New Pre-Clinical Data on RNAi Therapeutic Programs for Cardio-Metabolic Diseases

We presented pre-clinical data from our 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 (apoC3) for the treatment of hypertriglyceridemia; and ALN-ANG targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia.  The data, presented at the American Heart Association (AHA) Scientific Sessions 2014, included new pre-clinical multi-dose data in non-human primates (NHPs) 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.  These studies confirm the potential for a once-monthly, and possibly once-quarterly, low volume subcutaneous dose regimen, thus highlighting the emerging profile of our ESC-GalNAc conjugate delivery technology. We believe that ALN-PCSsc represents an innovative, differentiated, and well-validated approach for the treatment of hypercholesterolemia.

We also presented pre-clinical data with ALN-AC3 in mouse models that match human genetics of hypertriglyceridemia, showing that a single-dose of a GalNAc-siRNA against apoC3 led to knockdown of up to 94%, with more than 60% knockdown sustained for at least 30 days, and that multiple doses given every other week led to knockdown of 96% through day 35, the last time point in the study.

Finally, we presented new pre-clinical data with ALN-ANG, demonstrating that a single dose of a GalNAc-siRNA targeting ANGPTL3 led to robust, dose-dependent knockdown of serum ANGPTL3 protein of up to 99%, with a single dose ED90 of approximately 1 mg/kg.  In studies performed in an “ob/ob” mouse model of obesity and mixed hyperlipidemia, ALN-ANG treatment as a single 3 mg/kg dose resulted in a greater than 80% reduction in levels of triglycerides and LDL-C.  In addition, total cholesterol was reduced up to 68%. These data with ALN-ANG support further advancement of this program for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia.

ALN-AC3 and ALN-ANG expand our pipeline of investigational RNAi therapeutics toward genetically validated targets for cardio-metabolic diseases.  We see this as an attractive area for our continued investment given the significant disease burden and unmet need for new medicines, the large number of liver-expressed disease-causing genes important in cardio-metabolic disease, and the emerging tolerability, activity, and durability profile of our GalNAc-conjugate platform.