Background: BASIS (NCT03938792) is an open-label, phase 3 trial of anti-tissue factor pathway inhibitor (TFPI) antibody marstacimab in adult and adolescent participants (pts) with severe hemophilia A (HA; factor VIII <1%) or moderately severe to severe hemophilia B (HB; factor IX ≤2%) with or without inhibitors. Across all pts without inhibitors, marstacimab significantly reduced the annualized bleeding rate (ABR) of treated bleeds compared with prior on-demand (OD) or routine prophylaxis (RP) factor replacement therapy. We report outcomes in adolescent pts without inhibitors who received prior RP.

Methods: Screened male adolescents without inhibitors completed a 6-month observational phase (OP) on RP or OD therapy before receiving a single subcutaneous (SC) loading dose of 300 mg marstacimab followed by 150 mg once weekly (QW) in the 12-month active-treatment phase (ATP). After Day 180, pts meeting prespecified dose escalation criteria (weight ≥50 kg, ≥2 spontaneous bleeds requiring treatment in 6 months) could increase their dose to 300 mg QW. Efficacy assessments included ABRs of treated bleeds and specific bleed types. Safety (including incidence and severity of adverse events [AEs] and immunogenicity) and pharmacokinetic (PK)/pharmacodynamic (PD) parameters were also assessed.

Results: As of April 2023, 18 adolescent pts aged ≥12 to <18 years with HA (n=13) or HB (n=5) without inhibitors entered the OP and received RP before entering the ATP (data from OD pts [n=2] not reported). One pt (administered 1 dose of marstacimab in the ATP) was later excluded from analyses due to termination of study site. Most pts were from Europe (50.0%), predominately Turkey (38.9%). At baseline, 5 pts (27.8%) had ≥1 target joint. A numerical reduction in mean ABR of treated bleeds was observed with marstacimab in the ATP vs RP in the OP (2.98 vs 3.36, n=17; compared with 5.74 vs 9.11 in adults, n=66). Mean (median) ABR during the ATP was 1.63 (0.00) for joint bleeds, 0.75 (0.00) for spontaneous bleeds, 0.00 (0.00) for target joint bleeds, and 3.39 (0.00) for total (treated and untreated) bleeds. The median ABR of treated bleeds in the ATP was 0.00, with significant variability in pts with HB (n=4). Two pts with HB had 0 treated bleeds; 2 pts had ABRs of 19.48 and 11.10 (majority traumatic bleeds). Mean (SD) annualized total factor consumption unrelated to bleeding events also decreased in the ATP vs the OP: 20 (80) vs 3308 (1063) IU/kg, n=17. In all, 36 AEs were reported in 14/17 pts (82.4%) during the ATP vs 11 AEs in 7/18 pts (38.9%) in the OP. Treatment-related AEs were reported in 4 pts, all related to injection site (erythema, edema, and swelling [n=1 each]; pruritus [n=2]). One serious AE of tympanic membrane perforation was reported in 1 pt in the ATP who temporarily discontinued treatment 10 days prior to tympanoplasty/ear tube insertion. Preventative factor replacement therapy was given peri and post operatively, and the pt resumed treatment 6 days post procedure. One other pt temporarily discontinued treatment due to an AE of COVID-19. No deaths, study discontinuations, or thromboembolic events were recorded. Two pts had their dose increased to 300 mg QW; neither reported any AEs post dose escalation. Antidrug antibodies developed in 2/17 pts, 1 of whom was also positive for neutralizing antibodies, transient in nature. Marstacimab plasma levels were ~2 to 2.5-fold higher in adolescents vs adults. For pts receiving 150 mg QW marstacimab, median steady-state plasma concentrations were ~25,000–30,000 ng/mL in adolescents vs ~10,000–11,000 ng/mL in adults. Population PK analysis found marstacimab clearance (CL) was 29% lower in adolescents vs adults; weight-adjusted CL was 3% lower in adolescents, indicating weight accounted for most of the CL differences. In general, no clinically relevant differences were seen in steady-state median ranges of PD endpoints following 150 mg QW marstacimab in adolescents (n=17) vs adults (n=85): peak thrombin, 41–54 vs 63–66 nM; prothrombin fragment 1+2, 557–874 vs 492–579 pmoL/L; D-dimer, 0.3–0.4 vs 0.3 μg/mL; total TFPI, 389–495 vs 268–283 ng/mL.

Conclusion: Compared with previous RP therapy, SC QW marstacimab reduced bleeding in adolescent pts with HA or HB without inhibitors and was generally well tolerated. No clinically relevant differences in PD endpoints were observed compared with adults and PK differences were explained by weight.

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2025
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