Alnylam Initiates Phase 1/2 Clinical Trial for ALN-CC5, a Subcutaneously Administered RNAi Therapeutic Targeting Complement Component C5 in Development for the Treatment of Complement-Mediated Diseases


Company Expects to Present Initial Clinical Results in Mid-2015 with Additional Data in Late 2015

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics company, today announced that it has initiated a 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. The Phase 1/2 trial will be conducted in normal human volunteers, and then in patients with paroxysmal nocturnal hemoglobinuria (PNH). The company expects to present initial clinical data from this trial in mid-2015 with additional data expected in late 2015.

"As a first-in-class C5 synthesis inhibitor, we believe that ALN-CC5 represents an innovative, differentiated, and well-validated approach for the treatment of complement-mediated diseases. Our pre-clinical non-human primate data demonstrate the ability of ALN-CC5 to clamp down levels of serum C5, with knockdown of up to 99.2% and sustained effects with continuous dosing for over seven months. This level of knockdown was associated with a greater than 90% inhibition of hemolytic activity, exceeding the 80% threshold established by existing therapies to be associated with clinical benefit," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. "ALN-CC5 is now our fourth investigational RNAi therapeutic that utilizes our proprietary, clinically validated GalNAc conjugate delivery platform to enter clinical development, and the third that utilizes our optimized ESC-GalNAc technology. We look forward to the continued clinical advancement of ALN-CC5, and expect to present initial clinical data in mid-2015, with additional data expected in late 2015."

"Although significant progress has been made in the treatment of complement-mediated diseases, including paroxysmal nocturnal hemoglobinuria, we continually strive for even further improvements for our patients. Some patients would welcome an infrequent subcutaneous dosing option," said Anita Hill, M.D., Ph.D., MRCP, FRCPath, Consultant Haematologist for Leeds Teaching Hospitals NHS Trust, UK, and Honorary Senior Lecturer at the University of Leeds. "I have been encouraged by the pre-clinical data to date with ALN-CC5, showing potent and durable knockdown of serum C5. The start of the clinical program is an encouraging development as a potential for further treatment options for patients with PNH and other complement-mediated diseases."

The Phase 1/2 trial of ALN-CC5 is being conducted in the U.K., in three parts. Parts A and B will be randomized (3:1, drug:placebo), double-blind, placebo-controlled, single-dose (Part A) and multi-dose (Part B), dose-escalation studies, designed to enroll up to a total of 60 healthy adult volunteers. Subjects will receive fixed subcutaneous doses of ALN-CC5, administered once weekly for up to five weeks; bi-weekly and monthly dosing schedules may also be evaluated. The primary objective of these first two parts of the study is to evaluate safety and tolerability of single and multiple subcutaneous doses of ALN-CC5. Secondary objectives include evaluation of clinical activity for ALN-CC5 as measured toward knockdown of serum C5 and inhibition of serum complement activity. Part C will be an open-label, multi-dose study in up to eight patients with PNH, and will assess safety, tolerability, and clinical activity of ALN-CC5, administered as multiple subcutaneous doses for up to 13 weeks, in PNH patients. This part of the study will include an exploratory evaluation of the effects of ALN-CC5 on levels of lactate dehydrogenase (LDH), a measure of red blood cell hemolysis.

Alnylam recently presented pre-clinical data from its ALN-CC5 program at the American Society of Hematology (ASH) meeting in December 2014. These data showed an up to 99.2% knockdown of serum C5 and up to 96.2% inhibition of serum hemolytic activity in non-human primates (NHPs) with bi-weekly or monthly subcutaneous dosing for over seven months. Based on human translational data for ESC-GalNAc conjugates, the company believes that this level of activity can be achieved in humans using a low-dose, low-volume monthly subcutaneous dosing regimen. Further, new pre-clinical results were reported for a C5 GalNAc-siRNA in a rat model of membranous nephropathy (MN). The results demonstrated that knockdown of liver-expressed C5 results in disease modifying effects, while local expression of C5 appears to play no significant role.

About ALN-CC5

ALN-CC5 is an investigational RNAi therapeutic targeting the C5 component of the complement pathway for the treatment of complement-mediated diseases. 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.

About GalNAc Conjugates and Enhanced Stabilization Chemistry (ESC)-GalNAc Conjugates

GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology enables subcutaneous dosing with increased potency and durability, and a wide therapeutic index. This delivery platform is being employed in nearly all of Alnylam's pipeline programs, including programs in clinical development.

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 Idec, 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.

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 for the treatment of complement-mediated diseases, the design and timing of clinical studies, the expected timing for reporting of data from clinical studies, its expectations regarding the potency and therapeutic index of GalNAc-siRNA conjugates, including Enhanced Stabilization Chemistry (ESC)-GalNAc conjugates, 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.

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

Source: Alnylam Pharmaceuticals, Inc.

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