Alnylam Reports New Positive Clinical Data for ALN-AT3, a Subcutaneously Administered, Investigational RNAi Therapeutic Targeting Antithrombin (AT) for the Treatment of Hemophilia and Rare Bleeding Disorders


- New Interim Data from Ongoing Phase 1 Study in Hemophilia Subjects Demonstrate an up to 86% AT Knockdown and a Re-Balancing of Hemostasis with Normalization of Thrombin Generation up to a Mean Increase of 350% and Marked Improvements in Whole Blood Clotting -

- In Exploratory Post Hoc Analysis, Reduced Bleeding Events Associated with AT Knockdown, with a Maximum Bleed-Free Interval of 114 Days -

- ALN-AT3 Administration Remains Generally Well Tolerated, Including No Clinically Significant Increases in D-Dimer -

- Based on Promising Results, Company Now Expects to Advance ALN-AT3 into Pivotal Studies in Mid-2016 -

- Company to Host Conference Call Today, June 23, at 4:30 p.m. ET to Discuss Data -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, today announced that new positive data from its ongoing Phase 1 clinical trial with ALN-AT3 - an investigational RNAi therapeutic for the treatment of hemophilia and rare bleeding disorders (RBD) - were reported in an oral presentation at the International Society on Thrombosis and Haemostasis (ISTH) 2015 Congress being held June 20 - 25, 2015 in Toronto, Ontario, Canada. Additional study results from 12 hemophilia A and B subjects demonstrated that subcutaneous administration of ALN-AT3 achieved potent and dose-dependent knockdown of AT of up to 86%. AT knockdown was highly durable, with effects lasting over two months after the last dose, supporting further evaluation of a once-monthly subcutaneous dose regimen. In addition, AT knockdown was associated with statistically significant increases in thrombin generation with a mean increase of up to 350% and marked improvements in whole blood clotting; these results demonstrate a re-balancing of hemostasis in severe hemophilia subjects. In an exploratory post-hoc analysis, a reduced frequency of bleeding was observed at higher AT knockdown levels including a maximum bleed-free interval of 114 days. Importantly, ALN-AT3 was found to be generally well tolerated, including no clinically significant increases in D-dimer, a biomarker of pathologic clot formation. Based on these data, the company expects to accelerate the advancement of ALN-AT3 with pivotal studies planned to begin in mid-2016.

"With the potential for infrequent subcutaneous dose administration and possible correction of disease phenotype, we believe that ALN-AT3 represents an innovative investigational medicine for the treatment of hemophilia and rare bleeding disorders. We regard these new results from our ongoing Phase 1 study as very promising, as they demonstrate clinical activity for ALN-AT3 toward AT knockdown and a re-balancing of hemostasis with a normalization of thrombin generation and improved whole blood clot formation. Moreover, we're encouraged by results from an exploratory analysis of effects on bleeding, where we've observed a reduced estimated annualized bleeding rate (ABR) at higher levels of AT knockdown. Importantly, ALN-AT3 has continued to be generally well tolerated in the study, including no clinically significant increases in D-dimer levels," saidAkshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer at Alnylam. "Based on these results and upon completion of the Phase 1 study, we now intend to proceed to pivotal Phase 3 studies of ALN-AT3 that we expect to start in mid-2016. In addition, we plan to initiate an open-label extension study later this year for subjects from the Phase 1 study, and we expect to present data from that study on an ongoing basis at least once per year beginning in 2016. In the meantime, we also look forward to presenting additional data from our ongoing Phase 1 study, including results from hemophilia subjects receiving a once-monthly subcutaneous dose regimen, later this year."

"New therapeutic options are needed to manage bleeding in hemophilia and other rare bleeding disorders. This is particularly important 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 subcutaneously administered therapeutic with a long duration of action - such as a once-monthly regimen - that is shown to be safe and effective would represent a marked improvement over currently available approaches for prophylaxis," said Claude Negrier, M.D., Ph.D, Professor of Medicine at the Claude Bernard University and Chairman of the Hematology Division at Edouard Herriot University Hospital and Louis Pradel Cardiology Hospital in Lyon, France. "I am very encouraged by the continued tolerability and new clinical activity results emerging from the ongoing Phase 1 study of ALN-AT3. Indeed, the ability of ALN-AT3 to potentially increase thrombin generation in severe hemophilia subjects toward normal levels is an important finding, and this appears to be associated with improvements in whole blood clotting and bleeding frequency. I believe that these new findings support the continued advancement of this novel investigational therapeutic agent."

The ongoing Phase 1 trial of ALN-AT3 is being conducted in Bulgaria, Russia, Switzerland, and the U.K. as a single- and multi-dose, dose-escalation study comprised of three 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 received a single subcutaneous dose of ALN-AT3 at 30 micrograms per kilogram (mcg/kg). Part B of the study - which is now complete - was an open-label, multi-dose, dose-escalation study that enrolled 12 subjects with severe hemophilia A or B. Subjects in Part B received 3 weekly subcutaneous doses of ALN-AT3 at doses of 15, 45, or 75 mcg/kg with a volume per injection ranging from 0.2 to 0.7 mL. Part C of the study - which is ongoing - is an open-label, multi-dose, dose escalation study of up to 12 subjects with moderate or severe hemophilia A or B in which subjects are receiving 3 monthly subcutaneous doses of ALN-AT3. The initial dose cohort of Part C has received ALN-AT3 at a dose of 225 mcg/kg (volume less than 1mL), which is equivalent to the cumulative dose level from 3 weekly doses of 75 mcg/kg that was found to be generally well tolerated in Part B. The primary objective of Parts B and C 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. For subjects enrolled at select sites in theU.K. and Switzerland, the effects of ALN-AT3 are also being monitored by ROTEM® thromboelastometry, which measures clotting time and clot strength in whole blood following a physiologic coagulation stimulus. In addition, exploratory analyses of bleeding are being performed. In the U.K., enrollment has been aided by the Southern Academic Coagulation Consortium(SACC).

New results were presented from 12 hemophilia subjects in Part B of the ongoing Phase 1 study in an oral presentation at ISTH and include all available data as of the data cut-off date of June 2, 2015. Subcutaneous doses of ALN-AT3 resulted in potent, dose-dependent and statistically significant knockdown of plasma AT of up to 86%. At the top dose of 75 mcg/kg (n=3), the mean maximum AT knockdown was 59 ± 7% (p less than 0.05), with nadir levels achieved between days 28 and 42. AT knockdown was found to be highly durable, with effects lasting over two months after the last dose. For example, at the 45 mcg/kg dose, mean AT knockdown was 36 ± 11% at day 70.

AT knockdown with ALN-AT3 was associated with statistically significant increases in thrombin generation and improvements in whole blood clot formation, providing continued evidence for a re-balancing of hemostasis and potential correction of the hemophilia phenotype in severe hemophilia subjects. The association between levels of AT knockdown and thrombin generation was assessed in a post hoc exploratory analysis in which AT knockdown was categorized into tertiles. In the highest tertile (greater than 66% AT knockdown), ALN-AT3 administration resulted in mean increases in thrombin generation of 350 ± 239% (p less than 0.05). In this same tertile, the observed level of thrombin generation (120 ± 81 nM peak thrombin) was comparable to levels observed in healthy volunteers (120 ± 33 nM peak thrombin) from Part A of the Phase 1 study, demonstrating an apparent normalization of thrombin generation. 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)).

Additional evaluation of the effects of ALN-AT3 employed the use of ROTEM® thromboelastometry in 3 severe hemophilia subjects in which ALN-AT3 administration resulted in statistically significant, AT knockdown-dependent improvements in whole blood clot formation, including a shortening of clot formation time (CFT). At day 35, the CFT for all 3 subjects was significantly shorter than on day 1, with an over three-fold shortening of CFT from 1166 ± 614 sec to 323 ± 46 sec (p less than 0.05).

While the Phase 1 study was not designed to evaluate the effects of ALN-AT3 on bleeding, an exploratory post hoc analysis was performed by examining the frequency of on-study bleeding events in all subjects in Part B of the study. During the period of time when subjects had AT knockdown less than 33%, a total of 33 bleeding events were reported, and the mean estimated annualized bleeding rate (ABR) was 22 ± 5; this ABR is generally consistent with values reported in prospective clinical trials for hemophilia subjects treated "on-demand" with factor replacement. The mean estimated ABR was reduced to 14 ± 5 at levels of AT knockdown between 33 and 66% and was reduced yet further to a mean estimated ABR of zero during the period of time when AT knockdown exceeded 66%. The reduced ABR associated with increased AT knockdown was statistically significant (p less than 0.001 based on negative binomial regression model). The maximum bleed-free interval for any given subject was 114 days, observed in a subject who achieved an up to 86% level of AT knockdown. This subject with severe hemophilia had a self-reported ABR of over 20 bleeds per year prior to entering the ALN-AT3 Phase 1 study.







AT Knockdown



Less than 33%






Greater than 66%

Subjects (N)










Cumulative Days










Peak Thrombin Generation (nM, Mean +/- SD)



18 ± 8



35 ± 24



120 ± 81*

% Increase in Peak Thrombin Generation (Mean +/- SD)



25 ± 72%



69 ±92%



350 ± 239%*

Cumulative Bleeds










Estimated Annualized Bleeding Rate (ABR) (Mean +/- SEM)**



22 ± 5



14 ± 5











*p less than 0.05, compared with AT knockdown less than 33%
**p less than 0.001, based on negative binomial regression model

As of the current data cut off, ALN-AT3 continues to be generally well tolerated in all subjects. There have been no serious adverse events, no discontinuations, and no significant changes in physical exams, vital signs, or electrocardiography. One subject experienced mild injection site pain lasting two minutes, but otherwise there were no injection site reactions. 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 pathologic clot formation, and no 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, with no adverse events associated with factor administration.

Based on these promising results, Alnylam plans to advance directly to pivotal studies for ALN-AT3 and is providing new guidance that it intends to start a pivotal Phase 3 clinical trial in mid-2016. The company also intends to open a Phase 1 open label extension (OLE) study in late 2015 to provide hemophilia subjects enrolled in the Phase 1 study the opportunity for continued dosing; Alnylam intends to report data from the Phase 1 OLE at least once per year with initial data expected in 2016. Finally, the company still plans on presenting additional data from the ongoing Phase 1 study in late 2015.

Alnylam scientists and collaborators also are presenting new pre-clinical data on ALN-AT3 at the ISTH meeting. Earlier this morning, the company presented data from an oral presentation entitled "Antithrombin Reduction Improves Coagulation in Rare Bleeding Disorder Plasma." Specifically, ex vivo AT depletion was demonstrated to result in increased thrombin generation in plasma from donors with deficiencies in factors V, VII, and XI. These new pre-clinical data support the clinical evaluation of ALN-AT3 in these rare bleeding disorders. Additional data reports from the meeting will be made available on the company's website following their presentation.

Genzyme Alliance
In January 2014, Alnylam and Genzyme, a Sanofi company, 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 Genzyme obtained the right to access certain programs in Alnylam's current and future Genetic Medicines pipeline, including ALN-AT3, in the rest of the world. In certain defined instances, Genzyme has co-development/co-commercialization and/or global product rights. Genzyme has the right, under specified circumstances, to elect to co-develop and co-promote ALN-AT3, with Alnylam maintaining development and commercialization control. Genzyme's rights are structured as an opt-in that is triggered upon achievement of human proof-of-principle.

Conference Call Information
Alnylam management will discuss these new interim Phase 1 results with ALN-AT3 in a webcast conference call on Tuesday, June 23 at 4:30 p.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 64377549. A replay of the call will be available beginning at 7:30 p.m. ET. To access the replay, please dial 855-859-2056 (domestic) or 404-537-3406 (international), and refer to conference ID 64377549.

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, 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

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 and the potential clinical activity and durability of ALN-AT3, expectations regarding the reporting of data from clinical studies, in particular the ongoing Phase 1 clinical trial of ALN-AT3, as well as the Phase 1 OLE for ALN-AT3, expectations regarding the initiation of pivotal Phase 3 studies for ALN-AT3, expectations regarding its STAr pipeline growth strategy, and its plans regarding commercialization of RNAi therapeutics, including ALN-AT3, 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.

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Alnylam Pharmaceuticals, Inc.
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