Alnylam and Collaborators Report First-Ever Evidence that Patisiran Reduces Pathogenic, Misfolded Transthyretin (TTR) Monomers and Oligomers in TTR-Mediated Amyloidosis (ATTR Amyloidosis) Patients with Familial Amyloidotic Polyneuropathy (FAP)

Sep 28,2015

- Patisiran, an Intravenously Administered Investigational RNAi Therapeutic Targeting TTR, Achieves an Approximately 90% Reduction in Misfolded Non-Native Conformations of TTR (NNTTR) as Measured in Serum -

- In Addition, Complete 12 Month Data (N=27) from Phase 2 Open-Label Extension (OLE) Study Show a Mean 3.1-Point Decrease in Neuropathy Impairment Score (mNIS+7) at 12 Months, Providing Continued Support for the Hypothesis that Patisiran has Potential to Halt Neuropathy Progression in ATTR Amyloidosis -

- Further, Patisiran Administration Associated with Highly Sustained and Robust Mean Maximum Reductions in Total Serum TTR of 91% for Over 18 Months and Found to be Generally Well Tolerated for out to 21 Months -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, and collaborators announced today new results from the company's ongoing Phase 2 open-label extension (OLE) study of patisiran, an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR amyloidosis) patients with familial amyloidotic polyneuropathy (FAP). In collaboration with investigators at The Scripps Research Institute and Misfolding Diagnostics, Inc., patisiran administration was shown to reduce pathogenic, misfolded TTR monomers and oligomers in FAP patients in the Phase 2 OLE study. Specifically, patisiran administration resulted in a rapid and sustained reduction of approximately 90% in serum non-native conformations of TTR (NNTTR). Since NNTTR is pathogenic in ATTR amyloidosis, these results provide direct mechanistic evidence supporting the therapeutic hypothesis that TTR knockdown has the potential to result in clinical benefit. In addition, Alnylam presented complete 12-month data from all 27 patients initially enrolled in the patisiran OLE study, showing a mean 3.1-point decrease in the modified Neuropathy Impairment Score (mNIS+7) at 12 months as well as sustained mean maximum reductions in total serum TTR of 91% for over 18 months. Moreover, patisiran administration was found to be generally well tolerated out to 21 months of treatment.

"In ATTR amyloidosis, mutations in TTR lead to generation of misfolded TTR monomers and oligomers that convert to amyloid deposits in tissues such as the nerves, gut, and heart. This process of amyloidogenesis ultimately causes damage to these organs. Accordingly, misfolded NNTTR conformations correlate with the pathophysiological root cause of ATTR amyloidosis, and reduction of these non-native conformations is a necessary step in achieving disease modifying therapies," said Jeffery Kelly, Ph.D., Lita Annenberg Hazen Professor of Chemistry and Chairman, Department of Molecular and Experimental Medicine at The Scripps Research Institute.

"These new results are the first to document an effect of an RNAi therapeutic toward NNTTR, providing key support for the therapeutic hypothesis that TTR knockdown has the potential to result in clinical benefit. Indeed, the over 90% lowering of NNTTR, both in the absence and presence of TTR stabilizers, is an important result, and these findings support the potential of RNAi therapeutics for the treatment of ATTR amyloidosis," said Xin Jiang, Ph.D., Chief Scientific Officer, Misfolding Diagnostics, Inc.

"We are indeed encouraged by these new data showing robust patisiran knockdown of misfolded TTR monomers and oligomers that are known to be pathogenic in ATTR. Moreover, our now complete 12-month data from our ongoing Phase 2 OLE study provide continued support for our hypothesis that patisiran has the potential to halt neuropathy progression in patients with FAP. Specifically, we believe the 3.1-point mean decrease in the mNIS+7 score at 12 months is a promising result in light of analysis of multiple historical data sets that would have predicted an increase of 13 to 18 points for untreated FAP patients with similar baseline characteristics. It will be of great interest to see how these data mature going forward, and we plan to share initial 18-month OLE results in early November," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer of Alnylam. "In addition, continued patisiran administration has resulted in sustained mean maximum total TTR knockdown of 91% for over 18 months. Patisiran has also exhibited a favorable tolerability profile out to 21 months, with no drug-related discontinuations to date with 26 patients remaining on study. We continue to treat patients in our OLE study, and are actively enrolling FAP patients around the world in our APOLLO Phase 3 study, where we aim to obtain definitive evidence for patisiran efficacy and safety to support our planned applications for marketing authorization."

Alnylam's ongoing Phase 2 OLE study is an open-label, multi-center trial designed to evaluate the long-term safety and tolerability of patisiran administration in FAP patients 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 ongoing Phase 3 APOLLO trial of patisiran in FAP patients.

In a poster presented at the American Neurological Association (ANA) 2015 Annual Meeting being held September 27 - 29 in Chicago, Alnylam scientists and collaborators from The Scripps Research Institute and Misfolding Diagnostics, Inc., presented the first-ever evidence that patisiran administration reduces pathogenic, misfolded TTR monomers and oligomers in FAP patients. NNTTR was measured using a proprietary sandwich ELISA assay, developed by Misfolding Diagnostics, that specifically recognizes misfolded TTR protein. An approximately 90% reduction in NNTTR was achieved, which was sustained out to Day 248, the full treatment duration during which NNTTR levels were analyzed. Further, the level of NNTTR reduction correlated with total TTR knockdown. The observed reduction in NNTTR provides a mechanistic link between TTR knockdown and potential clinical benefit in patients.

In a separate poster at the ANA meeting, Alnylam presented complete 12-month results from all 27 patients initially enrolled in the patisiran Phase 2 OLE study. All reported results are from data in the database as of July 15, 2015. New study findings showed a mean decrease in mNIS+7 of 3.1 points at 12 months, which compares favorably to an estimated increase in mNIS+7 of 13 to 18 points at 12 months based upon analysis of 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: 2658-67, 2013; Tafamidis European Medicines Agency Assessment Report, 2011). Previously, the company reported a mean 2.5 point decrease in mNIS+7 at 12 months based on initial results in 20 patients. The effects on mNIS+7 were similar in patients with or without concurrent use of TTR tetramer stabilizers. A number of additional exploratory clinical measures are also being assessed in the OLE study. Updated results (N=27) presented at the ANA meeting showed that these clinical measures remain largely unchanged over the 12-month evaluation period. Finally, repeat dosing with patisiran achieved sustained mean maximum TTR knockdown of 91% for over 18 months, with an up to 96.2% maximal level of TTR knockdown observed in between doses. A similar degree of TTR knockdown was observed in patients with or without concurrent use of TTR tetramer stabilizers.

Patisiran administration was also found to be generally well tolerated in FAP patients, with minimal drug-related adverse events reported for a period of up to 21 months. As of the time of the current data cutoff on July 15, 2015, 669 doses had been administered with a median of 25 doses per patient. Mean treatment duration was approximately 17 months, and the longest treatment duration was out to 21 months. There were no drug-related serious adverse events. One subject has discontinued the Phase 2 OLE study due to development of gastroesophageal cancer, unrelated to study drug, and has subsequently died; a total of 26 patients remain on study. The most common drug-related or possibly drug-related adverse events were flushing (22.2%) and infusion-related reactions (18.5%), which were both mild in severity and did not result in any discontinuations. There were no clinically significant, drug-related changes in liver function tests, renal function tests, or other laboratory or hematologic parameters.

Genzyme Alliance

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 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 Genzyme will advance the product in the ROW.

About Transthyretin-Mediated Amyloidosis

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 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 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

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 TTR-mediated amyloidosis in patients with familial amyloidotic polyneuropathy, and the potential implications of the complete 12-month Phase 2 OLE data for patisiran and the first-ever data demonstrating the reduction in misfolded non-native conformations of TTR as measured in serum, expectations regarding the reporting of data from clinical studies, in particular the ongoing Phase 2 OLE clinical trial of patisiran, expectations regarding its STAr pipeline growth strategy, and its plans regarding commercialization of RNAi therapeutics, including patisiran, 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.
Michael Mason, 617-551-8327
Vice President, Finance and Treasurer
Liz Bryan, 202-955-6222 x2526

Source: Alnylam Pharmaceuticals, Inc.

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