HAVEN-4

Background

Phase 3 single-arm study (HAVEN-4). N=48 adults with severe hemophilia A (FVIII ≤1%), with or without FVIII inhibitors, previously on episodic/prophylactic bypassing agents or FVIII. Evaluated once-monthly (q4w) emicizumab, a bispecific antibody bridging activated FIX and FX to mimic FVIII cofactor function. FDA approved Oct 2018 (q4w dosing added).

Interventions and follow up

Treatment: Emicizumab 6 mg/kg SC every 4 weeks (after loading 3 mg/kg weekly × 4) in adult hemophilia A with or without inhibitors
Primary endpoint: Annualized bleed rate (ABR) of treated bleeds
Median follow-up: 24 weeks

Results

Estimated mean ABR (treated bleeds): 2.4 (95% CI 1.4–4.3) full cohort
Zero treated bleeds: 56% of patients
Treated joint bleeds: Median ABR 0.0; 67% had zero treated joint bleeds
Overall ABR (all bleeds): 4.5 (95% CI 2.8–7.3)

Adverse events

Injection site reactions: 19% (all mild-moderate)
Other common: Headache 15%, fatigue 10%
Thrombotic/TMA: None (TMA/TE in HAVEN-1 occurred with concurrent high-dose aPCC; none here)
Grade ≥3 AEs: 10%
Anti-emicizumab antibodies / deaths: None

Conclusions

Once-monthly emicizumab (6 mg/kg q4w) effectively reduced bleeding in hemophilia A with or without inhibitors, with 56% achieving zero treated bleeds, supporting q4w dosing as a convenient prophylactic option.

Key Limitations

Single-arm, no randomized comparator. Small cohort (n=48), short 24-week primary follow-up. Mixed inhibitor/non-inhibitor population. ABR is a surrogate; no head-to-head vs q1w/q2w schedules. Concurrent aPCC use carries TMA/thrombosis risk not captured here.

Clinical Context

Extended FDA label to q4w emicizumab (Oct 2018), adding to q1w/q2w options. Emicizumab is standard prophylaxis for hemophilia A with and without inhibitors per ISTH/WFH guidance; q4w improves adherence/convenience. Avoid concurrent high-dose aPCC.

References