Safety and efficacy of a fitusiran antithrombin-based dose regimen in people with hemophilia A or B: the ATLAS-OLE study

Abstract

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.

Graphical abstract

Figure 1.

Fitusiran AT-DR. ∗Clinical criteria for dose escalation at AT activity levels of <35% may also be considered; †Start of dosing after deescalation from higher dose to occur only after centrally measured AT activity levels of ≥22%. Participants receiving fitusiran at a dose of 20 mg q2m who experience >1 AT level of <15% (as per central laboratory assessment) within a 12-month period must permanently discontinue fitusiran treatment. q2m, every 2 months; qm, once monthly; SS, steady state.

Figure 2.

ATLAS-OLE: participant disposition and proportion of participants on each dose regimen. ∗Percentage denominator is 180 patients who had the ODR; †93.9% of participants required no or only 1 dose change to achieve AT activity levels of 15% to 35%; ‡These participants were permitted to continue receiving 80 mg qm after the introduction of the AT-DR because they had not experienced >1 AT activity level of <15% during prior fitusiran treatment (based on at least 3 months of prior AT measurements); §Percentage denominator is 213 patients who had AT-DR. qm, once monthly.