Alnylam

Alnylam Completes Enrollment in APOLLO Phase 3 Study with Patisiran, an Investigational RNAi Therapeutic for Patients with Transthyretin (TTR)-Mediated Amyloidosis (ATTR Amyloidosis)

02.01.2016

- Company Remains on Track to File New Drug Application in 2017 without Interim Analysis for Efficacy -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), the leading RNAi therapeutics company, today announced that it has completed enrollment - with well over 200 patients accrued - in its APOLLO Phase 3 study with patisiran, an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR amyloidosis) in patients with familial amyloidotic polyneuropathy (FAP). The Company also reiterated its previous guidance that it expects to report data from the APOLLO study in 2017, and due to the competitiveness of this timing, it is not planning to perform an interim analysis for efficacy. If APOLLO is positive, the Company expects to submit a New Drug Application (NDA) and Marketing Authorisation Application (MAA) for patisiran, based on an analysis of the full APOLLO data set, in late 2017.

ATTR amyloidosis is an inherited, progressive, and life-threatening orphan disease affecting approximately 50,000 patients worldwide, including approximately 10,000 persons with FAP. Halting disease progression remains the primary treatment goal and represents a significant unmet need.

"ATTR amyloidosis, including FAP, is a generally fatal, orphan disease with limited treatment options. We believe data reported to date in our clinical studies provide encouraging preliminary evidence for patisiran's clinical activity and tolerability, while definitive evidence to support registration awaits results from our randomized, placebo-controlled study. Accordingly, we're excited to have rapidly completed enrollment in our APOLLO Phase 3 study," said Eric Green, Vice President, General Manager, TTR Program. "We're also pleased to see the strong patient interest in patisiran, with APOLLO significantly over-enrolled. Regarding our decision to forego an interim analysis for efficacy, our timely and highly competitive completion of APOLLO enrollment supports our continued plan to file an NDA and MAA with a full and comprehensive analysis of primary and secondary endpoint data in 2017, if the study is positive."

The APOLLO Phase 3 trial is a randomized, double-blind, placebo-controlled, global study designed to evaluate the efficacy and safety of patisiran in patients with FAP. The primary endpoint of the study is the difference in the change in a modified neuropathy impairment score, "mNIS+7," from baseline to 18 months between patisiran and placebo. mNIS+7 measures disease progression including muscle weakness, impaired reflexes, and changes in other sensory measures. Secondary study endpoints include: the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) score; modified body mass index (mBMI); timed 10-meter walk; an autonomic symptom score called "COMPASS-31," amongst other endpoints. In addition, nerve regeneration by measurement of sweat gland nerve fiber density will be assessed in patients who elected to provide skin punch biopsy samples. The study was significantly over-enrolled with a total of 225 FAP patients with Stage 1 or Stage 2 disease, compared to the original anticipated enrollment of 200. Patients were randomized 2:1 (patisiran:placebo) with patisiran administered at 0.30 mg/kg once every three weeks for 18 months. The study was designed with 90% power to conservatively detect as little as a 37.5% difference in change in mNIS+7 between treatment groups, with a two-sided alpha of 0.05. The expected placebo mNIS+7 progression rate of 24 points over 18 months was derived from an analysis of natural history data from 283 FAP patients (Adams et al., Neurology, 2015;85:675-682). All patients completing the APOLLO Phase 3 study are eligible to enroll in the ongoing APOLLO Phase 3 open-label extension (OLE) study (APOLLO-OLE).

In an ongoing Phase 2 OLE study of patisiran in FAP patients (N=27) with similar baseline characteristics, patisiran administration was associated with a mean increase in mNIS+7 of just 1.7 points over 18 months in the 20 patients that had reached that timepoint as of the data cutoff. The ongoing Phase 2 OLE study has provided initial evidence that patisiran has the potential to halt neuropathy progression in FAP patients, including the first-ever evidence for positive effects on nerve regeneration. Patisiran administration was also found to be generally well tolerated in FAP patients out to nearly two years, with minimal drug-related adverse events reported.

To view these Phase 2 OLE data with patisiran, visit www.alnylam.com/capella.

About Transthyretin-Mediated Amyloidosis

Transthyretin (TTR)-mediated amyloidosis (ATTR amyloidosis) is an inherited, progressively debilitating, and life-threatening 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 in multiple organs, but primarily in the peripheral nerves and heart, resulting in sensory, motor, and autonomic dysfunction, resulting in significant disability and death. ATTR amyloidosis 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 five to 15 years from symptom onset, and the only approved treatment options for early stage disease are liver transplantation and tafamidis (approved in Europe, Japan and certain countries in Latin America). FAC is fatal within two to five 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 amyloidosis.

Sanofi Genzyme Alliance

In January 2014, Alnylam and Sanofi Genzyme, the specialty care global business unit of Sanofi, 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 Sanofi 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 for certain programs. In the case of patisiran, Alnylam will advance the product in North America and Western Europe, while Sanofi Genzyme will advance the product in the ROW.

About LNP Technology

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

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 Sanofi Genzyme. 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, expectations regarding the reporting of clinical data from its ongoing patisiran clinical trials, its expectations regarding the timing for filing an NDA and MAA for patisiran, 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 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 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.

Alnylam Pharmaceuticals, Inc.
Investors and Media:
Christine Regan Lindenboom, 617-682-4340
or
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Source: Alnylam Pharmaceuticals, Inc.

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