Alnylam Reports Complete 18-Month Data from Ongoing Phase 2 Open-Label Extension Study of Patisiran, an Investigational RNAi Therapeutic Targeting Transthyretin for the Treatment of Hereditary ATTR Amyloidosis with Polyneuropathy (hATTR-PN)

Apr 20,2016

- Patisiran Achieves a Mean 0.8 Point Decrease in Modified Neuropathy Impairment Score (mNIS+7) at 18 Months, Showing Continued Evidence of Potential Halting of Neuropathy Progression -

- Company Reports First-Ever Clinical Correlative Evidence that the Degree of TTR Knockdown May Be Associated with Improvement in mNIS+7 -

- Company to Host Conference Call Today, Wednesday, April 20, at 8:30 am ET to Discuss Results -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today complete 18-month data from its ongoing Phase 2 open-label extension (OLE) study with patisiran, an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN), also known as familial amyloidotic polyneuropathy (FAP). These new clinical data are being presented in an oral talk at the 68th Annual Meeting of the American Academy of Neurology (AAN) being held April 15 - 21, 2016 in Vancouver, British Columbia, Canada. Complete 18-month data (N=27) from the study provide continued evidence that patisiran has the potential to halt neuropathy progression in patients with hATTR-PN. In the first reported exploratory analysis of its kind, the degree of TTR knockdown observed in patients was shown to correlate with improvement in neuropathy impairment scores. Further, in this Phase 2 OLE trial, patisiran was found to be generally well tolerated with up to 25 months of treatment. Dosing continues in the patisiran Phase 2 OLE study, and the Company plans to report initial 24-month data from the trial in mid-2016.

"We are pleased to see continued evidence for potential halting of neuropathy progression after 18 months of treatment in the ongoing Phase 2 OLE study with patisiran. The mean 0.8-point decrease in mNIS+7 is an encouraging finding, as the change in mNIS+7 from baseline to 18 months is the primary endpoint in our ongoing APOLLO Phase 3 trial with patisiran. Furthermore, the safety profile of patisiran, with up to 25 months of treatment, continues to be encouraging," said Eric Green, Vice President, General Manager, TTR Program. "In addition, we are excited to share data from an exploratory analysis showing statistically significant correlations between the degree of TTR knockdown and improvements in mNIS+7. Taken together, we believe the data from this ongoing Phase 2 OLE study further support patisiran's potential as an innovative medicine for hATTR-PN, a progressive, debilitating disease with few treatment options. We look forward to the continued advancement of patisiran, including the expected readout of our ongoing APOLLO Phase 3 trial in mid-2017."

New results presented at the AAN meeting were as of a data cut off of February 23, 2016, and showed that mean neuropathy impairment scores were essentially unchanged from baseline values after 18 months of treatment. Specifically, there was a mean decrease in mNIS+7 of 0.8 points, which compares favorably to an estimated mean increase in mNIS+7 of 22 to 26 points over 18 months based upon analysis of historical data sets in untreated hATTR-PN patients with similar baseline characteristics. Similar results were observed in patients with or without concurrent tetramer stabilizer use. In addition, patisiran administration was associated with a statistically significant, approximately 77% median improvement in nerve fiber density as read histologically in a blinded manner from distal thigh sweat gland biopsy samples (p less than 0.001). Over the 18 month period, patients with associated cardiomyopathy (N=11) showed stability in their echocardiographic, biomarker, and functional measures, including 10-meter-walk speed. Serum TTR levels were also measured throughout the OLE study, and showed sustained TTR knockdown for over 24 months with a mean maximal knockdown of 92% over the entire period and a mean post-dose knockdown of 87% at 18 months.

In addition, Alnylam also presented the results of an exploratory analysis examining the relationship between the degree of TTR knockdown with subsequent changes in mNIS+7. In the analysis, inter-subject differences in the degree of TTR knockdown were compared to changes in mNIS+7 at 6, 12, and 18 months to assess the effects of patisiran administration. There was a linear correlation between the degree of serum TTR knockdown and changes in mNIS+7. Specifically, greater degrees of TTR knockdown resulted in greater levels of mNIS+7 improvement; these results were significant at 6 and 12 months (p less than 0.01) and showed a trend at 18 months (p equal to 0.055). Importantly, this is the first reported evidence that correlates the degree of TTR knockdown with improvements in mNIS+7, supporting the therapeutic hypothesis that reduction of mutant and wild-type TTR may be associated with potential for a halting of neuropathy progression in patients with hATTR-PN.

Patisiran administration was also found to be generally well tolerated in hATTR-PN patients with 18 to up to 25 months of treatment. Of the most common adverse events reported in 10% or more of patients, the most frequent drug-related or possibly drug-related adverse events (AEs) were flushing (22.2%) and infusion-related reactions (18.5%), which were all mild in severity and did not result in any discontinuations. There were eight reports of serious adverse events (SAEs) in five patients, all of which were unrelated to study drug, including one discontinuation for gastroesophageal cancer at approximately 20 months in a patient who subsequently died. After the data cut-off date, an additional unrelated SAE of myocardial infarction was reported in a 79 year-old patient who subsequently died after having completed the full 24 months of treatment. Overall, there were no clinically significant changes in liver function tests, renal function, or hematologic parameters, including platelets.

To view the 18-month patisiran OLE study results, please visit

Conference Call Information
Alnylam management will discuss these data in a webcast conference call on Wednesday, April 20 at 8:30 a.m. ET. A slide presentation will also be available on the 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 92074780. A replay of the call will be available beginning at 10:30 a.m. ET. To access the replay, please dial 855-859-2056 (domestic) or 404-537-3406 (international), and refer to conference ID 92074780.

About the Patisiran Phase 2 OLE Study
The ongoing patisiran Phase 2 OLE study is an open-label, multi-center trial designed to evaluate the long-term safety and tolerability of patisiran administration in patients with hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN) 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 APOLLO Phase 3 trial of patisiran in patients with hATTR-PN.

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 hATTR
Hereditary transthyretin (TTR)-mediated amyloidosis (hATTR) 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. hATTR represents a major unmet medical need with significant morbidity and mortality; hATTR with polyneuropathy (hATTR-PN) - also known as familial amyloidotic polyneuropathy (FAP) - affects approximately 10,000 people worldwide and hATTR with cardiomyopathy (hATTR-CM) - also known as familial amyloidotic cardiomyopathy (FAC) - is estimated to affect at least 40,000 people worldwide. hATTR-PN 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, certain countries in Latin America and Japan, where it is approved for all stages of disease). hATTR-CM is fatal within 2.5 to 5 years of diagnosis and treatment is currently limited to supportive care. Wild-type amyloidosis (wtATTR) - also called 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 hATTR.

About LNP Technology
Alnylam has licenses to Arbutus Biopharma 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 Ionis, Novartis, Roche, Takeda, Merck, 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

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 the potential of patisiran to halt neuropathy progression in patients with hATTR-PN, expectations regarding the reporting of data from the ongoing Phase 2 open-label extension trial and APOLLO Phase 3 trial with 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 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.

Alnylam Pharmaceuticals, Inc.
Investors and Media
Christine Regan Lindenboom, 617-682-4340
Josh Brodsky, 617-551-8276

Source: Alnylam Pharmaceuticals, Inc.

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