Alnylam Receives Orphan Drug Designation from the United States Food & Drug Administration for Revusiran, an Investigational RNAi Therapeutic for the Treatment of Transthyretin (TTR)-Mediated Amyloidosis (ATTR Amyloidosis)

May 20, 2015

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics company, announced today that the United States Food & Drug Administration (FDA) has granted Orphan Drug Designation to revusiran, an investigational RNAi therapeutic, for the treatment of transthyretin (TTR)-mediated amyloidosis (ATTR amyloidosis). Revusiran is currently in Phase 3 development for the treatment of Familial Amyloidotic Cardiomyopathy (FAC), one of the predominant clinical manifestations of ATTR amyloidosis.

"We are very pleased to have received Orphan Drug Designation from the FDA for revusiran, a key program in our Genetic Medicines pipeline. We believe RNAi therapeutics represent a promising new approach for the treatment of ATTR amyloidosis, with the potential to make a meaningful impact for patients with this progressive and debilitating disease," said Saraswathy (Sara) Nochur, Ph.D., Senior Vice President, Regulatory Affairs and Quality Assurance at Alnylam. "We look forward to the continued advancement of revusiran, including enrollment in our ENDEAVOUR Phase 3 trial in ATTR amyloidosis patients with FAC. In addition, we continue dosing TTR cardiac amyloidosis patients in our Phase 2 open-label extension study with revusiran, and plan to present initial data from that study in late 2015."

Revusiran is currently enrolling FAC patients in the ENDEAVOUR Phase 3 trial, a randomized, double-blind, placebo-controlled, global study designed to evaluate the efficacy and safety of revusiran in patients with FAC. The co-primary endpoints of the study are the change compared to baseline in 6-minute walk distance (6-MWD) and the percent reduction in serum TTR between placebo- and revusiran-treated patients at 18 months. Secondary endpoints include a composite endpoint of cardiovascular mortality and cardiovascular hospitalization, New York Heart Association (NYHA) class, Kansas City Cardiomyopathy Questionnaire (KCCQ), CV mortality, CV hospitalization and all-cause mortality. The trial is designed to enroll up to 200 FAC patients with a documented TTR mutation, including V122I or other mutations, in addition to amyloid deposits as identified by biopsy. Patients are being randomized 2:1, revusiran:placebo, with revusiran administered subcutaneously at 500 mg daily for five days then weekly for 18 months. The trial design was informed by natural history data which showed a mean decline of 140 meters in 6MWD over an 18-month period in FAC patients with mild-to-moderate heart failure. The ENDEAVOUR study was designed with 90% power to detect as little as a 39% difference in the 18-month change from baseline for 6-MWD between treatment groups, with a significance level of p < 0.05. An unblinded interim analysis for futility may be conducted when 50% of patients reach 18 months. All patients completing the ENDEAVOUR Phase 3 study will be eligible to enroll in a Phase 3 open-label extension (OLE) study.

The FDA Office of Orphan Products Development (OOPD) mission is to advance the evaluation and development of products that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions. The Orphan Drug Act provides incentives for sponsors to develop products for rare diseases. The Orphan Drug Designation program provides orphan status to drugs and biologics which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S.

In April 2014, the European Medicines Agency (EMA) Committee for Orphan Medicinal Products (COMP) adopted a positive opinion recommending revusiran for designation as an orphan medicinal product for the treatment of ATTR amyloidosis.

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 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 revusiran, Alnylam and Genzyme will co-develop/co-commercialize the product in North America and Western Europe, while Genzyme will advance the product in the ROW.

About ATTR

Transthyretin (TTR)-mediated amyloidosis (ATTR amyloidosis) 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 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 revusiran for the treatment of FAC, its expectations with respect to the design, timing, and success of its clinical trials, including with revusiran, its expectations regarding the presentation of data from clinical trials with revusiran, its expectations regarding the potential market opportunity for revusiran, its 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 manage operating expenses, 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 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 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 Quarterly Report on Form 10-Q 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.

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