Alnylam Pharma (ALNY) Announces Positive Fitusiran Phase 1 Data as Hemophilia and Rare Bleeding Disorders Treatment

July 25, 2016 12:19 PM EDT

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Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY) announced new positive results from its ongoing Phase 1 study with fitusiran, 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 and prevent bleeding in patients with hemophilia and RBD. These new data will be presented in an oral presentation at the World Federation of Hemophilia (WFH) 2016 World Congress, on Wednesday, July 27, 2016 in Orlando, Florida. Due to an inadvertent posting for a short period this morning of a draft version of the presentation on the WFH website, the Company will now host a conference call today, Monday, July 25, at 1:00 pm ET, to discuss these results.

New clinical data showed that once-monthly subcutaneous administration of fitusiran achieved dose-dependent lowering of AT and increases in thrombin generation, resulting in a median estimated annualized bleeding rate (ABR) of zero in evaluable patients with hemophilia A or B without inhibitors (N=17). In addition, data from an initial cohort of hemophilia patients with inhibitors (N=6) demonstrated AT lowering, increased thrombin generation, and preliminary evidence for reduced bleeding. Importantly, fitusiran was found to be generally well tolerated to date in patients with and without inhibitors, including no thromboembolic events. Finally, the Company announced that it now plans to initiate fitusiran pivotal studies in people with hemophilia with and without inhibitors in early 2017.

“As a once-monthly, fixed dose, subcutaneous prophylactic treatment option that could be shown to provide durable and consistent bleed prevention, fitusiran has the potential to transform the management of hemophilia and RBD, including patients with inhibitors. We believe these new data bring us closer to realizing that potential, as our exploratory analysis indicates that fitusiran can achieve a median estimated ABR of zero in patients with hemophilia A or B without inhibitors,” said Akin Akinc, Ph.D., Vice President and General Manager, Fitusiran. “Moreover, we believe our preliminary data in the first cohort of inhibitor patients receiving a low monthly subcutaneous fixed dose of 50 mg are promising, and we look forward to additional data at higher fitusiran doses in this patient sub-group with very high unmet need. Importantly, we continue to be encouraged by the tolerability profile for fitusiran.”

New results were presented from Part C (N=18) and Part D (N=6) of the ongoing Phase 1 study, and include all available data as of the data transfer up to July 11, 2016. Part C evaluated a monthly subcutaneous regimen at doses ranging from 225 micrograms per kilogram (mcg/kg) to 1800 mcg/kg, and also includes a cohort of six patients that received a fixed dose of 80 mg. Part D is evaluating monthly subcutaneous dosing in people with hemophilia A and B with inhibitors, and is designed to enroll up to a total of 18 patients. The first cohort of six patients with inhibitors received a 50 mg fixed, once-monthly, subcutaneous dose regimen. The second cohort has completed enrollment with six inhibitor patients receiving an 80 mg fixed, once-monthly, subcutaneous dose regimen.

Phase 1 Part C Interim Study Results in Hemophilia A or B without InhibitorsTreatment with fitusiran resulted in potent, dose-dependent, and statistically significant lowering of AT. At the 80 mg fixed monthly dose, fitusiran achieved 87 ± 1 percent mean maximal AT lowering with low inter-patient variability. The association between AT lowering and increased thrombin generation was assessed in a post hoc exploratory analysis in which AT lowering was grouped by 25 percent increments for completed patients in Parts B (N=12) and C (N=17) of the study. In the highest quartile of greater than or equal to 75 percent AT lowering (N=16), fitusiran administration resulted in mean increases in thrombin generation of approximately 290 percent relative to baseline (p less than 0.001, as compared to the lowest AT lowering quartile). Furthermore, there was a statistically significant, AT lowering-dependent reduction in bleeding frequency, with the greatest effect seen at greater than or equal to 75 percent AT lowering (p less than 0.05, based on a negative binomial regression model). These data support the therapeutic hypothesis that AT lowering of 75 percent or greater is associated with attenuation of the hemophilia phenotype in non-inhibitor patients.

To obtain a more comprehensive assessment of potential fitusiran effects on bleeding, a post hoc analysis was performed in evaluable patients from all five cohorts in Part C (N=17). Specifically, bleed events that occurred over the six month period prior to study entry (based on review of medical records) and bleed events that were assessed prospectively during days 0-28 following the initial fitusiran dose (the “onset period”) were compared with bleed events that occurred beyond day 29 up to day 112 (the “observation period”), the time period during which fitusiran achieves its therapeutic pharmacodynamic effect. Median estimated ABR values were determined accordingly. In addition, bleed events classified as “spontaneous” were analyzed separately to determine the estimated annualized spontaneous bleeding rate (AsBR).

Prior to study entry, evaluable patients (N=17) had an estimated median ABR of 28 for patients receiving on-demand factor therapy (N=4) and an estimated median ABR of two for patients receiving prophylactic factor therapy (N=13). During the prospectively monitored “onset period” interval, the estimated median ABR was 13 among all evaluable patients. In contrast, during the observation period, fitusiran administration achieved an estimated median ABR of zero. In all Part C dose cohorts during the observation period, the majority of patients (9 of 17; 53 percent) were bleed-free, and 82 percent of patients reported no spontaneous bleeds. In the 80 mg fixed dose cohort, the estimated median ABR of zero compared favorably with the pre-study ABR of 6 for the same patients when they were receiving prophylactic replacement factor therapy. While not based on direct comparative studies, the median estimated ABR achieved with once-monthly, subcutaneous fitusiran compares favorably to the range of median ABR values of zero to four reported in clinical studies of frequent prophylactic intravenous infusions of recombinant Factors VIII or IX.

Initial Phase 1 Part D Study Results in Hemophilia A or B Patients with InhibitorsPatients with hemophilia A or B with inhibitors were enrolled in the initial Part D dose cohort. Prior to study entry, all patients utilized bypass agents, including recombinant Factor VIIa and activated prothrombin complex concentrate (aPCC), to manage their bleeds, and had a notably high pre-study ABR of up to 80, based on review of medical records.

In order to obtain an initial experience with fitusiran, the first cohort (N=6) of inhibitor patients received a once-monthly, fixed subcutaneous dose of 50 mg. Fitusiran achieved a mean maximal AT lowering of 81 ± 2 percent and a mean maximal thrombin generation increase of approximately 368 percent, comparable to results observed from Part C in non-inhibitor patients at similar doses. In addition, preliminary evidence for reduced bleeding was observed, with a 49-100 percent reduction in estimated ABR during the observation period compared with pre-study values. Dose escalation has occurred, and the next cohort of inhibitor patients has been fully enrolled with once-monthly subcutaneous dosing at 80 mg (N=6). The Company expects to present additional data from inhibitor patients in Part D of the study in late 2016.

Interim Phase 1 Study Safety ResultsAs of the data transfer on July 11, 2016, fitusiran continues to be generally well tolerated in patients with hemophilia with or without inhibitors (N=31, with five patients participating in both Parts B and C). There have been no serious adverse events (SAEs) related to study drug, and no thromboembolic events or laboratory evidence (based on D-dimer, platelet count, fibrinogen, and/or PT/INR) of pathologic clot formation. All bleeds were successfully managed with standard replacement factor or bypass agent administration. One non-inhibitor patient in Part C at the 80 mg fixed dose cohort discontinued due to an adverse event considered severe and possibly related to study drug per. This event was described as non-cardiac chest pain and was accompanied by transient elevations of ALT (10x upper limit of normal, ULN), AST (8x ULN), C-reactive protein, and D-dimer, without increase in total bilirubin. Extensive evaluation was unremarkable, and venous thromboembolism was excluded by serial CT angiograms and liver and lower extremity ultrasound. This patient’s event resolved with symptomatic management, including antacids and analgesics. Eleven patients (35 percent) reported mild, drug-related injection site reactions (ISRs), which were mostly pain or erythema at the injection site. Additional AEs reported in greater than or equal to 10 percent of patients included upper respiratory tract infection (10 percent) and arthralgia (10 percent); the majority of these AEs were mild or moderate in severity. With the exception of the case noted above, there were no other clinically significant drug related changes in laboratory parameters. Finally, there have been no instances of anti-drug antibody formation to fitusiran.

Additional Data and Development Plans“Turning to our development plans, we’ve completed constructive initial discussions with regulatory authorities and as an update to previous guidance, we now plan to initiate our Phase 3 studies in patients with and without inhibitors in early 2017 following completion of the second inhibitor patient dose cohort in the Phase 1 study,” Dr. Akinc added. “Moreover, we plan on presenting additional data later this year, including additional results from inhibitor patients and initial data from the ongoing Phase 1/2 open-label extension study, where patients have now received up to 13 monthly doses of fitusiran.”

Alnylam plans to report additional data from fitusiran studies in late 2016. These data are expected to include additional results from Part D of the ongoing Phase 1 study and initial results from the Phase 1/2 open-label extension (OLE) study. Twenty-one patients who have completed treatment in the Phase 1 study have now rolled over to the OLE study, where they are receiving monthly fitusiran administration. Additional patients are expected to enroll in the OLE study as they become eligible.

To view the clinical results presented by Alnylam at the WFH meeting, please visit

Conference Call InformationAlnylam management will discuss these data in a webcast conference call today, Monday, July 25, at 1:00 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 51834298. A replay of the call will be available at 3:00 p.m. ET. To access the replay, please dial 855-859-2056 (domestic) or 404-537-3406 (international), and refer to conference ID 51834298.

About the Fitusiran Phase 1 StudyThe ongoing Phase 1 trial of fitusiran is being conducted in United States, 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 has completed dosing – is an open-label, multi-dose, dose escalation study that enrolled 18 patients with moderate or severe hemophilia A or B without inhibitors. Twelve patients in Part C received three monthly subcutaneous doses of fitusiran at doses of 225, 450, 900, or 1800 mcg/kg. In addition, six patients in Part C received three fixed monthly subcutaneous doses of fitusiran at 80 mg. Part D of the study is designed to enroll up to 18 patients with inhibitors. Patients in Part D will receive three fixed monthly subcutaneous doses of fitusiran at 50 mg or 80 mg. 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, with and without inhibitors. 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 DisordersHemophilia is a bleeding disorder characterized by insufficient thrombin generation following hemostatic challenge and resulting in recurrent bleeds into joints, muscles, and other internal organs. There are approximately 200,000 diagnosed patients with hemophilia worldwide. Hemophilia A is defined by loss-of-function mutations in Factor VIII, and represents approximately 80 percent of the hemophilia population. Hemophilia B, is defined by loss-of-function mutations in Factor IX, and represents approximately 20 percent of the hemophilia population. Other Rare Bleeding Disorders (RBD) are defined by deficiencies of blood coagulation factors, including Factors II, V, VII, X, and XI. There are an estimated 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 AllianceIn 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 product 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 GalNAc Conjugates and Enhanced Stabilization Chemistry (ESC)-GalNAc ConjugatesGalNAc-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 RNAiRNAi (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.

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