Sanofi Genzyme, the specialty care global business unit of Sanofi, and Alnylam Pharmaceuticals, Inc, the leading RNAi therapeutics company, announced new positive results from the ongoing phase 2 open-label extension (OLE) study with fitusiran in patients with hemophilia A and B, with or without inhibitors (N=33).  These results were presented  in an oral presentation at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress, being held from July 8 - 13, 2017 in Berlin, Germany.

Fitusiran is an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of patients with hemophilia A and B, that is designed to lower levels of AT with the goal of promoting sufficient thrombin generation upon activation of the clotting cascade to restore hemostasis and prevent bleeding. The companies also announced that phase 1 clinical trial results demonstrating an encouraging preliminary safety and tolerability profile and initial evidence that monthly subcutaneously administered fitusiran lowered AT levels and increased thrombin generation in patients with hemophilia A and B without inhibitors were published online today and will appear in the September 7, 2017, print issue of The New England Journal of Medicine (NEJM).

The updated clinical results in the fitusiran phase 2 OLE study showed that the safety and tolerability profile of fitusiran remains encouraging, with no thromboembolic events, including during co-administration of replacement factor or bypassing agents. The majority of adverse events (AEs) were mild or moderate in severity, with the most common AEs consisting of transient, mild injection site reactions (ISRs). In addition, once-monthly subcutaneous (SC) administration of fitusiran achieved lowering of AT, increases in thrombin generation, and, in a post-hoc exploratory analysis, reductions in the median estimated annualized bleeding rate (ABR) in patients with and without inhibitors. Based on these results, the companies announced last week the initiation of the ATLAS phase 3 program for fitusiran in patients with hemophilia A and B with or without inhibitors.

 "With up to 20 months of dosing in patients, we are encouraged by the results from our fitusiran clinical studies presented at the ISTH meeting today, demonstrating what we believe to be promising support for further clinical development," said Akin Akinc, Ph.D., Alnylam's vice president and general manager, Fitusiran. "We're also pleased to have announced initiation of our ATLAS phase 3 program just last week, where the safety and efficacy of fitusiran will be evaluated and where we expect initial results in mid-to-late 2019."

"We've achieved an encouraging safety and tolerability profile and low median ABRs with a monthly subcutaneous dosing regimen, highlighting fitusiran's potential to become a differentiated and innovative treatment option for patients with hemophilia," said Baisong Mei, M.D., Ph.D., Sanofi's Senior Global Project Head, Alnylam Portfolio. "We're now focused on our ATLAS phase 3 program, a comprehensive set of studies focused on the unmet needs of patients with hemophilia A and B with or without inhibitors, which, if positive, will support global regulatory filings for fitusiran."

The ongoing fitusiran phase 2 OLE study includes patients (N=33) with hemophilia A (N=27) and hemophilia B (N=6). The study includes 14 patients with inhibitors, including one with hemophilia B. Fitusiran was administered as a low volume (less than 1 mL), monthly, subcutaneous, fixed dose of 50 mg (N=13) or 80 mg (N=20).  All results are as of a June 15, 2017 data transfer date.

Patients were treated for up to 20 months in the phase 2 OLE, with a median of 11 months on study. The majority of AEs were mild or moderate in severity, with the most common non-laboratory AEs consisting of transient, mild ISRs (18 percent of patients). There was one discontinuation due to an AE, an asymptomatic alanine aminotransferase (ALT) elevation in a patient with chronic hepatitis C virus (HCV) infection. Serious adverse events (SAEs) considered possibly related to drug were reported in two patients: asymptomatic ALT elevation in one patient with chronic HCV infection, as noted above, and seizure with confusion in one patient with a prior history of seizure disorder. Asymptomatic ALT increases greater than 3x the upper limit of normal (ULN), without concurrent elevations in bilirubin  greater than 2x ULN, were observed in 11 patients, all of whom were hepatitis C antibody positive; at current follow-up, all ALT elevations are resolved (N=10) or resolving (N=1). No thromboembolic events, laboratory evidence for pathological clot formation, or instances of anti-drug antibody (ADA) formation were reported.

Regarding clinical activity results, treatment with fitusiran resulted in approximately 80 percent lowering of AT with corresponding increases in thrombin generation.  Increases in thrombin generation remained within the lower end of the range of values observed in normal healthy volunteers. In an exploratory post-hoc analysis of bleeding events, a median ABR of one (interquartile range [IQR]: 0-3) was achieved for all patients (N=33), and a median  ABR of zero (IQR: 0-3) was achieved for the subset of patients with inhibitors (N=14), corresponding favorably to pre-study median ABR values of 20 (IQR: 4-36)  in all patients and 38 (IQR: 20-48) in inhibitor patients. There was a high proportion of patients (16 of 33; 48 percent) who remained bleed-free in the observation period, and most patients (22 of 33; 67 percent) experienced zero spontaneous bleeds. All breakthrough bleed events were successfully managed with replacement factor (recombinant factor VIII or recombinant factor IX) or bypassing agents (recombinant factor VIIa or activated prothrombin complex concentrate).

As noted above, the companies also announced today that a paper titled, "Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy," was published online today in The New England Journal of Medicine Alnylam and its collaborators, including lead author and principal study investigator John Pasi, M.D., Ph.D., Professor of Haemostasis and Thrombosis, Clinical Director of Haemophilia at The Royal London Hospital Barts Health NHS Trust, and Barts and the London School of Medicine and Dentistry, London, UK, provided results from Parts A-C of the phase 1 multicenter, international, open-label single- and multiple-ascending dose escalation study in healthy volunteers and patients with hemophilia A and B without inhibitors. This is the first publication of safety, tolerability and initial clinical activity data for fitusiran in patients with hemophilia A and B.

"Current hemophilia management is based on factor replacement therapies that require frequent intravenous infusions to maintain adequate factor trough levels. Significant unmet need remains for additional therapeutic agents," said John Pasi. "The results of our phase 1 clinical study published in The New England Journal of Medicine support the growing body of evidence to continue the clinical development program for fitusiran."