Fitusiran prophylaxis in people with hemophilia A or B who switched from prior BPA/CFC prophylaxis: the ATLAS-PPX trial

Abstract

Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance hemostasis in people with hemophilia A or B (PwHA/B), irrespective of inhibitor status. This phase 3, open-label study evaluated the efficacy and safety of fitusiran prophylaxis in males aged ≥12 years with hemophilia A or B, with or without inhibitors, who received prior bypassing agent (BPA)/clotting factor concentrate (CFC) prophylaxis. Participants continued their prior BPA/CFC prophylaxis for 6 months before switching to once-monthly 80 mg fitusiran prophylaxis for 7 months (onset and efficacy periods). Primary end point was annualized bleeding rate (ABR) in the BPA/CFC prophylaxis and fitusiran efficacy period. Secondary end points included spontaneous ABR (AsBR) and joint ABR (AjBR). Safety and tolerability were assessed. Of 80 enrolled participants, 65 (inhibitor, n = 19; noninhibitor, n = 46) were eligible for ABR analyses. Observed median ABRs were 6.5 (interquartile range [IQR], 2.2-19.6)/4.4 (IQR, 2.2-8.7) with BPA/CFC prophylaxis vs 0.0 (IQR, 0.0-0.0)/0.0 (IQR, 0.0-2.7) in the corresponding fitusiran efficacy period. Estimated mean ABRs were substantially reduced with fitusiran by 79.7% (P = .0021) and 46.4% (P = .0598) vs BPA/CFC prophylaxis, respectively. Forty-one participants (63.1%) experienced 0 treated bleeds with fitusiran vs 11 (16.9%) with BPAs/CFCs. Median AsBR and AjBR were both 2.2 with BPA/CFC prophylaxis and 0.0 in the fitusiran efficacy period. Two participants (3.0%) experienced suspected or confirmed thromboembolic events with fitusiran. Once-monthly fitusiran prophylaxis significantly reduced bleeding events vs BPA/CFC prophylaxis in PwHA/B, with or without inhibitors, and reported adverse events were generally consistent with previously identified risks of fitusiran. This trial was registered at www.ClinicalTrials.gov as #NCT03549871.

Graphical abstract

Figure 1.

Participant disposition. ∗Among the 19 screen failures, the main reasons for screen failure were exclusion criterion of the coexisting thrombophilic disorder (7 [7.1%] of the overall participants screened; 2 [5.7%] in cohort A; and 5 [7.8%] in cohort B) or withdrawn consent (7 [7.1%] of the overall participants screened; 1 [2.9%] in cohort A; and 6 [9.4%] in cohort B). ^†A subgroup of cohort A included PwHB with inhibitors who were not responding adequately to BPA prophylaxis before enrollment (historical ABR, ≥ 20). ^‡After sponsor initiated pause in dosing and subsequent protocol amendment. ^§Nine participants with fitusiran 80 mg prophylaxis who discontinued therapy remained in the study to complete study assessments and follow-up to allow for the best study integrity and interpretation. ^¶One participant with fitusiran 50 mg prophylaxis who discontinued therapy remained in the study to complete study assessments and follow-up to allow for the best study integrity and interpretation.

Figure 2.

Bleeding events in the fitusiran efficacy and BPA/CFC prophylaxis period (EAS 1). (A) ABRs for treated bleeds (estimated by negative binomial model). (B) ABRs for treated bleeds by inhibitor status (estimated by negative binomial model). (C) Number of treated bleeds. ∗Includes all participants who received BPA/CFC prophylaxis and at least 1 dose of 80 mg fitusiran before dose resumption (after the sponsor initiated pause in dosing). ^†P value from a negative binomial regression model with study period (fitusiran efficacy period or BPA/CFC prophylaxis period) as a fixed effect and a robust sandwich covariance matrix constructed to account for the within subject dependence, the logarithm of the duration (in years) that each participant spends in each study period matching the bleeding episode data being analyzed as an offset variable (P value vs null hypothesis of ratio = 1). ^‡The BPA/CFC prophylaxis period was defined as starting on day –168 to day –1 or the last day of bleeding follow-up, whichever was the earliest. ^§Fitusiran efficacy period was defined as starting on day 29 after the first dose of fitusiran up to day 197 or the last day of bleeding follow-up, whichever was the earliest.

Figure 3.

Pharmacodynamic outcomes. (A) Mean change in AT levels from baseline. (B) Mean peak TG. Measurements after fitusiran discontinuation +28 days were excluded. Measurements from start date of heparin, AT concentrate, and FXa inhibitor to the final date on which those products were administered plus 5 half-lives of that specific product were excluded. Measurements in the period of missing at least 2 consecutive fitusiran doses were excluded. Only central laboratory assessments were taken into account. SE, standard error.