Alnylam Reports Six-Month Clinical Data from Patisiran Phase 2 Open-Label Extension (OLE) Study in Patients with Familial Amyloidotic Polyneuropathy (FAP)

CAMBRIDGE, Mass.--Alnylam Pharmaceuticals, Inc. (ALNY), a leading RNAi therapeutics company, announced today six-month clinical data from its ongoing Phase 2 open-label extension (OLE) study with patisiran (ALN-TTR02), an investigational RNAi therapeutic in development for the treatment of transthyretin (TTR)-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP). These data are being presented at the American Neurological Association's 2014 Annual Meeting being held October 12 – 14 in Baltimore. Results showed a mean 0.95 point decrease in modified Neuropathy Impairment Score (mNIS+7) at six months in 19 patients with mNIS+7 data available for the current analysis. This decrease in neuropathy progression compares favorably with the 7 to 10 point increase in mNIS+7 at six months that can be estimated from 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: 26588-67, 2013; Tafamidis European Medicines Agency Assessment Report, 2011). In addition, patisiran treatment achieved a sustained mean serum TTR knockdown at the 80% target level for over nine months, with an up to 89.6% knockdown achieved between doses. Patisiran was found to be generally well tolerated in this study out to one year of therapy, with no drug-related serious adverse events to date, and all 27 patients enrolled in the study continue to receive drug treatment.

"In this open-label study with patisiran, we are very encouraged to see what we believe to be evidence for possible stabilization of neuropathy progression after the first six months of treatment. Indeed, we believe the approximate one point decrease in neuropathy impairment score is an encouraging result in light of multiple historical data sets that would have predicted an increase of 7 to 10 points for untreated patients with similar baseline characteristics. These data will be increasingly meaningful as we monitor neuropathy progression in patisiran-treated patients over time, and we look forward to sharing those results at least once annually hereafter," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. "In addition, patisiran treatment showed robust knockdown of serum TTR of up to 90% for over nine months, and was associated with a favorable tolerability profile out to one year of treatment. We believe the potent, rapid, and durable knockdown of TTR achieved by patisiran could be important since TTR protein reduction in patients with ATTR may have the potential to delay or even reverse disease progression with associated clinical benefit. We will continue to treat patients on our OLE study, and are enrolling FAP patients in our APOLLO Phase 3 study in sites around the world."

Alnylam's ongoing OLE study is treating patients that were previously enrolled in a Phase 2 study of patisiran in ATTR patients with FAP. The OLE study is an open-label, multi-center trial designed to evaluate the long-term safety and tolerability of patisiran administration. The two-year study has completed enrollment with 27 patients who receive 0.3 mg/kg of patisiran once every three weeks. This study is also 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 mNIS+7 measurement is the primary endpoint in the company's Phase 3 APOLLO trial of patisiran in FAP patients. A number of additional clinical measures are also being assessed, 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; and nerve fiber density in skin biopsies. Patients with cardiac abnormalities at baseline comprise a cardiac subgroup (N=11) where cardiac biomarkers (NT-proBNP and troponin I) and echocardiographic parameters are measured at baseline and every three to six months. In addition, serum TTR levels are being measured throughout the study.

The initial results from the ongoing open-label study showed that after six months of treatment with patisiran, neuropathy impairment scores were essentially unchanged from baseline values. As noted above, there was a mean decrease in mNIS+7 of 0.95 points (N=19), which compares favorably to the rapid increase in mNIS+7 of 7 to 10 points estimated at six months from historical data sets in untreated FAP patients with similar baseline characteristics. Similar results were observed for the change in Neuropathy Impairment Score (NIS), where there was a mean increase of 0.22 points at six months (N=20). The stabilization in mNIS+7 was similar in patients with or without concurrent use of TTR tetramer stabilizers. In addition, no significant evidence for disease worsening was observed in measurements of QOL, 10MWT, mBMI, R-ODS, and nerve fiber density, amongst other clinical assessments performed. In the cardiac subgroup, there were no significant changes in cardiac biomarkers (N=5) or in echocardiographic parameters (N=7) after six months of dosing. Finally, repeat dosing of patisiran achieved sustained TTR knockdown at the 80% target level for over nine months, and an up to 89.6% level of TTR knockdown was achieved in post-dose measurements. A similar degree of TTR knockdown was observed in patients with or without concurrent use of TTR tetramer stabilizers.

"These preliminary clinical activity and safety data from Alnylam's OLE study with patisiran are quite encouraging. In particular, the stabilization in neuropathy impairment scores at six months may have important implications 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 treating patients on the ongoing Phase 2 OLE study and enrolling patients onto the APOLLO Phase 3 study, as there are currently few options for our patients suffering from FAP."

Patisiran administration was found to be generally well tolerated in FAP patients (N=27), with minimal adverse events reported for a period of up to one year. As of the time of the data cutoff on September 8, 2014, 282 doses had been administered with a median of 11 doses per patient. Mean treatment duration was seven months and the longest treatment duration was out to one year. There were no drug-related serious adverse events. Infusion-related reactions were infrequent (14.8%), mild in severity, and did not result in any discontinuations. All other reported adverse events were mild to moderate, and there were no clinically significant changes in liver function tests, renal function tests, or other laboratory or hematological parameters.

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 Monday, October 13 at 8:00 a.m. ET. A slide presentation will also be available on the News & Investors page of the company's website,, 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 19356541. A replay of the call will be available beginning at 11:00 a.m. ET. To access the replay, please dial 855-859-2056 (domestic) or 404-537-3406 (international), and refer to conference ID 19356541.

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 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); 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; 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 ALN-TTRsc 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

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 FAP, its expectations regarding its "Alnylam 5x15" product strategy, its expectations with respect to the design, timing, and success of its clinical trials, including its Phase 3 APOLLO study, its expectations regarding the reporting of data from its clinical trials and the potential implications of early clinical data reported, 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.

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