Interim Clinical Results from Fitusiran, an investigational RNAi therapeutic for the Treatment of Hemophilia and Rare Bleeding Disorders
We reported positive interim results from our Phase 1 study of fitusiran in patients with hemophilia with inhibitors as well as from our Phase 2 open-label extension (OLE) study in hemophilia patients without inhibitors at the 58th Annual Meeting of the American Society of Hematology (ASH), held December 3 – 6, 2016 in San Diego, California.
New results showed that once-monthly subcutaneous administration of fitusiran at two fixed dose levels, 50 mg (N=6) and 80 mg (N=10), achieved potent and dose-dependent lowering of antithrombin (AT) and increases in thrombin generation in patients with hemophilia A or B with inhibitors. In an exploratory analysis of bleeding events, a median ABR of zero was achieved for patients in combined dose cohorts in the observation period, compared to the pre-study median ABR of 31. The majority of patients treated in both cohorts (9 of 16; 56%) were bleed-free and most patients (11 of 16; 69%) experienced zero spontaneous bleeds. In the 80 mg cohort, 70% (7 out of 10) of patients were bleed-free and 90% (9 out of 10) of patients experienced zero spontaneous bleeds.
As of October 6, 2016, fitusiran was generally well tolerated, with all adverse events (AEs) mild or moderate in severity and the most common AEs consisting of mild injection site reactions (ISRs) in 8 out of 16 patients (50%). Asymptomatic and reversible alanine aminotransferase (ALT) increases >3x the upper limit of normal (ULN), without concurrent elevations in bilirubin >2x ULN, were observed in three patients, all of whom have medical history of hepatitis C infection (HCV). There were no drug-related serious adverse events (SAEs), no discontinuations due to AEs, and no thromboembolic events through the data cut-off date. All breakthrough bleed events were successfully managed with bypassing agents.
Prophylactic treatment options for hemophilia patients with inhibitors are currently limited and may be suboptimal for many. We look forward to the continued advancement of fitusiran as we strive to provide superior therapeutic choices for this patient population with extraordinarily high unmet need.
In the Phase 2 OLE study, fitusiran was administered subcutaneously once-monthly at two fixed dose levels, 50 mg (N=8) and 80 mg (N=8), with patients receiving up to 14 months of continuous dosing. Both dose levels achieved consistent, mean AT lowering of approximately 80% and mean increases in thrombin generation levels approaching the lower end of the range observed in normal healthy individuals who were enrolled in Part A of the Phase 1 study. In an exploratory post hoc analysis of bleed events, fitusiran achieved a median overall ABR of 1.0, over a median observation period of 5.7 months, compared to a median pre-study ABR of 4.0. Further, 8 out of 16 patients (50%) reported zero bleeds and 11 out of 16 patients (69%) experienced zero spontaneous bleeds.
As of October 6, 2016, Fitusiran was generally well tolerated, with all AEs mild or moderate in severity and the most common AEs consisting of mild ISRs in 4 out of 16 patients (25%). Asymptomatic and reversible alanine aminotransferase (ALT) increases >3x ULN, without concurrent elevations in bilirubin >2x ULN, were observed in three patients in the OLE study, all of whom have medical history of hepatitis C infection (HCV). All breakthrough bleeding events were successfully managed with replacement factor. There were no drug-related SAEs, no discontinuations due to AEs, and no thromboembolic events or laboratory evidence of pathologic clot formation in the OLE through the data cut-off date.
We believe fitusiran represents an innovative and differentiated approach to the treatment of hemophilia and other rare bleeding disorders, with the potential to transform disease management and improve the lives of patients.