Alnylam Reports Positive Phase 1 Study Results for Once-Monthly, Subcutaneous Fitusiran (ALN-AT3) in Patients with Hemophilia A and B

Dec 07,2015

- Achieves Dose-Dependent Lowering of Antithrombin of Up to 88 Percent, Clinically Meaningful Increases in Thrombin Generation, and Reductions of 85 Percent in Median Estimated Annualized Bleeding Rates -

- Fitusiran Shown to be Generally Well Tolerated to Date, with no Significant Changes in Levels of D-Dimer, a Biomarker of Excessive Clot Formation -

- Company Remains on Track to Initiate Phase 3 Studies in Mid-2016 -

- Management to Discuss Results at Upcoming R&D Day on Thursday, December 10, 2015 -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), the leading RNAi therapeutics company, announced today positive results from its ongoing Phase 1 clinical study with fitusiran (fi-TOO-si-ran), the recommended International Nonproprietary Name (INN) for ALN-AT3. 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 lower levels of AT with the goal of promoting sufficient thrombin generation to restore hemostasis, thereby preventing bleeding in patients with hemophilia. The new clinical data were presented in an oral session at the American Society of Hematology (ASH) 2015 Annual Meeting, held December 5 - 8 in Orlando, Florida. Results demonstrated that subcutaneous administration of fitusiran achieved potent and dose-dependent lowering of AT of up to 88 percent. In addition, AT lowering was associated with statistically significant and clinically meaningful increases in thrombin generation and decreases in bleeding frequency in patients with hemophilia. In particular, fitusiran administration resulted in an 85 percent reduction in median estimated annualized bleeding rates (ABR) in nine evaluable patients. Importantly, fitusiran was found to be generally well tolerated to date, including no clinically significant increases in D-dimer, a biomarker of excessive clot formation. Consistent with previous guidance, the company expects to begin pivotal studies of fitusiran in mid-2016.

"We regard these new results from the ongoing Phase 1 clinical trial as very promising, as they demonstrate clinical activity for once-monthly, subcutaneous fitusiran with robust AT lowering and clinically meaningful increases in thrombin generation. In addition, while exploratory and only in a limited number of patients, the reduction in the median estimated ABR resulted in bleeding rates that are comparable to those reported in the literature for prophylactic intravenous infusions of replacement factors or ‘bypass agents' in patients with hemophilia. We're also encouraged by our overall safety results, that now include patients with an aggregate of over 300 days of exposure at levels of AT lowering greater than 75 percent," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer of Alnylam. "We have now initiated enrollment of patients in our Phase 1 open-label extension study, and expect to present data from that study on an ongoing basis at least once per year beginning in 2016. In addition, we expect to start our fitusiran Phase 3 program in hemophilia A and B, including patients with and without inhibitors, in mid-2016."

"Hemophilia is a bleeding disorder characterized by an underlying defect in the ability to generate adequate levels of thrombin needed for effective clot formation. I believe that fitusiran represents a unique and innovative investigational medicine, as it shows the potential to promote the generation of sufficient levels of thrombin needed to restore hemostasis in people with hemophilia. Further, the availability of a monthly, subcutaneously administered therapeutic would be welcomed by patients," said John Pasi, M.D., Ph.D., Professor of Haemostasis and Thrombosis and Consultant Haemotologist at Barts Health NHS Trust, UK. "I am excited by the continued tolerability and new clinical activity results emerging from the ongoing Phase 1 study. The findings reported today appear to demonstrate meaningful improvements in bleeding frequency and support the continued development and study of this novel investigational therapeutic agent."

New results were presented from 24 patients with hemophilia in Parts B (N=12) and C (N=12) of the ongoing Phase 1 study, and include all available data as of the data cutoff date of November 12, 2015.

Alnylam and collaborators will discuss these new clinical results with fitusiran at the company's upcoming R&D Day, to be held on Thursday, December 10, 2015 at the Sofitel New York in New York City. This event will be webcast live on the Investors section of the company's website, An audio replay of the event will be available on the Alnylam website approximately 90 minutes after the event.

Preliminary Phase 1 Study Clinical Activity Results

Monthly subcutaneous doses of fitusiran resulted in potent, dose-dependent, and statistically significant lowering of AT of up to 88 percent. At the top dose of 1800 micrograms per kilogram (mcg/kg), the mean maximum AT lowering was 79 ± 3 percent. The dose response for fitusiran was examined by comparing the mean maximum AT lowering with the monthly equivalent doses administered to volunteers and patients in Parts A, B, and C of the study (N=27). As anticipated, dose-dependent AT lowering and durability were demonstrated upon exploring the full spectrum of doses in the MAD phases. AT lowering with fitusiran was associated with statistically significant increases in thrombin generation, providing continued evidence for the potential restoration of hemostasis in patients with hemophilia. The association between AT lowering and increased thrombin generation was assessed in a post hoc exploratory analysis in which AT lowering was categorized into quartiles. In the highest quartile (greater than 75 percent AT lowering) (N=9), fitusiran administration resulted in mean increases in thrombin generation of 285 ± 165 percent (p less than 0.001 based on paired t-test). At this level of AT lowering, the mean peak thrombin generation was 62 ± 27 nM, and the range of peak thrombin generation values was found to overlap with those observed in healthy volunteers (64 - 210 nM).

A sub-study was performed to correlate patient-specific thrombin generation levels achieved following fitusiran administration with those achieved with Factor VIII dosing. Severe hemophilia A patients (N=3) received a single intravenous dose of recombinant Factor VIII prior to receiving their first dose of subcutaneous fitusiran. Following Factor VIII administration, both Factor plasma levels and thrombin generation were measured at various time points to generate a patient-specific standard curve relating Factor level to thrombin generation. Thrombin generation values achieved after washout of Factor VIII and following fitusiran administration were then converted to Factor equivalence levels based on the patient-specific standard curve. In this sub-study, fitusiran dosing resulted in peak thrombin generation values equivalent to those achieved at plasma Factor VIII levels greater than 40-50 percent of normal. Accordingly, in these three subjects, subcutaneous fitusiran treatment resulted in restoration of thrombin generation to levels consistent with what are essentially normal functional levels of Factor VIII.

An exploratory post hoc analysis was performed by examining the frequency of prospectively measured, on-study bleeding events in all patients in Parts B and C of the study (N=24). During the period of time when patients had AT lowering less than 25 percent, a total of 43 bleeding events were reported in 24 patients, and the mean and median estimated ABRs were 34 ± 10 and 13, respectively. In the ongoing Phase 1 fitusiran study, an AT lowering-dependent reduction in the mean and median estimated ABR values was achieved. At the highest quartile of greater than 75 percent AT lowering, where 9 patients experienced an aggregate exposure of 304 days, the mean and median estimated ABR values were reduced to 6 ± 3 and 0, respectively. The reduction in mean estimated ABR associated with increased AT lowering was statistically significant (p less than 0.05 based on a negative binomial regression model).

An additional post hoc analysis was performed in patients from three cohorts in Part C of the study to evaluate fitusiran effects on bleeding (data for the 1800 mcg/kg cohort were not sufficiently mature for this analysis). Here, the effect of fitusiran administration on estimated ABR was evaluated through prospective measurement of bleeding events during an "onset period" (the period from day 0 through day 28 when initial AT lowering is ongoing) and an "observation period" (defined as the period from day 29 to the last day available, to a maximum of day 112, during which AT levels exhibit sustained lowering). In addition, and where available, data on patient-reported, historical on-demand ABR were collected. In this analysis, there was a marked 85 percent reduction in the median estimated ABR during the observation period as compared with the median historical on-demand ABR for all nine evaluable Part C patients. Specifically, the median historical on-demand median ABR was 28 and the onset period median estimated ABR was 12.6. In contrast, the median estimated ABR during the post-fitusiran dosing observation period was 4.3. In the highest two evaluable dose cohorts (N=6), the median estimated ABR during the observation period was even lower at 2.2. Notably, this median estimated ABR achieved with once monthly, subcutaneous fitusiran compares favorably to the range of median ABR values of 1.1 to 3.7 reported in clinical studies of prophylactic intravenous infusions of recombinant Factor VIII or IX1-4 and the median ABR of 7.9 reported in a clinical study of prophylactic bypass agent regimen in hemophilia patients with inhibitors5.

Preliminary Phase 1 Study Safety Results

As of the current data cutoff of November 12, 2015, fitusiran continues to be generally well tolerated in all patients with hemophilia (Parts B and C, N=24). As noted above, this includes a total of 9 patients who achieved a greater than 75 percent lowering of AT for an aggregate of 304 days. There have been no serious adverse events (SAEs) related to study drug, no discontinuations, and no significant changes in physical exams, vital signs, or electrocardiography. One patient was hospitalized due to re-activation of hepatitis C, which was not related to fitusiran administration. There were three drug related adverse events (AEs), all of which were mild. Among these AEs, there were two injection site reactions (ISRs), each consisting of mild, transient pain. There have been no clinically significant changes in any laboratory parameter, including liver function tests, hematology, and coagulation measures. There have been no thromboembolic events or clinically significant increases in D-dimer. All bleeds were successfully managed with standard replacement factor administration, with no associated adverse events. Finally, there have been no instances of anti-drug antibody formation to fitusiran.

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 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 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 3 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 3 monthly subcutaneous doses of fitusiran at doses of 225, 450, 900, or 1800 mcg/kg. The primary objective of Parts B and C 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.

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.

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 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, Genzyme has elected to opt into the program for its rest-of-world 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 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

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 (ALN-AT3), expectations regarding the timing of clinical trials with fitusiran, including the expected initiation of the Phase 3 program, and the reporting of clinical data from these clinical trials, including the reporting of data from the ongoing Phase 1 OLE study during 2016 and beyond, 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.


1 Lentz et al., Haemophilia. 2013;19(5):691-7

2 Powell et al., N Engl J Med. 2013;369(24):2313-23

3 Mahlangu et al., Blood. 2014;123(3):317-25

4Valentinoet al., J Thromb Haemost. 2012;10(3):359-67

5 Antunes et al., Haemophilia. 2014;20(1):65-72

Alnylam Pharmaceuticals, Inc.
Christine Regan Lindenboom, 617-682-4340
(Investors and Media)
Josh Brodsky, 617-551-8276

Source: Alnylam Pharmaceuticals, Inc.

News Provided by Acquire Media