Alnylam Reports 12-Month Clinical Data from Phase 2 Open Label Extension (OLE) Study of Patisiran, an Investigational RNAi Therapeutic for Patients with Familial Amyloidotic Polyneuropathy (FAP)

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today initial 12-month clinical data from its ongoing Phase 2 open-label extension (OLE) study with patisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin (TTR)-mediated amyloidosis (ATTR amyloidosis) in patients with familial amyloidotic polyneuropathy (FAP). These new clinical data are being presented at the 67th Annual Meeting of the American Academy of Neurology (AAN) being held April 18 – 25 in Washington, D.C. Study results showed a mean 2.5 point decrease in modified Neuropathy Impairment Score (mNIS+7) at 12 months in patients who had reached the 12-month endpoint (N=20) 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 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. In aggregate, these results are consistent with the therapeutic hypothesis that TTR knockdown has the potential to halt neuropathy progression in patients with FAP. Patisiran was also found to be generally well tolerated out to 17 months of drug administration, with no drug-related serious adverse events to date; all 27 patients enrolled in the study continue to receive patisiran. Alnylam has also announced today that it plans to report 18-month OLE data in late 2015.

“In this ongoing open-label study with patisiran, we are very encouraged to see what we believe to be continued evidence for possible halting of neuropathy progression after the first 12 months of treatment. Indeed, we believe the 2.5-point mean decrease in the modified neuropathy impairment score is a promising result in light of analysis of multiple historical data sets that would have predicted an increase of 13 to 18 points for untreated FAP patients with similar baseline characteristics. It will be of great interest to see how these data mature going forward, and we now look forward to sharing 18-month clinical results in late 2015,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President, R&D and Chief Medical Officer of Alnylam. “In addition, patisiran treatment showed robust mean knockdown of serum TTR of up to 88%, and was associated with a favorable tolerability profile out to 17 months of drug administration. In aggregate, we believe that these results are consistent with the therapeutic hypothesis that TTR knockdown has the potential to halt neuropathy progression in patients with FAP. We continue to treat patients in our OLE study, and are actively enrolling FAP patients around the world in our APOLLO Phase 3 study, where we aim to obtain definitive evidence for patisiran efficacy and safety in FAP.”

Alnylam’s ongoing OLE study is an open-label, multi-center trial designed to evaluate the long-term safety and tolerability of patisiran administration in FAP patients that were previously enrolled in a Phase 2 study. Patisiran is being administered once every 3 weeks at a dose of 0.3 mg/kg by intravenous infusion. The study is measuring a number of clinical endpoints every six months, including mNIS+7 which is an evaluation of muscle weakness, sensory and autonomic function, and nerve conductance, where neuropathy progression leads to an increased score over time. The change in the mNIS+7 measurement from baseline to 18 months is the primary endpoint in the company’s Phase 3 APOLLO trial of patisiran in FAP patients. New results – presented at the AAN meeting for patients (N=20) who reached the 12-month endpoint as of a data cut off of March 13, 2015 – showed that neuropathy impairment scores were essentially unchanged from baseline values after 12 months of treatment. Specifically, there was a mean decrease in mNIS+7 of 2.5 points, which compares favorably to an estimated increase in mNIS+7 of 13 to 18 points at 12 months based upon analysis of historical data sets in untreated FAP patients with similar baseline characteristics (Adams et al., International Symposium on Amyloidosis, April 2014; Berk et al., JAMA 310: 2658-67, 2013; Tafamidis European Medicines Agency Assessment Report, 2011). Similar results were observed for the change in Neuropathy Impairment Score (NIS), where there was a mean increase of 0.4 points at 12 months (N=20), which compares favorably to an estimated 10 to 14 point increase in NIS at 12 months derived from historical data sets in untreated FAP patients with similar baseline characteristics. The effects on mNIS+7 and NIS were similar in patients with or without concurrent use of TTR tetramer stabilizers. In addition, complete 6-month results were presented for all 27 patients, and showed mean decreases of 1.4 and 0.7 points in mNIS+7 and NIS endpoints, respectively; these data are consistent with previously reported data for patients that reached the 6 month endpoint (N=19), as reported at the American Neurological Association meeting in October, 2014.

A summary of mNIS+7 and NIS results (mean ± standard error of the mean (SEM)) at 6 and 12 months is provided in the table below.

A number of additional exploratory clinical measures are also being assessed in the OLE study, including: quality of life (QOL); timed 10-meter walk test (10MWT) to evaluate mobility; hand grip strength test; modified body mass index (mBMI) as a measure of nutritional status; level of disability by R-ODS; autonomic neuropathy symptoms by COMPASS-31; and nerve fiber density in skin biopsies. New results presented at the AAN meeting showed that these clinical measures were largely unchanged over the 12-month evaluation period. Patients with cardiac abnormalities at baseline comprise a cardiac subgroup (N=11) in the study, where cardiac biomarkers (NT-proBNP and troponin I) and echocardiographic parameters are measured at baseline and every three or six months, respectively. Results in the cardiac subgroup showed no clinically significant changes in cardiac biomarkers (N=7-8) or in echocardiographic parameters (N=6-7) after 12 months of dosing. Finally, serum TTR levels are being measured throughout the OLE study. New results showed that repeat dosing with patisiran achieved sustained mean TTR knockdown at the 80% target level for approximately 16 months, and an up to 88% mean level of TTR knockdown was achieved in between doses. A similar degree of TTR knockdown was observed in patients with or without concurrent use of TTR tetramer stabilizers.

Patisiran administration was also found to be generally well tolerated in FAP patients (N=27), with minimal adverse events reported for a period of up to 17 months. As of the time of the current data cutoff on March 13, 2015, 511 doses had been administered with a median of 19 doses per patient. Mean treatment duration was 13 months and the longest treatment duration was out to 17 months. There were no drug-related serious adverse events. The most common drug-related or possibly drug-related adverse events were flushing (22.2%) and infusion-related reactions (18.5%), which were both mild in severity and did not result in any discontinuations. Additional reported drug-related adverse events seen in >5% of patients were mild to moderate in severity and included diarrhea (7.4%) and peripheral edema (7.4%). There were no clinically significant changes in liver function tests, renal function tests, or other laboratory or hematological parameters.

“I view these new clinical activity and safety data from Alnylam’s ongoing patisiran OLE study as 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. If these results are replicated in a randomized, double-blind, placebo-controlled study, I believe that patisiran could emerge as an important treatment option for patients suffering from this debilitating, progressive and life-threatening disease,” said David Adams, M.D., Ph.D., Head of Department of Neurology and Coordinator of the French Reference Center for FAP (NNERF)/APHP/CHU Bicêtre/France. “I very much look forward to continuing to participate in the clinical advancement of this investigational RNAi therapeutic, including enrolling patients onto the APOLLO Phase 3 study, as there are currently few options for our patients suffering from FAP.”

Conference Call Information
Alnylam management will discuss these new Phase 2 open-label extension study results with patisiran for the treatment of familial amyloidotic polyneuropathy in a webcast conference call on Tuesday, April 21 at 9:00 a.m. ET. A slide presentation will also be available on the Investors page of the company’s website, www.alnylam.com, to accompany the conference call. To access the call, please dial 877-312-7507 (domestic) or 631-813-4828 (international) five minutes prior to the start time and refer to conference ID 30385115. A replay of the call will be available beginning at 12:00 p.m. ET. To access the replay, please dial 855-859-2056 (domestic) or 404-537-3406 (international), and refer to conference ID 30385115.

About Transthyretin-Mediated Amyloidosis
Transthyretin (TTR)-mediated amyloidosis (ATTR) is an inherited, progressively debilitating, and often fatal disease caused by mutations in the TTR gene. TTR protein is produced primarily in the liver and is normally a carrier of vitamin A. Mutations in TTR cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy. ATTR represents a major unmet medical need with significant morbidity and mortality; familial amyloidotic polyneuropathy (FAP) affects approximately 10,000 people worldwide and familial amyloidotic cardiomyopathy (FAC) is estimated to affect at least 40,000 people worldwide. FAP patients have a life expectancy of 5 to 15 years from symptom onset, and the only approved treatment options for early stage disease are liver transplantation, and tafamidis (approved in Europe). FAC is fatal within 2.5 to 5 years of diagnosis and treatment is currently limited to supportive care. Senile systemic amyloidosis (SSA) is a non-hereditary form of TTR cardiac amyloidosis caused by idiopathic deposition of wild-type TTR; its prevalence is generally unknown, but is associated with advanced age. There is a significant need for novel therapeutics to treat patients with TTR amyloid polyneuropathy and/or cardiomyopathy.

About LNP Technology
Alnylam has licenses to Tekmira LNP intellectual property for use in RNAi therapeutic products using LNP technology.

About the Genzyme Collaboration
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 obtains the right to access Alnylam’s current “5x15” and future genetic medicines pipeline in the rest of the world (ROW), including co-development/co-commercialization and/or global product rights for certain programs. 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.

About RNAi
RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.

About Alnylam Pharmaceuticals
Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is leading the translation of RNAi as a new class of innovative medicines. Alnylam’s pipeline of investigational RNAi therapeutics is focused in 3 Strategic Therapeutic Areas (STArs): Genetic Medicines, with a broad pipeline of RNAi therapeutics for the treatment of rare diseases; Cardio-Metabolic Disease, with a pipeline of RNAi therapeutics toward genetically validated, liver-expressed disease targets for unmet needs in cardiovascular and metabolic diseases; and Hepatic Infectious Disease, with a pipeline of RNAi therapeutics that address the major global health challenges of hepatic infectious diseases. In early 2015, Alnylam launched its “Alnylam 2020” guidance for the advancement and commercialization of RNAi therapeutics as a whole new class of innovative medicines. Specifically, by the end of 2020, Alnylam expects to achieve a company profile with 3 marketed products, 10 RNAi therapeutic clinical programs – including 4 in late stages of development – across its 3 STArs. The company’s demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and Genzyme, a Sanofi company. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 200 peer-reviewed papers, including many in the world’s top scientific journals such as Nature, Nature Medicine, Nature Biotechnology, Cell, New England Journal of Medicine, and The Lancet. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information about Alnylam’s pipeline of investigational RNAi therapeutics, please visit www.alnylam.com.

Alnylam Forward-Looking Statements
Various statements in this release concerning Alnylam’s future expectations, plans and prospects, including without limitation, Alnylam’s views with respect to the potential for RNAi therapeutics, including patisiran for the treatment of transthyretin (TTR)-mediated amyloidosis (ATTR amyloidosis) in patients with familial amyloidotic polyneuropathy (FAP), and the potential implications of the 12-month Phase 2 OLE data for patisiran, expectations regarding the reporting of data from clinical studies, in particular the ongoing Phase 2 OLE clinical trial of patisiran, expectations regarding its STAr pipeline growth strategy, and its plans regarding commercialization of RNAi therapeutics, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including, without limitation, Alnylam’s ability to discover and develop novel drug candidates and delivery approaches, successfully demonstrate the efficacy and safety of its drug candidates, the pre-clinical and clinical results for its product candidates, which may not be replicated or continue to occur in other subjects or in additional studies or otherwise support further development of product candidates, actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials, obtaining, maintaining and protecting intellectual property, Alnylam’s ability to enforce its patents against infringers and defend its patent portfolio against challenges from third parties, obtaining regulatory approval for products, competition from others using technology similar to Alnylam’s and others developing products for similar uses, Alnylam’s ability to manage operating expenses, Alnylam’s ability to obtain additional funding to support its business activities and establish and maintain strategic business alliances and new business initiatives, Alnylam’s dependence on third parties for development, manufacture, marketing, sales and distribution of products, the outcome of litigation, and unexpected expenditures, as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam’s most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) and in other filings that Alnylam makes with the SEC. In addition, any forward-looking statements represent Alnylam’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation to update any forward-looking statements.