Alnylam Initiates Phase 3 Open Label Extension Study with Patisiran, an Investigational RNAi Therapeutic Targeting Transthyretin (TTR) for the Treatment of TTR-Mediated Amyloidosis (ATTR Amyloidosis)

Alnylam Pharmaceuticals, Inc.

, a leading RNAi therapeutics company, announced today that it has initiated its Phase 3 open-label extension study (abbreviated "APOLLO-OLE") with patisiran, an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR amyloidosis) in patients with Familial Amyloidotic Polyneuropthy (FAP). All patients who complete the APOLLO Phase 3 trial with patisiran are eligible to enroll in APOLLO-OLE. The study will evaluate the long-term safety and efficacy of patisiran and will also measure effects of treatment toward a number of clinical endpoints, including the modified Neuropathy Impairment Score, or "mNIS+7," which is an evaluation of muscle weakness, sensory and autonomic function, and nerve conductance. The company is also reiterating its previous guidance that – assuming positive study results in the APOLLO Phase 3 study – it expects to be in a position to file a New Drug Application (NDA) for patisiran in the 2017 timeframe. "Patisiran is the leading investigational candidate in our pipeline of RNAi therapeutics. We are very encouraged with the clinical activity and tolerability seen to date with patisiran, including in our Phase 2 OLE study where we have recently reported what we believe to be continued evidence for a possible halting of neuropathy progression after the first 12 months of treatment," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer of Alnylam. "The initiation of APOLLO-OLE marks our continued progress with patisiran, and we are pleased to provide patients previously treated in APOLLO with the opportunity to receive patisiran on an ongoing basis. The APOLLO trial continues enrolling patients with FAP, and, assuming positive results, we expect to be in a position to file an NDA in the 2017 timeframe. Accordingly, we believe successful execution of the APOLLO Phase 3 trial is a critical step toward achieving our ‘Alnylam 2020' goals where, by the end of 2020, we expect to have 3 marketed products, as well as 10 programs in clinical development, including 4 in late stages of development, across our 3 Strategic Therapeutic Areas, or ‘STArs.'" "Therapeutic options for ATTR amyloidosis patients with FAP are limited, and there is a significant need for novel therapies to treat this debilitating disease. I am pleased with Alnylam's progress to date with patisiran, and find the recent Phase 2 OLE data to be very encouraging. In particular, the possibility of halting neuropathic progression over 12 months of treatment is promising in light of the rapid increase in neuropathy impairment scores observed in analysis of other historical data sets," said Juan Buades, M.D., Ph.D., Internal Medicine Specialist, and Head of the TTR-FAP Clinic, Hospital Son Llatzer, Palma de Mallorca, Spain. "I very much look forward to continuing to participate in the clinical advancement of this investigational medicine." APOLLO-OLE is an open-label, multi-center study designed to evaluate the long-term safety and tolerability of patisiran in ATTR amyloidosis patients with FAP who were previously enrolled in the APOLLO Phase 3 study. Eligible patients treated in APOLLO can enroll in the study, where they will receive patisiran at a dose of 0.3 mg/kg every three weeks for up to the earlier of two years or until the drug is commercially available in their market. The primary objective of APOLLO-OLE is to evaluate the long-term safety and efficacy of patisiran administration. The study will measure a number of clinical endpoints, including Neuropathy Impairment Score at baseline and every 12 months thereafter. A number of additional clinical endpoints will be assessed, including: quality of life; timed 10-meter walk test to evaluate mobility; modified body mass index as a measure of nutritional status; level of disability; and nerve fiber density in skin biopsies. In addition to the APOLLO and APOLLO-OLE trials, Alnylam is also currently conducting a Phase 2 OLE study, where patients previously treated in a Phase 2 study are receiving open-label patisiran at a dose of 0.3 mg/kg every 3 weeks. Initial 12-month clinical data from this study were presented recently at the 67th Annual Meeting of the American Academy of Neurology (AAN) held April 18 – 25, 2015. Patisiran was found to be generally well tolerated out to 17 months of drug administration, with no drug-related serious adverse events to date. In addition, patisiran treatment achieved a sustained mean serum TTR knockdown at the 80% target level for approximately 16 months, with an up to 88% mean knockdown achieved between doses. Results of neuropathy assessments showed a mean 2.5 point decrease in mNIS+7 at 12 months in patients (N=20) who had reached the 12-month endpoint at the time of data cutoff. This decrease in neuropathy progression compares favorably to the 13 to 18 point increase in mNIS+7 at 12 months that can be estimated from the literature in untreated FAP patients with similar baseline characteristics. In aggregate, these results are consistent with the therapeutic hypothesis that TTR knockdown has the potential to halt neuropathy progression in patients with FAP. Alnylam plans to report complete 12-month data (N=27) and preliminary 18-month data from the patisiran Phase 2 OLE study in late 2015. Genzyme Alliance In January 2014, Alnylam and Genzyme, a Sanofi company, formed an alliance to accelerate and expand the development and commercialization of RNAi therapeutics across the world. The alliance is structured as a multi-product geographic alliance in the field of rare diseases. Alnylam retains product rights in North America and Western Europe, while Genzyme obtained the right to access certain programs in Alnylam's current and future Genetic Medicines pipeline in the rest of the world (ROW), including co-development/co-commercialization and/or global product rights in certain defined instances. In the case of patisiran, Alnylam will advance the product in North America and Western Europe, while Genzyme will advance the product in the ROW.