AHA. ALN-AC3 is a subcutaneously administered investigational RNAi therapeutic targeting apoC3 for the treatment of hypertriglyceridemia. ApoC3 is a component of lipoprotein particles in the blood; it inhibits lipoprotein lipase and hepatic lipase, reducing hepatic uptake of triglyceride-rich particles. Polymorphisms in apoC3 have been associated with hypertriglyceridemia; specifically, a gain-of function phenotype leads to higher apoC3 and triglyceride levels, and reduced triglyceride clearance. In contrast, loss-of-function mutations in apoC3 result in greater triglyceride hydrolysis into free fatty acids and increased triglyceride clearance; heterozygous individuals have lower triglycerides and lower levels of very low density lipoprotein.
Alnylam Pharmaceuticals, Inc. - Special Call
Nov 14 14
To discuss initial Phase 2 results with revusiran (ALN-TTRsc), for the treatment of TTR cardiac amyloidosis
Alnylam Adds ALN-HDV for the Treatment of Chronic Hepatitis Delta Virus (HDV) Infection and ALN-PDL for the Treatment of Chronic Liver Infections
Nov 11 14
Alnylam Pharmaceuticals, Inc. announced 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. 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 treatment. 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 expression 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 studies, 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 previously 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 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.