Interim Data from Ongoing Phase 1 Trial with Fitusiran for the Treatment of Hemophilia and Rare Bleeding Disorders

We reported new data from Parts C and D of our Phase 1 study with fitusiran, an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders, at the World Federation of Hemophilia (WFH) World Congress, held July 24-28, 2016 in Orlando, Florida.

Interim results from Part C (N=18) of the study showed that monthly, subcutaneous administration of fitusiran resulted in potent, dose-dependent, and statistically significant lowering of AT and increases in thrombin generation. In addition, there was a statistically significant, AT lowering-dependent reduction in the frequency of bleeding events. Together, these data support the therapeutic hypothesis that AT lowering of 75% or higher is associated with attenuation of the hemophilia phenotype.

In an exploratory post hoc analysis, pre-study bleed events that occurred during the 6 months prior to study entry (based on review of medical records), and bleed events that were measured 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”).  During the observation period, the estimated median ABR for all evaluable patients in Part C of the study (N=17) was zero, which compares favorably to pre-study median ABR values of 28 for patients receiving on-demand Factor therapy (N=4), two for patients receiving prophylactic Factor therapy (N=13), and 13 for all patients during the onset period.  Further, 53% of patients were bleed-free, and 82% of patients reported no spontaneous bleeds during the observation period.

In Part D of the study, six patients with inhibitors in the first cohort received a 50 mg fixed, once-monthly subcutaneous dose regimen. In this cohort, fitusiran achieved AT lowering and thrombin generation increases comparable to results observed in Part C non-inhibitor patients at similar doses.  Importantly, the estimated ABR values reported from the observation period of the study showed a 49-100% reduction as compared with pre-study values, providing preliminary evidence supporting the potential for fitusiran to reduce bleeding in patients with inhibitors.  The second cohort in Part D has completed enrollment with six inhibitor patients receiving an 80 mg fixed, once-monthly subcutaneous dose regimen.

As of the data transfer on July 11, 2016, fitusiran continues to be generally well tolerated in patients with hemophilia, both with and without inhibitors Parts B, C and D; N=31, with five patients participating in both Parts B and C).  There have been no serious adverse events related to study drug, and no thromboembolic events or laboratory evidence of pathologic clot formation.  All bleeds were successfully managed with standard replacement factor or bypass agent administration, with no associated adverse events.  There was one study drug discontinuation at the 80 mg fixed dose cohort due to a severe adverse event considered possibly related to study drug.  This event was described as non-cardiac chest pain and was accompanied by transient elevations of ALT, AST, 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 AEs all resolved with symptomatic management, including antacids and analgesics. Eleven patients (35%) reported mild, drug-related injection site reactions, which were mostly pain or erythema at the injection site. Additional AEs reported in 10 percent or more of patients included upper respiratory tract infection and arthralgia; 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.

We believe that fitusiran is an innovative investigational medicine with the potential to transform the management of hemophilia and rare bleeding disorders. We look forward to the continued advancement of fitusiran as we strive to provide the hemophilia community with improved therapeutic options.