Alnylam Pharmaceuticals Completes Phase 2 Enrollment And Initiates Open-Label Extension (OLE) Study With Revusiran (ALN-TTRsc), An Investigational Rnai Therapeutic Targeting Transthyretin (TTR) For The Treatment Of TTR Cardiac Amyloidosis

– Company Plans to Present Initial Phase 2 Results at Meeting in November –

– On Track to Initiate Phase 3 Trial by Year End Following Successful Completion of Regulatory Discussions in U.S. and EU –


CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it has completed enrollment in its Phase 2 clinical trial with revusiran (re-VOO-si-ran), the recommended International Nonproprietary Name (INN) for ALN-TTRsc. Revusiran is an investigational RNAi therapeutic targeting wild-type and all mutant forms of transthyretin (TTR) and utilizes Alnylam’s proprietary GalNAc-conjugate delivery platform that enables subcutaneous delivery of RNAi therapeutics with a wide therapeutic index. The pilot Phase 2 study enrolled 26 patients with TTR cardiac amyloidosis, who received revusiran for a five week course of treatment. The company also announced today that its open-label extension (OLE) study with revusiran is now open for enrollment for patients who participated previously in the Phase 2 clinical trial. The Phase 2 OLE study will evaluate the safety and tolerability of long-term dosing with revusiran for up to two years, and will also measure effects of treatment on clinical endpoints, including mortality, hospitalization, and 6-minute walk distance (6-MWD), in addition to cardiac amyloid burden and function, and cardiac biomarkers. The company intends to report clinical data from this study about once per year, with initial data expected in 2015. Finally, Alnylam is also announcing today that it has completed its discussions with regulatory authorities in the U.S. and EU regarding the design of a Phase 3 study for revusiran in TTR cardiac amyloidosis patients; the company remains on track to initiate the study before year’s end.

“We believe that revusiran has the potential to be an important therapeutic option for the treatment of TTR cardiac amyloidosis – a disease with significant morbidity and mortality, and no approved therapies. Our Phase 1 clinical study demonstrated robust knockdown of circulating TTR – the disease-causing gene – of up to 96%, and was generally well tolerated,” said Jared Gollob, M.D., Vice President, Clinical Research of Alnylam. “We have now completed enrollment in our pilot Phase 2 study in 26 TTR cardiac amyloidosis patients, where revusiran was administered over a five-week period, and we look forward to presenting these initial results in the coming weeks. With the start of our Phase 2 OLE study, we are pleased to be able to provide patients the opportunity to continue receiving revusiran. We believe that longer term treatment with revusiran in the OLE study will provide important data on tolerability with chronic dosing and could provide potential evidence for clinical activity. We plan on presenting data from the OLE study at least once annually starting in 2015. Finally, we are pleased to have completed our discussions with U.S. and EU regulatory authorities on the design of our Phase 3 study, and are on track to initiate the study before year’s end.”

TTR-mediated amyloidosis (ATTR) is an inherited, progressively debilitating, and often fatal disease caused by mutations in the TTR gene. These mutations cause misfolding of the protein and the formation of amyloid fibrils that deposit in tissues. One of the clinical manifestations of ATTR is familial amyloidotic cardiomyopathy (FAC), in which TTR amyloid deposition in the heart leads to cardiac wall thickening and heart failure. In addition, wild-type TTR can accumulate as amyloid deposits in the heart of elderly people in a disease known as senile systemic amyloidosis (SSA). FAC and SSA are fatal within 2.5 to 5 years of diagnosis and treatment is currently limited to supportive care.

The pilot Phase 2 study was aimed at evaluating the safety, tolerability, pharmacodynamic and preliminary clinical activity of revusiran in patients with FAC and SSA. This trial was conducted as an open-label, multi-dose study, and completed enrollment with 26 patients, including 14 diagnosed with FAC and 12 with SSA. Revusiran was administered initially as daily subcutaneous doses for five days and then once weekly at doses of 5 mg/kg or 7.5 mg/kg over a period of five weeks for a total of 10 doses. The primary objective of the study was to evaluate the safety and tolerability of revusiran. The secondary objectives were to assess the pharmacodynamic effect on serum levels of TTR and characterize the pharmacokinetic profile. In addition, exploratory clinical endpoint data were collected at baseline and days 42 and 90 after start of dosing; this includes 6-MWD, echocardiogram and cardiac MRI to assess cardiac amyloid burden and function, circulating cardiac biomarkers including NT-proBNP and troponin to assess heart wall stress and injury, and questionnaires to assess cardiomyopathy symptoms and quality of life. Alnylam expects to present initial results from the Phase 2 study at a meeting to be held during the American Heart Association meeting in November.

The company has now initiated its Phase 2 OLE study of revusiran. All patients that completed dosing in the Phase 2 trial are eligible to be enrolled in the OLE study. Revusiran will be administered at a fixed subcutaneous dose of 500 mg, with once-daily dosing for the first five days followed by weekly dosing thereafter. The study is designed to evaluate the tolerability and clinical activity of revusiran with long-term dosing for up to two years. In addition to data on mortality, hospitalization, general tolerability, and measurement of serum TTR levels, the study will assess every six months the same clinical measures included in the pilot Phase 2 trial noted above as well as additional measures of amyloid burden including technetium imaging of the heart and quantitation of amyloid in abdominal fat pad aspirates. The company expects to present results from the revusiran Phase 2 OLE study at least once annually starting in 2015.

Finally, Alnylam has now completed its meetings with regulatory authorities from the U.S. and EU regarding the design of a Phase 3 trial for revusiran in TTR cardiac amyloidosis. Specifically, the company completed an End-of-Phase 2 meeting with the U.S. Food and Drug Administration (FDA) and received scientific advice from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). Alnylam will provide details of the Phase 3 design upon initiation of the study, which is expected by the end of this year.

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. In the case of revusiran, Alnylam and Genzyme are co-developing and co-commercializing the investigational RNAi therapeutic in North America and Western Europe, while Genzyme is developing and commercializing revusiran in the rest of world.

About ATTR
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 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 with a core focus on RNAi therapeutics as genetic medicines, including programs as part of the company’s “Alnylam 5x15™” product strategy. Alnylam’s genetic medicine programs are RNAi therapeutics directed toward genetically defined targets for the treatment of serious, life-threatening diseases with limited treatment options for patients and their caregivers. These include: patisiran (ALN-TTR02), an intravenously delivered RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); revusiran (ALN-TTRsc), a subcutaneously delivered RNAi therapeutic targeting TTR for the treatment of ATTR in patients with TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting aminolevulinic acid synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease; ALN-HBV, an RNAi therapeutic targeting the hepatitis B virus (HBV) genome for the treatment of HBV infection; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3, an RNAi therapeutic targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia; ALN-AGT, an RNAi therapeutic targeting angiotensinogen (AGT) for the treatment of hypertensive disorders of pregnancy (HDP), including preeclampsia; ALN-GO1, an RNAi therapeutic targeting glycolate oxidase (GO) for the treatment of primary hyperoxaluria type 1 (PH1); and other programs yet to be disclosed. As part of its “Alnylam 5x15” strategy, as updated in early 2014, the company expects to have six to seven genetic medicine product candidates in clinical development – including at least two programs in Phase 3 and five to six programs with human proof of concept – by the end of 2015. The company’s demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, and The Medicines Company. In early 2014, Alnylam and Genzyme, a Sanofi company, formed a multi-product geographic alliance on Alnylam's genetic medicine programs in the rare disease field. Specifically, Alnylam will lead development and commercialization of programs in North America and Europe, while Genzyme will develop and commercialize products in the rest of world. In addition, Alnylam and Genzyme will co-develop and co-commercialize revusiran in North America and Europe. In March 2014, Alnylam acquired Sirna Therapeutics, a wholly owned subsidiary of Merck. 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, 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 (ALN-TTRsc) for the treatment of FAC, its expectations with respect to timing of regulatory filings and the reporting of initial data from a clinical trial for revusiran and the start of a Phase 3 trial, the potential therapeutic opportunities for revusiran, as well as its expectations regarding its “Alnylam 5x15” product 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 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.

Contacts

Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
Vice President, Investor Relations and Corporate Communications
or
Media
Spectrum
Liz Bryan, 202-955-6222 x2526

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