Alnylam presents positive Phase 1 ALN-AT3 trial results in hemophilia at ISTH 2015 Congress

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

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,” said Akshay 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 the U.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.

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.