Background
Phase 3 open-label single-arm study (BASIS). N=128 males aged 12–74 yr with severe hemophilia A (FVIII <1%) or moderately severe to severe hemophilia B (FIX ≤2%) without inhibitors. Sequential design: 6-mo observational phase (OP, own baseline regimen) then 12-mo active treatment phase (ATP) with marstacimab (PF-06741086; Hympavzi), a fully human anti-TFPI monoclonal antibody. FDA approved Aug 2024 for hemophilia A or B without inhibitors, ≥12 yr.
Interventions and follow up
Treatment: 6-mo observational phase on current on-demand or prophylactic regimen, then 12-mo ATP with marstacimab 150 mg SC weekly (after 300 mg loading dose)
Primary endpoint: ABR of treated bleeds in ATP vs OP (on-demand and prophylaxis groups analyzed separately)
Median follow-up: 12 months (ATP)
Primary endpoint: ABR of treated bleeds in ATP vs OP (on-demand and prophylaxis groups analyzed separately)
Median follow-up: 12 months (ATP)
Results
ABR reduction (on-demand group, n=33): From 39.86 (OP) to 3.20 (ATP); ratio 0.080 (95% CI 0.057–0.113), P<.0001 (superiority vs OP)
ABR reduction (prophylaxis group, n=83): From 7.90 (OP) to 5.09 (ATP); difference −2.81 (95% CI −5.42 to −0.20), P=.0349 (non-inferiority and superiority vs OP)
Zero treated bleeds (on-demand group, ATP): 57%
ABR reduction (prophylaxis group, n=83): From 7.90 (OP) to 5.09 (ATP); difference −2.81 (95% CI −5.42 to −0.20), P=.0349 (non-inferiority and superiority vs OP)
Zero treated bleeds (on-demand group, ATP): 57%
Adverse events
Deaths/thromboembolic events: None
Injection site reactions: ~25% (mild-moderate)
Antidrug antibodies: 8% (no impact on efficacy)
ALT elevation grade ≥3: 2%
Grade ≥3 AEs: 14%
Discontinuation: 2 patients (1 due to rash)
Injection site reactions: ~25% (mild-moderate)
Antidrug antibodies: 8% (no impact on efficacy)
ALT elevation grade ≥3: 2%
Grade ≥3 AEs: 14%
Discontinuation: 2 patients (1 due to rash)
Conclusions
Weekly SC marstacimab substantially reduced ABR vs on-demand factor therapy and was superior to prior routine prophylaxis in severe hemophilia A or B without inhibitors, with no thromboembolic events.
Key Limitations
Single-arm with within-patient observational comparison, not randomized. Modest absolute ABR reduction in already-prophylaxis group. 12-mo ATP limits long-term thrombotic-risk assessment for TFPI inhibition. Males only; small on-demand subgroup (n=33). ABR is a surrogate endpoint.
Clinical Context
Supported FDA approval of Hympavzi (Oct 2024), first anti-TFPI rebalancing agent for hemophilia A or B without inhibitors. Offers SC weekly dosing and applies to both hemophilia A and B (unlike emicizumab, A only). TFPI-class agents require thrombotic-risk vigilance.