Efficacy and Safety of the Anti-Tissue Factor Pathway Inhibitor Marstacimab in Participants with Severe Hemophilia without Inhibitors: Results from the Phase 3 Basis Trial

Background:Marstacimab (PF-06741086) is a monoclonal antibody targeted to the tissue factor pathway inhibitor protein to improve hemostasis via the extrinsic pathway of blood coagulation. Previous phase 1/2 studies demonstrated the efficacy and safety of long-term administration of marstacimab up to 450 mg weekly for reducing bleeding episodes in adults with severe hemophilia A (HA) or hemophilia B (HB), with or without inhibitors, compared with on-demand (OD) therapy. We evaluated the efficacy and safety of marstacimab in participants with severe HA or moderately severe to severe HB without inhibitors compared with previous factor replacement therapy. Methods: BASIS (NCT03938792) is an open-label, multicenter, pivotal phase 3 study that enrolled male participants aged ≥12 to ˂75 y with severe HA (factor [F] VIII ˂1%) or moderately severe to severe (FIX ≤2%) HB, with or without inhibitors. Following screening, participants entered a 6-month observational phase (OP) and were categorized by factor replacement treatment: (1) OD or (2) routine prophylaxis (RP). Participants who completed the OP crossed over to 12-month active treatment phase (ATP) and received a single subcutaneous loading dose of 300 mg followed by once weekly 150 mg marstacimab. Primary endpoints were annualized bleeding rate (ABR) for treated bleeds and safety outcomes. Secondary endpoints included incidence of various types of breakthrough bleeds and health-related quality of life (HRQoL) measures. Participants who completed the ATP were eligible to enroll in the long-term extension (LTE) study. Informed consent/ethics committee approvals were obtained. Results for participants without inhibitors are presented. Results: Participants (N=128; 108 adults, 20 adolescents) with HA or HB without inhibitors entered the OP (OD: HA n=29, HB n=8; RP: n=72, HB n=19); of these, 116 entered the ATP. The median age was 30 [range, 13-66] y, most participants were White (50.8%) or Asian (47.7%) and predominately from Europe and India (51.6%). At baseline, 89 participants (69.5%; OD: n=36; RP: n=53) had ≥1 target joint. Mean (range) duration of marstacimab treatment was 12.1 (11.5-13.1) months for OD and 11.6 (0.9-12.8) months for RP. Eighty-eight participants entered the LTE (OD: HA n=22, HB n=7; RP: HA n=45; HB n=13). Data were not available by the cutoff date for 1 RP participant and was not included in the LTE safety analysis set. The mean (range) treatment duration in the LTE was 8.0 (1.2-14.5) months for OD and 6.5 (1.1-16.1) months for RP. In the phase 3 study, the OD group reported 12 (36.4%) adverse events (AEs) during ATP vs 9 (24.3%) in OP whereas the RP group reported 62 (74.7%) AEs in ATP vs 20 (22.0%) in OP. Both groups reported more treatment-related AEs during ATP ( Table 1). ADAs developed in 23/112 participants (20.5% incidence), of which titers were low and resolved in 22 participants by end of study. One RP participant discontinued due to a non-treatment-related SAE, and no deaths or thromboembolic events were recorded in the phase 3 study or the LTE. Mean (95% CI) ABR for treated bleeds was reduced for OD (91.6% [88.1-94.1%]) and RP (35.2% [5.6-55.6%]) participants over the 12-month ATP and marstacimab demonstrated superiority vs OD (P<0.001) and non-inferiority and superiority vs RP (P=0.0376) therapy. Marstacimab was also associated with significant reductions in ABR across all breakthrough bleed categories vs OD, and numerical reductions vs RP (non-inferiority). Overall, mean ABR declined over the first 6 months of ATP, which continued to Month 12 (data not shown). Bleed rates for an additional 16 months of follow-up in the LTE were consistent with those observed during the first 12 months of treatment in the phase 3 study ( Table 2). The ABR reductions observed with marstacimab during ATP were consistent across hemophilia types and age groups for OD and were generally consistent across hemophilia types and age groups for RP, with all point estimates for a difference <2.5 (non-inferiority margin for the ABR of treated bleeds). HRQoL parameters demonstrated non-significant improvements vs OD therapy and non-inferiority vs RP therapy. Conclusion: Compared with previous OD or RP therapy, once weekly subcutaneous marstacimab was safe and effective for reducing bleeding events in participants with severe HA or moderately severe to severe HB without inhibitors beyond 12 months in the phase 3 study and up to an additional 16 months in the LTE study.