Alnylam Reports Initial Evidence for Potential Correction of the Hemophilia Phenotype in Phase 1 Study of ALN-AT3, a Subcutaneously Administered, Investigational RNAi Therapeutic Targeting Antithrombin for the Treatment of Hemophilia

Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics company, announced today updated results from its ongoing Phase 1 study of ALN-AT3, a subcutaneously administered, investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD). New results were presented at the 2015 Goring Coagulation Conference, being held January 11 – 12 in London. Specifically, data were presented from the study’s second dose cohort in hemophilia subjects (n=3), where subcutaneous administration of ALN-AT3 resulted in an up to 70% knockdown of AT. New results provide initial evidence for potential correction of the hemophilia phenotype associated with ALN-AT3 administration and AT knockdown. Specifically, ALN-AT3 administration resulted in an 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 has remained bleed free for 47 days without replacement factor prophylaxis. Finally, ALN-AT3 administration continues to be generally well tolerated. Alnylam intends to provide additional results from the ongoing Phase 1 study in mid-2015 and then in late 2015, and expects to start a Phase 2 study of ALN-AT3 in late 2015.

“We believe that these new results from our ongoing Phase 1 study with ALN-AT3 provide initial evidence for potential disease-modifying effects in hemophilia. Specifically, data from the study’s second dose cohort provide clinical evidence for the first time suggesting that AT knockdown with ALN-AT3 has the potential to correct the hemophilia phenotype. In particular, we’ve observed clear increases in thrombin generation and marked improvements in whole blood clotting, as if the severe hemophilia A disease phenotype has been modified to a milder form. Further, we are encouraged to see that the most advanced subject has remained free from bleeding for a significant period without need for replacement factor prophylaxis. Importantly, ALN-AT3 treatment continues to be generally well tolerated, with no serious adverse events and no study discontinuations reported to date,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “While early and based on a limited number of subjects, we believe that these new data support human proof-of-concept for ALN-AT3, a promising and innovative strategy for the treatment of hemophilia and rare bleeding disorders. Indeed, we believe that once-monthly subcutaneous administration of ALN-AT3 could provide a functional correction of the hemophilia phenotype, representing an attractive disease-modifying therapy. We look forward to the continued data from this Phase 1 study and expect to present additional results in mid-2015 and then later in the year.”

“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’ or patients who have developed inhibitory antibodies. I believe that the availability of a safe and effective, subcutaneously administered therapeutic with a long duration of action would represent a marked improvement over currently available approaches for prophylaxis,” said Dr. Savita Rangarajan, MBBS, FRCP, FRCPath, Director of the Southern Haemophilia Network and Consultant Haematologist at the Haemophilia, Haemostasis & Thrombosis Centre at Hampshire Hospitals NHS Foundation Trust, UK. “I am very encouraged by these new results emerging from the ongoing Phase 1 study of ALN-AT3. In particular, the increased thrombin generation and improved whole blood clotting results provide initial, yet compelling evidence for the potential of disease modification in severe hemophilia. Of great interest, these results are consistent with case reports documenting a milder clinical phenotype in people with bleeding disorders who have co-inherited AT deficiency or other thrombophilic traits. Together, I believe that these new findings strongly support the continued advancement of this novel, investigational therapeutic agent.”

The ongoing Phase 1 trial of ALN-AT3 is being conducted in Bulgaria, Switzerland, and the U.K. as a single- and multi-dose, dose-escalation study comprised of two parts. In the U.K., enrollment has been aided by the Southern Academic Coagulation Consortium (SACC). 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.

Updated results were presented from the second dose cohort of hemophilia subjects – which is now fully enrolled (n=3) – where ALN-AT3 is administered subcutaneously once weekly for three weeks (qW x 3) at a low dose of 45 mcg/kg. All preliminary results are as of a data cut off on January 6, 2015. ALN-AT3 administration resulted in an up to 70% knockdown of AT. The mean AT knockdown was 44 +/- 6.5% at day 16 (n=3; p=0.02, relative to baseline) and 64 +/- 6.8% at day 21 (n=2; p=0.09, relative to baseline). Based on the most advanced subject in the cohort, the nadir effect appears to occur at approximately day 28. Based on the essentially complete time course for AT knockdown from the first dose cohort receiving 15 mcg/kg (qW x 3), the effects of ALN-AT3 were also found to be highly durable, lasting about 60 days.

Initial evidence for the potential correction of the hemophilia phenotype was observed in the severe hemophilia A subjects. Specifically, ALN-AT3 administration resulted in thrombin generation increases of up to 334%. Increase in thrombin generation was closely correlated with degree of AT knockdown. When AT knockdown levels exceeded 50%, the mean increase in thrombin generation was 112 +/- 38% (p less than 0.05) relative to baseline. Thrombin generation is known to be a biomarker for bleeding frequency and severity in people with hemophilia (Dargaud, et al., Thromb Haemost; 93, 475-480 (2005)), and the results achieved following ALN-AT3 administration are consistent with thrombin generation levels measured in mild hemophilia. Moreover, the observed maximal increase in thrombin generation in the hemophilia subjects (peak thrombin of 71 nM) remained at the low end of the range for peak thrombin levels in the healthy volunteers enrolled in Part A of the study (mean of 92 +/- 15 nM; range from 69-135nM). These data show that AT knockdown of up to 70% in hemophilia subjects should not lead to an excessive increase in thrombin generation beyond normal.

Further evaluation of the effects of ALN-AT3 employed the use of ROTEM® thromboelastometry, which measures clotting time and clot strength in whole blood following a physiologic coagulation stimulus; this assay method was available for a single severe hemophilia A subject in the second dose cohort, who happens to be the most advanced subject. ALN-AT3 administration was found to result in AT knockdown-dependent improvements in whole blood clotting in this subject. As described in the table below, ALN-AT3 administration resulted in marked improvements in clotting time (CT) – which is a measure of the initiation phase of clot formation – and clot formation time (CFT) – which is a measure of the propagation phase of clot formation; both parameters that are known to be significantly impaired in people with hemophilia. As with observed effects on thrombin generation, the improved CT and CFT values following ALN-AT3 administration were found to be similar to those reported in the literature in subjects with mild hemophilia. Finally, as of the current data cut-off date of January 6, 2015, this hemophilia subject was free of any bleeds for 47 days, which compares favorably to his physician-reported Annual Bleeding Rate (ABR) of 10-12 bleeds/year during on-demand therapy prior to enrolling in the study.

Summary of AT Knockdown and Improvement in Whole Blood Clotting in Most Advanced Subject

As of the current data cut off, ALN-AT3 continues to be generally well tolerated in all subjects receiving study drug in the study (n=9), including subjects enrolled in the second dose cohort (n=3). There have been no serious adverse events, no discontinuations, no injection site reactions, and no significant changes in physical exams, vital signs, or electrocardiography. Further, there have been no clinically significant changes in any laboratory parameter, including liver function tests, hematology, and coagulation measures. There have been no clinically significant increases in D-dimer, a marker of fibrin clot formation, or any thromboembolic events. The most common adverse event observed in hemophilia subjects was the occurrence of mild to moderate bleeds unrelated to study drug. All bleeds were successfully managed with replacement factor administration. In the second dose cohort and as of the data cut-off date, all five reported bleeds occurred on day 6 or earlier – at low levels of AT knockdown – with the exception of a trauma-related bleed in one subject at day 16, which was managed with a low, 1000 IU dose of Factor VIII.

The ALN-AT3 Phase 1 study continues to enroll hemophilia subjects in additional dose cohorts, including the potential to explore a once-monthly subcutaneous dose regimen following a protocol amendment. The company plans to present additional data from the Phase 1 study in mid-2015, and then additional results in late 2015. In addition, Alnylam expects to initiate a Phase 2 study of ALN-AT3 in late 2015.

Conference Call Information

Alnylam management will discuss these new results with ALN-AT3 in a webcast conference call on Monday, January 12 at 8:30 a.m. ET (5:30 a.m. PT). A slide presentation will also be available on the Investors page of the company’s website, www.alnylam.com, to accompany the conference call. To access the call, please dial 877-312-7507 (domestic) or 631-813-4828 (international) five minutes prior to the start time and refer to conference ID 65072960. A replay of the call will be available beginning at 11:30 a.m. ET. To access the replay, please dial 855-859-2056 (domestic) or 404-537-3406 (international), and refer to conference ID 65072960.

About Hemophilia and Rare Bleeding Disorders

Hemophilias are hereditary disorders caused by genetic deficiencies of various blood clotting factors, resulting in recurrent bleeds into joints, muscles, and other major 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 with Hemophilia A. Hemophilia B, defined by loss-of-function mutations in Factor IX, affects greater than 9,500 registered persons in the U.S. and E.U. Other Rare Bleeding Disorders (RBD) are defined by congenital deficiencies of other blood coagulation factors, including Factors II, V, VII, X, and XI, and there are about 1,000 persons worldwide with a severe bleeding phenotype. Standard treatment for persons living with hemophilia involves replacement of the missing clotting factor either as prophylaxis or on-demand therapy. However, as many as one third of people with severe hemophilia A will develop an antibody to their replacement factor - a very serious complication; persons in this ‘inhibitor’ subset become refractory to standard replacement therapy. There exists a small subset of persons living with hemophilia who have co-inherited a prothrombotic mutation, such as Factor V Leiden, antithrombin deficiency, protein C deficiency, and prothrombin G20210A. People who have co-inherited these prothrombotic mutations are characterized as having a later onset of disease, lower risk of bleeding, and reduced requirements for Factor VIII or Factor IX treatment as part of their disease management. 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 as an important endogenous anticoagulant by inactivating Factor Xa and thrombin. AT plays a key role in normal hemostasis, which has evolved to balance the need to control blood loss through clotting with the need to prevent pathologic thrombosis through anticoagulation. In hemophilia, the loss of certain procoagulant factors (Factor VIII and Factor IX, in the case of hemophilia A and B, respectively) results in an imbalance of the hemostatic system toward a bleeding phenotype. In contrast, in thrombophilia (e.g., Factor V Leiden, protein C deficiency, antithrombin deficiency, amongst others), certain mutations result in an imbalance in the hemostatic system toward a thrombotic phenotype. Since co-inheritance of prothrombotic mutations may ameliorate the clinical phenotype in hemophilia, inhibition of AT defines a novel strategy for improving hemostasis.

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. 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, the 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, 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.