Fitusiran

Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, lowers antithrombin (AT) to increase thrombin generation and rebalance hemostasis in people with hemophilia. This phase 3 open-label extension study (ATLAS-OLE) evaluated safety and efficacy of an AT-based dose regimen (AT-DR) in males aged ≥12 years with severe hemophilia A/B, with/without inhibitors. The original dose regimen (ODR) of 80 mg monthly was optimized to AT-DR targeting AT activity levels 15% to 35% to mitigate thrombotic risk (starting dose of 50 mg once every 2 months, individually adjusted to 20 mg once every 2 months, or 20/50/80 mg monthly as needed). Primary and secondary end points were safety and efficacy, respectively. Integrated safety analyses assessed safety of AT-DR and ODR across all fitusiran studies and integrated efficacy analyses compared efficacy of AT-DR in ATLAS-OLE with phase 3 parent study control groups. At interim data cutoff, 213 participants were enrolled on AT-DR (78% on regimens of once every 2 months). Integrated safety analyses of participants receiving AT-DR (n = 286) demonstrated that AT-DR was well tolerated. In ATLAS-OLE, median observed annualized bleeding rate (ABR) with AT-DR was 3.7 (interquartile range, 0.0-7.5). Integrated efficacy analyses demonstrated superiority of AT-DR over on-demand clotting factor concentrates (CFCs; 71% mean ABR reduction; P < .0001), and on-demand bypassing agents (BPAs; 73% mean ABR reduction; P = .0006); improvement over BPA prophylaxis (70% mean ABR reduction); and ABR comparable with that observed with CFC prophylaxis. Fitusiran AT-DR was well tolerated and maintained bleed protection with as few as 6 injections per year. This trial was registered at www.ClinicalTrials.gov as #NCT03754790.