Objective:

Hemophilia A and B arise from the inability to generate sufficient thrombin to prevent and stop bleeding, due to deficiency in factors VIII and IX, respectively. Fitusiran is a once-monthly subcutaneously administered investigational therapy that harnesses the natural RNA interference mechanism to regulate antithrombin (AT), enhancing thrombin generation (TG) and promoting hemostasis in people with hemophilia A or B, with or without inhibitors. The mechanism of action of fitusiran is independent of intrinsic and extrinsic coagulation pathways. An overview of the clinical development plan for fitusiran for the treatment of hemophilia is presented herein.

Methods:

The completed phase 1 study evaluated safety, dosing, and clinical activity. The ongoing phase 1/2 open-label extension (OLE) study includes subjects who completed the phase1 study. The phase 3 ATLAS program consists of 4 pivotal studies and 2 OLE studies, including a pediatric program, and is recruiting. Table 1 provides an overview of subject populations, study arms, and key endpoints.

Summary:

Of 42 subjects with hemophilia treated with fitusiran in the phase 1 study, 34 rolled over into the phase 1/2 OLE. As of September 30, 2019, the median exposure in the phase 1/2 OLE was 2.1years, the maximum exposure was 3.3 years, and the total exposure was 68.6 patient-years. As of April 20, 2020, 245 subjects are enrolled in the ATLAS program (ATLAS-INH, 57subjects; ATLAS-A/B, 116; ATLAS-PPX, 72). Data to date show that monthly fitusiran enables steady-state AT levels and increased TG, promoting hemostasis in hemophilia patients.

Conclusions:

Ongoing evaluation of the efficacy and safety of fitusiran will clarify its therapeutic potential for hemophilia A or B, with or without inhibitors.