Alnylam presents new pre-clinical data with ALN-AT3 for treatment of hemophilia and RBD

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it has presented new pre-clinical data with ALN-AT3, a subcutaneously administered RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD), at the 55^th Annual Meeting of the American Society of Hematology (ASH) held December 7 - 10, 2013 in New Orleans. In these new studies, repeat administration of ALN-AT3 was found to be well tolerated in Hemophilia A (HA) mice, with no adverse findings up to dose levels 200 times greater than levels required to achieve 50% AT knockdown. Further, the new studies demonstrate that ALN-AT3 administration achieves complete correction of the activated Partial Thromboplastin Time (aPTT) - an ex vivo measure of blood coagulation that is significantly prolonged in hemophilia - in HA mice. ALN-AT3 is a key program in the company's "Alnylam 5x15" product strategy, which is aimed at advancing five RNAi therapeutic programs directed toward genetically validated disease targets into clinical development, including programs in advanced stages, by the end of 2015.

"Hemophilia and other rare bleeding disorders are characterized by deficiencies in specific clotting factors that ultimately lead to inadequate thrombin generation and a bleeding diathesis. ALN-AT3 is aimed at correcting these bleeding disorders by knockdown of AT - an endogenous anticoagulant - thus, increasing thrombin generation and improving hemostasis," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. "These new data presented at ASH demonstrate that repeat administration of ALN-AT3 is well tolerated in animal models of hemophilia, and suggest that our RNAi therapeutic has the potential for a wide therapeutic index in subjects with hemophilia. With MHRA approval of our recently filed CTA, we look forward to the advancement of ALN-AT3 in our Phase I clinical trial that we expect to start in early 2014, with data from hemophilia subjects expected by the end of next year."

"The unmet need for new therapeutic options to treat hemophilia patients remains very high, particularly in those patients that develop inhibitory antibodies to their replacement factor. Indeed, availability of a safe and effective subcutaneously administered therapeutic with a long duration of action would represent a marked improvement over currently available approaches for prophylaxis," said Claude Negrier, M.D., head of the Hematology Department and director of the Haemophilia Comprehensive Care Centre at Edouard Herriot University Hospital in Lyon. "I continue to be encouraged by Alnylam's pre-clinical progress to date with ALN-AT3, including these new data demonstrating a wide therapeutic index and correction of aPTT for ALN-AT3 in animals with hemophilia. I look forward to the advancement of this innovative therapeutic candidate in clinical studies in the months to come."

In a presentation titled "Expanded Therapeutic Index of Antithrombin Silencing and Correction of APTT in a Hemophilia A Mouse Model," Alnylam scientists presented data demonstrating that, in contrast to wild type (WT) mice, repeat administration of ALN-AT3 was very well tolerated in HA mice. Specifically, HA mice treated with ALN-AT3 exhibited no adverse events up to 100 mg/kg - a dose that is 200-fold greater than the mouse ED₅₀ and that essentially ablates AT protein levels in blood. In fact, 100% of the treated HA mice survived, with no adverse clinical signs or changes to body weight parameters. In WT mice (with intact coagulation systems), repeat administration of over 10 mg/kg ALN-AT3 led to greater than 90% knockdown of plasma AT, and resulted in the expected procoagulant phenotype and poor tolerability. This result was expected since AT knockout in mice and homozygous AT deficiency in humans are known to be embryonic lethal (J. Clin. Invest. (2000) 106:873-878; Blood (2008) 112:19-27). To evaluate the potential reversal of ALN-AT3 efficacy, WT mice treated with 100 mg/kg ALN-AT3 were also treated with exogenous human AT protein. Co-administration of human AT conferred complete protection from prothrombotic adverse events observed in WT mice receiving ALN-AT3 alone, demonstrating that human AT protein could serve as a potential reversal agent for ALN-AT3, if needed. In addition, HA mice treated with ALN-AT3 exhibited significant reductions in aPTT relative to control HA mice. Specifically, the aPTT in HA mice, which is significantly prolonged, was corrected back to aPTT values observed in WT mice. Collectively, these data suggest a substantially expanded therapeutic index of AT knockdown in the hemophilia disease condition, and confirm the active effects for ALN-AT3 that are expected to reset insufficient thrombin generation in people with hemophilia.

Alnylam remains on track to begin a Phase I trial with ALN-AT3 early in 2014. Alnylam announced today that it has received CTA approval from the MHRA for the initiation of the Phase I clinical study. The study will be conducted in the U.K. as a single- and multi-dose, dose-escalation study consisting of two parts. The first part will be a randomized, single-blind, placebo-controlled, single-dose, dose-escalation study, enrolling up to 24 healthy volunteer subjects. Only low doses of ALN-AT3 will be administered in this part of the study with stopping rules at greater than 40% AT knockdown, which is believed to be a well tolerated level of AT knockdown based on pre-clinical studies, in addition to data from people with heterozygous AT deficiency. The primary objective of the first part of the study is to evaluate the safety and tolerability of a single dose of subcutaneously administered ALN-AT3. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels. The second part 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 ex vivo thrombin generation.