Alnylam Pharmaceuticals, Inc. announced that it has initiated a Phase 1 study with ALN-AT3, a subcutaneously administered RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD). ALN-AT3 has demonstrated efficacy in animal models of hemophilia, including in non-human primate models of induced hemophilia. Moreover, pre-clinical studies of ALN-AT3 support a wide therapeutic index in the hemophilia setting.

ALN-AT3 is a key program in the company's Alnylam 5x15 product strategy, which is aimed at advancing multiple RNAi therapeutic genetic medicine programs into clinical development. The company announced that it expects to exceed its original Alnylam 5x15 guidance with six to seven genetic medicine programs in clinical development by the end of 2015, including at least two programs in Phase 3 and five to six programs that will have achieved human proof-of-concept results supporting further development. The Phase 1 study is being conducted in the U.K. as a single- and multi-dose, dose-escalation study consisting of two parts.

Part A will be a randomized, single-blind, placebo-controlled, single-dose, dose-escalation study, enrolling up to 24 healthy volunteer subjects. The primary objective of this part of the study is to evaluate the safety and tolerability of a single low dose of ALN-AT3, with the potential secondarily to show changes in AT plasma levels at sub-pharmacologic doses. Part B of the study will be an open-label, multi-dose, dose-escalation study enrolling up to 18 people with moderate to severe hemophilia A or B. The primary objective of this part of the study is to evaluate the safety and tolerability of multiple doses of subcutaneously administered ALN-AT3 in hemophilia subjects.

Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels and increase in thrombin generation at pharmacologic doses of ALN-AT3. Thrombin generation is known to be a biomarker for bleeding frequency and severity in people with hemophilia (Dargaud, et al., Thromb Haemost; 93, 475-480 (2005)). The company expects to present initial data from the Phase 1 study in late 2014.