Background: Marstacimab is a tissue factor pathway inhibitor (TFPI) antagonist recently approved for prophylactic treatment of hemophilia A (HA) and hemophilia B (HB) in people without inhibitors. In the phase 3 BASIS trial (NCT03938792) and its open-label extension (OLE) study, marstacimab was well tolerated, with high efficacy in bleed prevention. The majority of participants in the BASIS trial presented with a severe bleeding phenotype with a high number of target joints (TJs) at the time of study entry. We report on the impact of marstacimab on TJ outcomes.

Methods: BASIS enrolled males aged ≥12 to <75 years with severe HA (factor VIII [FVIII] <1%) or moderately severe to severe HB (factor IX [FIX] ≤2%) who were receiving on-demand (OD) or routine prophylaxis (RP) treatment. Following a 6-month observational phase (OP), participants entered a 12-month active treatment phase (ATP) and received a single loading dose of marstacimab 300 mg subcutaneous (SC), followed by marstacimab 150 mg SC once weekly (dose escalation to 300 mg was allowed after Day 180 per investigator's discretion), which was continued in the OLE. TJs were defined by the International Society on Thrombosis and Hemostasis as in those experiencing ≥3 spontaneous bleeds within a consecutive 6-month period. A TJ was considered resolved if it had ≤2 bleeds in a consecutive 12-month period.

Results: 116 participants without inhibitors (n=33 OD, n=83 RP) entered the BASIS ATP. Of these, 107 (n=32 OD, n=75 RP) completed an additional 12 months in the OLE as of the April 2024 data cutoff. In total at ATP baseline, 80/116 participants (n=33 OD, n=47 RP) had ≥1 TJ and 25 had ≥3 TJs; 58/80 (72.5%) of participants with ≥1 TJ were <45 years old. There were 181 TJs (79 OD; 102 RP); the most frequent locations were knees (65), ankles (52), and elbows (48). Among OD participants with 1, 2, and ≥3 TJ, respectively, at baseline, the mean (SD) [median (Q1, Q3)] ABR of treated bleeds (any location) during OP was 26.15 (16.42) [23.19 (18.47, 36.31)], 42.32 (22.23 [40.37 (20.29, 57.17)], and 44.41 (23.52) [41.95 (24.65, 65.10)], and decreased during ATP to 1.01 (1.53) [0.00 (0.00, 2.03)], 3.88 (3.56) [2.03 (1.50, 6.10)], and 3.71 (5.0) [2.02 (0.00, 5.54)]. Among RP participants with 0, 1, 2, and ≥3 TJ, respectively, at baseline, mean (SD) [median (Q1, Q3)] ABR of treated bleeds (any location) during OP was 4.44 (6.75) [1.94 (0.00, 6.77)], 10.73 (16.44) [3.84 (0.00, 12.59)], 9.68 (13.74) [3.95 (0.00, 18.06)], and 11.49 (17.80) [4.35 (0.00, 11.78)] and during ATP was 2.69 (4.36) [1.01 (0.00, 3.05)], 4.68 (7.85) [1.01 (0.00, 5.09)], 7.39 (10.11) [5.04 (0.00, 7.10)], and 10.24 (11.06) [4.73 (2.32, 13.78)]. A total of 155/181 (85.6%; 73 OD, 82 RP) TJs resolved in the ATP. The mean (SD) [median (Q1, Q3)] ABR of treated TJ bleeds from baseline to ATP and OLE, respectively, was consistently and progressively reduced; OD: 23.20 (20.52) [15.63 (5.83, 35.28)], 1.82 (2.90) [1.01 (0.00, 2.02)], 1.16 (1.94) [0.51 (0.00, 1.65)], and RP: 3.38 (8.32) [0.00 (0.00, 1.97)], 2.29 (5.52) [0.00 (0.00, 1.38)], 1.40 (5.03) [0.00 (0.00, 0.69)]. The mean (SD) [median (Q1, Q3)] ABR of treated TJ bleeds from baseline to ATP and OLE, respectively, also progressively decreased when analyzed by hemophilia type: 10.09 (16.90) [0.00 (0.00, 12.41)], 2.37 (5.42) [0.00 (0.00, 2.00)] and 1.50 (4.84) [0.00 (0.00, 1.24)] for HA and 5.12 (9.67) [0.00 (0.00, 5.83)], 1.36 (2.15) [0.00 (0.00, 3.04)], and 0.73 (1.57) [0.00 (0.00, 0.75)] for HB. Resolution of ≥1 TJ occurred in 73/80 (91.3%) participants (n=32/33 OD, n=41/47 RP) during the ATP and in 68/72 (94.4%) participants (n=31/32 OD, n=37/75 RP) in the OLE. In the ATP and OLE, resolution of all TJs occurred in 23/26 (88.5%) and 19/22 (86.4%) participants with 1 TJ at baseline, 20/29 (69.0%) and 22/26 (84.6%) participants with 2 TJs, and 19/25 (76.0%) and 21/24 (87.5%) participants with ≥3 TJs.

Conclusion: Marstacimab prophylaxis was generally safe and led to sustained and clinically meaningful reductions in TJ bleeding and high rates of joint resolution, even among patients with severe baseline joint involvement. These findings reinforce the long-term efficacy of marstacimab in people with severe HA or HB without inhibitors.

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2025
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