Alnylam Reports Positive Initial Results for ALN-AT3, an Investigational RNAi Therapeutic Targeting Antithrombin (AT) for the Treatment of Hemophilia and Rare Bleeding Disorders, from Ongoing Phase 1 Trial


- Results Presented at American Society of Hematology (ASH) Meeting Demonstrate up to 57% AT Knockdown in Initial Multi-Dose Cohorts of Hemophilia Subjects and Show Preliminary Clinical Evidence for Potency and Durability of RNAi Therapeutics at Microgram/kg (mcg/kg) Doses -

- Subcutaneous Dose Administration of ALN-AT3 Found to be Well Tolerated in Healthy Volunteers and Initial Cohorts of Hemophilia Subjects -

- Company to Host Conference Call at 8:00 a.m. ET Tomorrow, December 9, to Discuss Data -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today positive initial Phase 1 data for ALN-AT3, an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders. Preliminary results were presented at the 56th Annual Meeting of the American Society of Hematology (ASH) from a single dose cohort in healthy volunteers (n=4) and from the initial multiple dose cohorts of hemophilia subjects (n=4) in the ongoing Phase 1 clinical trial. Amongst other data presented, subcutaneous administration of ALN-AT3 given once weekly for three weeks at low doses of 15 or 45 micrograms/kg (mcg/kg) resulted in an up to 57% knockdown of AT in hemophilia subjects. The effects of ALN-AT3 lasted for about 60 days after a single dose. ALN-AT3 was found to be well tolerated in both healthy volunteers and hemophilia subjects enrolled in the study. These initial results show preliminary evidence for potency and durability of RNAi therapeutics at mcg/kg subcutaneous doses in human studies, and are the first clinical data to be reported for Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc conjugate technology.

"These early results for ALN-AT3 from our ongoing Phase 1 study demonstrate knockdown of antithrombin of up to 57% at low microgram/kg subcutaneous doses of drug. As such, these data provide preliminary evidence for a high level of potency for RNAi therapeutics in humans with the improved pharmacologic properties for our ESC-GalNAc conjugate delivery technology. As supported by data we presented earlier this year, this improved potency appears to be due to the increased stabilization chemistry employed with our ESC platform, as well as an attenuated nuclease environment in human cells," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. "In addition, ALN-AT3 effects were found to be quite durable, lasting for months after a single dose. Accordingly, we will aim to evaluate a once-monthly dosing regimen in further clinical studies, as we believe this could provide a highly attractive prophylactic regimen for patients. We look forward to the continued dose escalation in this Phase 1 study and expect to present complete results in mid-2015."

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. 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. The primary objective of this part of the study was to evaluate the safety and tolerability of a single dose of ALN-AT3, with the potential secondarily to show changes in AT plasma levels at sub-pharmacologic doses. Part A of the study evaluated only low doses of ALN-AT3, with a dose-escalation stopping rule at no more than a 40% knockdown of AT. Based on the level of AT knockdown achieved in this part of the study, only the first and lowest 30 mcg/kg dose cohort of 4 healthy volunteers was enrolled. Part B of the study - which is ongoing and at early stages - 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; 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)). In this part of the study, dose-escalation is allowed to proceed beyond the 40% AT knockdown level. Initial results from the ongoing study presented today include safety, tolerability, and clinical activity data from: the single cohort of healthy volunteers in Part A; the lowest (15 mcg/kg), multi-dose cohort of three hemophilia subjects from Part B; and the initial hemophilia subject enrolled in the second multi-dose cohort (45 mcg/kg) from Part B. For the four subjects currently in Part B, three have severe hemophilia A (less than 1% levels of Factor VIII) and one has severe hemophilia B (less than 1% levels of Factor IX).

Preliminary results from the Phase 1 study to date show that ALN-AT3 was well tolerated in both healthy volunteers and hemophilia subjects. There were no serious adverse events, no discontinuations, no injection site reactions, and no significant changes in physical exams, vital signs, or electrocardiography. Further, there were no clinically significant changes in any laboratory parameter, including liver function tests, hematology, and coagulation measures. There were 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 mild to moderate bleeds unrelated to study drug. All bleeds were successfully managed with replacement factor administration.

Clinical activity of ALN-AT3, including knockdown of AT and thrombin generation, was measured in serial blood samples following study drug administration. In the healthy volunteer Part A of the study, subjects received a single subcutaneous dose of 30 mcg/kg. ALN-AT3 administration resulted in an up to 28% knockdown of AT with a mean maximum knockdown of 19% ±4.4% which was statistically significant relative to placebo (p < 0.01 by ANOVA). The nadir for AT knockdown was achieved at approximately day 21, and the overall effects from a single dose were found to be durable for approximately 60 days. ALN-AT3 knockdown of AT resulted in temporally related increases in thrombin generation of up to 152%, with a mean maximum increase of 138% ±8.9% that was statistically significant relative to placebo (p < 0.01 by ANOVA). In healthy volunteers, there was a statistically significant correlation of AT knockdown with thrombin generation increase with r=0.44, p=0.004 (post-hoc).

In the ongoing Part B of the study, which is in early stages of dose escalation, hemophilia subjects are receiving three weekly subcutaneous doses of ALN-AT3. All clinical activity results presented at the meeting are from a data cutoff date of December 5, and are subject to change upon final analysis. In the first, lowest dose cohort of 15 mcg/kg, ALN-AT3 administration resulted in an up to 52% knockdown of AT in the most advanced subject, with nadir achieved on day 35. The mean maximum knockdown for this group was 27% ±13% through day 28, and is expected to increase when all subjects reach nadir levels. In the first subject in the second multi-dose cohort of 45 mcg/kg, ALN-AT3 administration resulted in an up to 57% knockdown of AT as measured on day 14; knockdown in this subject has not yet reached expected nadir levels. Plasma samples from the 15 mcg/kg cohort were also evaluated for potential increases in thrombin generation. Excluding increases in thrombin generation observed around the time of replacement factor administration, no conclusions can be drawn from thrombin generation measurements at this dose and level of AT knockdown. This result is in line with data from an induced hemophilia model in non-human primates, where levels of AT knockdown greater than or equal to 60% were required to achieve consistent and significant increases in thrombin generation in the background of reduced levels of factor VIII. The ALN-AT3 Phase 1 study is continuing to enroll hemophilia subjects in the second dose cohort of 45 mcg/kg, and additional multi-dose cohorts are planned. The company expects to present complete results from the Phase 1 study in mid-2015.

"The unmet need for new therapeutic options to treat hemophilia patients remains very high, particularly in those patients who experience multiple annual bleeds such as patients receiving replacement factor ‘on demand' or patients who have developed inhibitory antibodies. Accordingly, I believe the availability of a subcutaneously administered therapeutic with a long duration of action that is shown to be safe and effective would represent a marked improvement 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. "I continue to be encouraged by Alnylam's progress to date with ALN-AT3, including these initial Phase 1 data reported from both healthy volunteers and severe hemophilia subjects showing knockdown of antithrombin. I look forward to the continued advancement of this innovative therapeutic candidate in hemophilia subjects."

Finally, in a symposium at ASH, Alnylam presented new pre-clinical data with ALN-AT3. In a study conducted in non-human primates, monthly subcutaneous dosing of ALN-AT3 was found to result in robust, durable, and dose-dependent knockdown of AT. Alnylam believes these data, combined with the emerging human durability data, may support monthly dosing of ALN-AT3 in hemophilia subjects. In addition, new results from a chronic toxicity study performed in hemophilia A mice showed that weekly dosing of ALN-AT3 confers a statistically significant survival benefit as compared with animals receiving placebo. Hemophilia A mice are prone to premature death due to their bleeding diathesis, and these results suggest that ALN-AT3 may be able to achieve a disease modifying effect by rebalancing the coagulation cascade through AT knockdown.

Alnylam management will discuss these new results with ALN-AT3 for the treatment of hemophilia and rare bleeding disorders in a webcast conference call on Tuesday, December 9 at 8:00 a.m. ET. A slide presentation will also be available on the Investors page of the company's website,, 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 48939136. A replay of the call will be available beginning at 11:00 a.m. ET. To access the replay, please dial 855-859-2056 (domestic) or 404-537-3406 (international), and refer to conference ID 48939136.

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 patients in the U.S. and E.U. Hemophilia B, defined by loss-of-function mutations in Factor IX, affects greater than 9,500 registered patients 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 patients worldwide with a severe bleeding phenotype. Standard treatment for hemophilia patients 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; these ‘inhibitor' patients become refractory to standard replacement therapy. There exists a small subset of hemophilia patients who have co-inherited a prothrombotic mutation, such as Factor V Leiden, antithrombin deficiency, protein C deficiency, and prothrombin G20210A. Hemophilia patients that 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 hemophilia patients.

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 several of Alnylam's genetic medicine 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 with a core focus on RNAi therapeutics as genetic medicines, including programs as part of the company's "Alnylam 5x15™" product strategy. Alnylam's genetic medicine programs are investigational RNAi therapeutics directed toward genetically defined targets for the treatment of serious, life-threatening diseases with limited treatment options for patients and their caregivers. These include: patisiran (ALN-TTR02) targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); revusiran (ALN-TTRsc) targeting TTR for the treatment of ATTR in patients with TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3 targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5 targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1 targeting aminolevulinic acid synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCSsc targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AAT targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease; ALN-HBV targeting the hepatitis B virus (HBV) genome for the treatment of HBV infection; ALN-TMP targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3 targeting apolipoprotein C-3 (apoC3) for the treatment of hypertriglyceridemia; ALN-AGT targeting angiotensinogen (AGT) for the treatment of hypertensive disorders of pregnancy (HDP), including preeclampsia; ALN-GO1 targeting glycolate oxidase (GO) for the treatment of primary hyperoxaluria type 1 (PH1); ALN-HDV targeting the hepatitis delta virus (HDV) genome for the treatment of HDV infection; ALN-PDL targeting programmed death ligand 1 (PD-L1) for the treatment of chronic liver infections; and other programs yet to be disclosed. As part of its "Alnylam 5x15" strategy, as updated in early 2014, the company expects to have six to seven genetic medicine product candidates in clinical development - including at least two programs in Phase 3 and five to six programs with human proof of concept - by the end of 2015. 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, and The Medicines Company. In early 2014, Alnylam and Genzyme, a Sanofi company, formed a multi-product geographic alliance on Alnylam's genetic medicine programs in the rare disease field. Specifically, Alnylam will lead development and commercialization of programs in North America and Europe, while Genzyme will develop and commercialize products in the rest of world. In addition, Alnylam and Genzyme will co-develop and co-commercialize revusiran in North America and Europe. In March 2014, Alnylam acquired Sirna Therapeutics, a wholly owned subsidiary of Merck. 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, please visit

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 and the potential for the reported preliminary results of its Phase 1 study to change upon final analysis, its expectations regarding the potency and therapeutic index of GalNAc-siRNA conjugates, including Enhanced Stabilization Chemistry (ESC)-GalNAc conjugates, its expectations regarding its "Alnylam 5x15" product 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 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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