Apr 13, 2015 Press Release for Alnylam

Alnylam and Collaborators Publish Pre-clinical Study Results in Nature Medicine on ALN-AT3, an Investigational RNAi Therapeutic Targeting Antithrombin (AT) for the Treatment of Hemophilia and Rare Bleeding Disorders (RBD)

Apr 13, 2015

- New Paper Documents Safety, Efficacy, and Durability of Subcutaneous Doses of ALN-AT3 in Rodent and Non-Human Primate (NHP) Models of Hemophilia -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today the publication in Nature Medicine of pre-clinical results with ALN-AT3, an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD). The paper, titled "An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia" (Sehgal et al., Nat Med, doi:10.1038/nm.3847), documents a broad set of pre-clinical data supporting the clinical advancement of ALN-AT3. Among the many findings reported, subcutaneous administration of ALN-AT3 led to potent, dose-dependent, and durable knockdown of AT in wild-type mice, hemophilia A mice, and non-human primates (NHPs). In addition, ALN-AT3 treatment improved hemostasis in hemophilia mice and normalized thrombin generation in a non-human primate "inhibitor" model of hemophilia A (HA). Furthermore, long-term ALN-AT3 administration - even at highly exaggerated doses - was shown to be well tolerated in hemophilia mice, supporting a wide therapeutic index in the disease setting.

"ALN-AT3 is a key program in our RNAi therapeutics pipeline, and is aimed at re-balancing the coagulation cascade as a potential disease modifying therapy for people with hemophilia and rare bleeding disorders. Indeed, we believe that once-monthly subcutaneous administration of ALN-AT3 could provide a functional correction of the bleeding phenotype in hemophilia, representing a significant advance in the field. Our pre-clinical research findings demonstrate robust efficacy, safety, and durability for ALN-AT3 in mouse and NHP models of hemophilia, and we are pleased to be publishing these peer-reviewed data in Nature Medicine. Amongst other study results, safety data in hemophilia mice suggest that ALN-AT3 administration - even at highly exaggerated doses - should be well tolerated in the disease condition," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer of Alnylam. "Meanwhile, we are continuing to advance ALN-AT3 in an ongoing Phase 1 clinical trial in subjects with hemophilia. Recent results from this trial presented earlier this year provided clinical evidence for the first time suggesting that AT knockdown with ALN-AT3 has the potential to correct the hemophilia phenotype. While early and based on a limited number of subjects, we believe that these data support further development of ALN-AT3, a potentially promising and innovative strategy for the treatment of hemophilia and rare bleeding disorders as a once-monthly subcutaneous injection. We look forward to the continued data from our Phase 1 study and expect to present additional results in mid-2015 and then again later in the year."

As documented in the new publication, single and multiple subcutaneous doses of ALN-AT3 led to dose-dependent and durable knockdown of serum AT in wild-type and HA mice and in NHPs. In microvessel laser injury and saphenous vein bleeding models in HA mice, subcutaneous administration of ALN-AT3 provided hemostatic protection that was comparable to or better than that achieved with intravenously administered factor VIII replacement therapy. Furthermore, in wild type NHPs, repeat dosing with ALN-AT3 resulted in potent, titratable, and reversible knockdown of plasma AT. Studies were also performed in an NHP hemophilia "inhibitor" model, in which a hemophilia phenotype was induced via administration of a polyclonal anti-factor VIII antibody. ALN-AT3 treated animals showed robust AT knockdown as well as dose-dependent increases in thrombin generation, restoring this hemostatic parameter back to normal levels. These results demonstrate that ALN-AT3 can normalize thrombin generation in the absence of functional levels of factor VIII and/or in the presence of anti-factor VIII antibodies in a large animal model, providing key pre-clinical proof of concept for the program.

In addition, the new paper documents the results of tolerability studies that suggest a wide therapeutic index for ALN-AT3 in the hemophilia setting. Specifically, highly exaggerated doses of ALN-AT3 resulting in essentially complete ablation of AT were evaluated in wild-type and hemophilia mice. Weekly administration of ALN-AT3 in HA mice for 7 weeks at 10, 30, or 100 mg/kg was well tolerated across all dose levels, with no toxicologically significant findings in clinical or anatomic pathology exams, including the absence of any evidence for thrombosis. Finally, a 26-week toxicity study was performed in HA mice to evaluate long-term safety. As in the 7-week study, ALN-AT3 was well tolerated across all dose levels, with no adverse clinical signs. Further, compared to placebo treatment, ALN-AT3 administration was shown to confer a statistically significant survival benefit (p < 0.0001; log-rank, Mantel-Cox test), consistent with the hypothesis that a reduction in AT levels leads to disease modification. In aggregate, these results suggest a wide therapeutic index for AT knockdown in the hemophilia setting.

Alnylam is currently evaluating ALN-AT3 in a Phase 1 clinical trial in subjects with hemophilia. The ongoing study is being conducted in Bulgaria, Switzerland and the U.K. as a single- and multi-dose, dose-escalation study comprised of two parts. Part A - which is complete - was a randomized, single-blind, placebo-controlled, single-dose, dose-escalation study (n=4 per cohort; 3:1 randomization of ALN-AT3:placebo) in healthy volunteer subjects. This part of the study was completed after the first dose cohort that received a single subcutaneous dose of ALN-AT3 at 30 micrograms/kilogram (mcg/kg). Part B of the study - which is ongoing - is an open-label, multi-dose, dose-escalation study enrolling up to 18 subjects with moderate or severe hemophilia A or B. The primary objective of this part of the study is to evaluate the safety and tolerability of multiple doses of subcutaneously administered ALN-AT3 in hemophilia subjects. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels and increase in thrombin generation at pharmacologic doses of ALN-AT3. In addition, the study is recording potential effects of ALN-AT3 on the incidence of bleeding.

At the Goring Coagulation Conference, held January 11 - 12, 2015, Alnylam presented initial positive results from the ongoing Phase 1 trial. Specifically, in the study's second dose cohort in hemophilia subjects (n=3), subcutaneous administration of ALN-AT3 at a dose of 45 mcg/kg administered once weekly for 3 weeks resulted in an up to 70% knockdown of AT. Furthermore, ALN-AT3 administration resulted in a statistically significant increase in thrombin generation of up to 334% and a marked improvement in whole blood clotting. In addition, the most advanced severe hemophilia A subject in the cohort was shown to be bleed-free for 47 days without replacement factor prophylaxis as of the data cut-off date of January 6, 2015. Finally, ALN-AT3 administration was generally well tolerated. Alnylam believes that, collectively, these results provide initial evidence for potential correction of the hemophilia phenotype associated with ALN-AT3 administration and AT knockdown. The company intends to provide additional results from the ongoing Phase 1 study in mid-2015 and then again in late 2015.

"New therapeutic options are needed to manage bleeding in hemophilia and other rare bleeding disorders, particularly for patients who experience multiple annual bleeds when receiving replacement factor ‘on demand' and for patients who have developed inhibitory antibodies. The availability of a safe and effective, subcutaneously administered therapeutic with a long duration of action has the potential to provide significant benefits over currently available approaches for prophylaxis," said David Lillicrap, M.D., FRCPC, Professor, Department of Pathology and Molecular Medicine at Queen's University, and Canada Research Chair in Molecular Hemostasis. "The clinical advancement of ALN-AT3 is supported by a broad pre-clinical data package that is now published in Nature Medicine. Of particular interest is the correlation of antithrombin knockdown with thrombin generation, since thrombin generation has been shown to be predictive of disease severity. In addition, I believe that the long-term safety of the drug in the mouse model of hemophilia is an important finding, suggesting that ALN-AT3 may have a wide therapeutic index in people with hemophilia. Finally, I am encouraged by the initial data emerging from Alnylam's Phase 1 trial and I look forward to seeing further progress in the coming months."

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-AT3 for the treatment of hemophilia and rare bleeding disorders, the design and timing of clinical studies, expectations regarding the reporting of data from clinical studies, in particular the Phase 1 clinical trial of ALN-AT3, 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.

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Source: Alnylam Pharmaceuticals, Inc.

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