Alnylam Initiates Dosing in PNH Patients in Phase 1/2 Clinical Trial for ALN-CC5

CAMBRIDGE, Mass.--(BUSINESS WIRE)--

Alnylam Pharmaceuticals, Inc. ALNY, the leading RNAi therapeutics company, today announced that it initiated the final phase (Part C) of its Phase 1/2 clinical trial with ALN-CC5, a subcutaneously administered investigational RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases. Part C, which is being conducted in patients with paroxysmal nocturnal hemoglobinuria (PNH), will evaluate the safety and tolerability of multiple doses of ALN-CC5 as well as measures of its clinical activity, including knockdown of serum C5 levels, levels of residual C5, inhibition of serum hemolytic activity, and reduction of lactate dehydrogenase (LDH), a measure of red blood cell hemolysis. The Company expects to report initial PNH patient data from this ongoing clinical study of ALN-CC5 in mid-2016 and initiate Phase 3 studies in 2017.

"Based on encouraging data recently presented at ASH, we've now advanced ALN-CC5 into patients with PNH, where clinical activity can be measured toward LDH, a key disease biomarker. If successful in lowering LDH levels, we believe that ALN-CC5 could emerge as a differentiated approach to address the continued unmet needs that exist for patients with PNH and other complement mediated diseases," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. "We look forward to the continued clinical advancement of ALN-CC5 and expect to report initial PNH patient data in mid-2016 ahead of an anticipated 2017 Phase 3 start."

Clinical data from the ongoing Phase 1/2 study were presented recently at the American Society of Hematology (ASH) 2015 Annual Meeting, held December 5 – 8 in Orlando, Florida. Results presented were from both the single-ascending dose (SAD) and multiple-ascending dose (MAD) parts of the ongoing study in healthy adult volunteers, showing that:

• ALN-CC5 achieved up to 99 percent knockdown of serum C5 and up to 98 percent inhibition of serum sheep red blood cell hemolytic activity, an assay for complement activity;
• ALN-CC5 administration resulted in low levels of residual C5, which – based on comparisons from separate studies – were at or below the estimated levels of free C5 observed at therapeutic doses of eculizumab, an approved anti-C5 monoclonal antibody;
• The effects of ALN-CC5 were found to be highly durable, with C5 knockdown and complement inhibition results supporting a once monthly and possibly a once quarterly subcutaneous dose regimen; and
• Importantly, ALN-CC5 was shown to be generally well tolerated, with no clinically significant, drug-related adverse events to date.

ALN-CC5 Phase 1/2 Study Design
The ongoing Phase 1/2 trial of ALN-CC5 is being conducted in three parts. Parts A and B are randomized (3:1, drug:placebo), double-blind, placebo-controlled, SAD and MAD studies, respectively, which enrolled up to a total of 60 healthy adult volunteers. These parts of the study were designed to evaluate safety and tolerability of single and multiple subcutaneous doses of ALN-CC5. Additional objectives include clinical activity as measured by knockdown of serum C5 and levels of residual C5, and by effects on inhibition of serum complement activity, including measurements of CAP and CCP activity, as well as serum sheep red blood cell hemolytic activity. A total of 5 SAD cohorts were enrolled in the study, with fixed doses ranging from 50 to 900 mg. A total of 3 MAD cohorts have been enrolled in the study with fixed doses of 100, 200 or 400 mg, where healthy adult volunteers are receiving once weekly, subcutaneous doses of ALN-CC5 or placebo for 5 weeks. Part C is an open-label, multi-dose study in approximately 16 patients with PNH, to assess safety, tolerability, and clinical activity of ALN-CC5, administered for up to 13 weeks. This part of the study will include an exploratory evaluation of ALN-CC5 effects on levels of LDH, a measure of endogenous red blood cell hemolysis.

About ALN-CC5
ALN-CC5 is an investigational RNAi therapeutic targeting the C5 component of the complement pathway, currently in early stage clinical development for the treatment of complement-mediated diseases. The safety and efficacy of ALN-CC5 have not been evaluated by the U.S. Food and Drug Administration or any other health authority. The complement system plays a central role in immunity as a protective mechanism for host defense, but its dysregulation results in life-threatening complications in a broad range of human diseases including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic-uremic syndrome (aHUS), myasthenia gravis, neuromyelitis optica, membranous nephropathy, amongst others. Complement component C5, which is predominantly expressed in liver cells, is a genetically and clinically validated target; loss of function human mutations are associated with an attenuated immune response against certain infections and intravenous anti-C5 monoclonal antibody (mAb) therapy has demonstrated clinical activity and tolerability in a number of complement-mediated diseases. A subcutaneously administered RNAi therapeutic that silences C5 represents a novel approach to the treatment of complement-mediated diseases. ALN-CC5 utilizes Alnylam's ESC-GalNAc conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index.

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, including ALN-CC5, in the rest of the world. In certain defined instances, Genzyme has co-development/co-commercialization and/or global product rights. Genzyme's rights are structured as an opt-in that is triggered upon achievement of human proof-of-principle.

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 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 ALN-CC5, expectations regarding the timing of clinical trials with ALN-CC5, including the expected initiation of a Phase 3 trial in 2017, and the reporting of clinical data from these trials, including the expected reporting of additional data from its ongoing Phase 1/2 trial in mid-2016, 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.

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