Mar 14, 2016 Press Release for Alnylam

Alnylam Initiates Fitusiran (ALN-AT3) Dosing in Hemophilia A and B Patients with Inhibitors in Ongoing Phase 1 Study

Mar 14, 2016

- Company Reinforces Global Commitment to Patients with Hemophilia During Bleeding Disorders Month -

- Fitusiran Phase 3 Initiation Remains on Track for Mid-2016 -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), the leading RNAi therapeutics company, today announced that it has initiated dosing of hemophilia patients with inhibitors in Part D of an ongoing Phase 1 clinical trial evaluating a once-monthly subcutaneous dose regimen of fitusiran (ALN-AT3). Patients with hemophilia A with inhibitors and with hemophilia B with inhibitors have now been dosed with fitusiran. Fitusiran is an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia A and B and rare bleeding disorders (RBD). Fitusiran is designed to prevent bleeding in patients with hemophilia by lowering levels of AT with the goal of promoting sufficient thrombin generation and fibrin clot formation to restore hemostasis. Hemostasis is the process that stops bleeding after an injury. Consistent with previous guidance, the Company expects to report additional data from the Phase 1 trial in mid-2016 and again in late 2016. In addition, the Company remains on track to begin pivotal studies of fitusiran in hemophilia A and B, including patients with and without inhibitors, in mid-2016.

"As many as one third of people with hemophilia develop inhibitory antibodies and become refractory to their replacement factor therapy. As a result, their clinical course becomes more difficult to manage and these patients generally have poorer clinical outcomes," said Akin Akinc, Ph.D., General Manager of Fitusiran at Alnylam. "Because of its novel mechanism of action, we believe that fitusiran represents a promising potential therapy for the management of hemostasis in people with hemophilia with and without inhibitors. We look forward to our continued evaluation of fitusiran activity and safety in this ongoing Phase 1 study, and expect to report new data from this study during the course of the year."

"In recognition of Bleeding Disorders Month, we are pleased to demonstrate our continued commitment to people with hemophilia by advancement of our fitusiran study in inhibitor patients," said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. "Alnylam and its employees are dedicated to developing innovative new treatments for people living with hemophilia around the world."

About the Fitusiran Phase 1 Study

The ongoing Phase 1 trial of fitusiran is being conducted in Bulgaria, Russia, Switzerland, and the U.K. as a single- and multi-dose, dose-escalation study comprised of four 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 fitusiran: placebo) in healthy volunteers. This part of the study was completed after the first dose cohort received a single subcutaneous dose of fitusiran at 30 mcg/kg. Part B of the study - which is also complete - was an open-label, multi-dose, dose-escalation study that enrolled 12 patients with severe hemophilia A or B. Patients in Part B received three weekly subcutaneous injections of fitusiran at doses of 15, 45, or 75 mcg/kg. Part C of the study - which is ongoing - is an open-label, multi-dose, dose escalation study of up to 18 patients with moderate or severe hemophilia A or B in which patients are receiving three monthly subcutaneous doses of fitusiran. Four cohorts of three patients each have been enrolled at doses of 225, 450, 900, or 1800 mcg/kg, and two additional cohorts of three patients each have been enrolled at a fixed dose. Part D of the study - which has recently commenced - is an open-label, multi-dose study in hemophilia A or B patients with inhibitors. The primary objective of Parts B, C, and D of the study is to evaluate the safety and tolerability of multiple doses of subcutaneously administered fitusiran in patients with hemophilia. Secondary objectives include assessment of clinical activity as determined by lowering of circulating AT levels and increase in thrombin generation at pharmacologic doses of fitusiran. In addition, exploratory analyses of bleeding are being performed. In the U.K., enrollment has been aided by the Southern Academic Coagulation Consortium (SACC).

Fitusiran is an investigational compound, currently in early stage clinical development. The safety and efficacy of fitusiran have not been evaluated by the U.S. Food and Drug Administration or any other health authority.

Fitusiran Clinical Data

Clinical data from the ongoing Phase 1 clinical study with fitusiran were presented at the American Society of Hematology (ASH) 2015 Annual Meeting, held December 5 - 8 in Orlando, Florida, showing that:

• Fitusiran achieved potent, dose-dependent, and statistically significant lowering of AT of up to 88 percent in patients with hemophilia. In addition, AT lowering was associated with statistically significant and clinically meaningful increases in thrombin generation and, in an exploratory post-hoc analysis, was associated with statistically significant decreases in bleeding frequency.
• In another post-hoc analysis, there was an 85 percent reduction in median estimated annualized bleeding rate (ABR) during the observed period of fitusiran administration, as compared with median historical on-demand ABR in nine evaluable patients.
• Fitusiran was found to be generally well tolerated through the data cutoff date of November 12, 2015, including no serious adverse events, discontinuations or thromboembolic events, no clinically significant changes in laboratory parameters or clinically significant increases in D-dimer, a biomarker of excessive clot formation. Three reported drug related adverse events were all mild, including two transient injection site reactions. Not related to fitusiran, one patient was hospitalized due to reactivation of hepatitis C.

As noted above, and consistent with previous guidance, the Company expects to report additional safety and clinical activity data from the Phase 1 study in mid-2016 and again in late 2016.

Also at the 2015 ASH conference, Alnylam and collaborators presented pre-clinical data demonstrating that AT lowering in vitro led to increased thrombin generation in plasma from patients with hemophilia who have developed inhibitory antibodies to replacement factor therapy.

The clinical and pre-clinical datasets described above can be accessed at www.alnylam.com/capella.

About Hemophilia and Rare Bleeding Disorders

Hemophilia is a bleeding disorder characterized by insufficient thrombin generation following hemostatic challenge and resulting in recurrent bleeds into joints, muscles, and other internal organs. Hemophilia A is defined by loss-of-function mutations in Factor VIII, and there are greater than 40,000 registered persons in the U.S. and E.U. Hemophilia B, defined by loss-of-function mutations in Factor IX, affects greater than 9,500 registered persons in the U.S. and EU. Other Rare Bleeding Disorders (RBD) are defined by deficiencies of blood coagulation factors, including Factors II, V, VII, X, and XI. There are about 1,000 persons worldwide with a severe bleeding phenotype because of these conditions. The goal of treatment for persons living with hemophilia is to prevent bleeding, establish prompt management of bleeds, and manage the complications of bleeding and treatment. Current guidelines recommend management of hemophilia with regular intravenous infusions of recombinant or human-derived clotting factors. However, the most serious treatment-related complication is the development of antibodies, known as "inhibitors", to replacement factor. Inhibitor development can occur in both hemophilia A and hemophilia B, impacting as many as one-third of people with severe hemophilia A, and persons in this ‘inhibitor' subset become refractory to standard replacement therapy. There exists a significant need for novel therapeutics to treat people living with hemophilia.

About Antithrombin (AT)

Antithrombin (AT, also known as "antithrombin III" and "SERPINC1") is a liver expressed plasma protein and member of the "serpin" family of proteins that acts by inactivating thrombin and other coagulation factors. AT plays a key role in normal hemostasis by helping to limit the process of fibrin clot formation. However, in hemophilia, insufficient thrombin generation results in impaired fibrin clot formation. Lowering AT in the hemophilia setting may promote the generation of sufficient levels of thrombin needed to form an effective fibrin clot and prevent bleeding. This rationale is supported by human genetic data suggesting that co-inheritance of thrombophilic mutations, including AT deficiency, may ameliorate bleeding in hemophilia. Lowering of AT is a unique and innovative strategy for restoring hemostasis in people with hemophilia.

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) through the end of 2019, together with certain broader co-development/co-commercialization rights and global rights for certain products. In the case of fitusiran, Sanofi Genzyme has elected to opt into the program for its ROW rights, while retaining its further opt-in right to co-develop and co-promote fitusiran with Alnylam in North America and Western Europe, subject to certain restrictions.

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 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 fitusiran, expectations regarding the reporting of data from its Phase 1 clinical trial with fitusiran, expectations regarding the timing for initiation of two Phase 3 trials with fitusiran, the expected patient population that could benefit from fitusiran, 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.

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