Background
Phase III single-arm study, N=109, congenital hemophilia A (any severity) with history of high-titer FVIII inhibitor (≥5 BU/mL), aged 2-11 years, previously on episodic or prophylactic bypassing agents. Emicizumab is a bispecific monoclonal antibody bridging factors IXa and X, mimicking missing FVIIIa; half-life 4-5 wks. It lowers aPTT and falsely elevates human-reagent chromogenic FVIII assays; bovine-reagent chromogenic assays required for monitoring.
Interventions and follow up
Arm A: emicizumab 1.5 mg/kg qwk*
Arm B: emicizumab 3.0 mg/kg q2wk*
Arm C: emicizumab 6.0 mg/kg q4wk*
Primary endpoint: annualized bleeding rate (ABR) for treated bleeds
*Loading: emicizumab 3.0 mg/kg qwk ×4 in all patients.
Arm B: emicizumab 3.0 mg/kg q2wk*
Arm C: emicizumab 6.0 mg/kg q4wk*
Primary endpoint: annualized bleeding rate (ABR) for treated bleeds
*Loading: emicizumab 3.0 mg/kg qwk ×4 in all patients.
Results
Annualized treated bleeding rate, weekly emicizumab vs prior bypassing agent: 0.3 (0.17-0.50) vs 21.1 (15.99-27.82), 99% risk reduction
Annualized treated bleeding rate (arm B vs C): 0.2 (0.03-1.72) vs 2.2 (0.69-6.81)
Zero treated bleeds (A vs B vs C): 77% vs 90.0% vs 60.0%
Annualized treated bleeding rate (arm B vs C): 0.2 (0.03-1.72) vs 2.2 (0.69-6.81)
Zero treated bleeds (A vs B vs C): 77% vs 90.0% vs 60.0%
Adverse events
Nasopharyngitis: 37.5%
Injection-site reactions: 30.7%
Thrombotic events/TMA: none; no fatalities. Protocol amended after HAVEN 1 to avoid concomitant aPCC (or use lowest dose, ≤50 U/kg initial, only if no alternative bypassing agent).
Injection-site reactions: 30.7%
Thrombotic events/TMA: none; no fatalities. Protocol amended after HAVEN 1 to avoid concomitant aPCC (or use lowest dose, ≤50 U/kg initial, only if no alternative bypassing agent).
Conclusions
In children with inhibitor-positive hemophilia A, emicizumab prophylaxis reduced bleeding by 99% vs prior bypassing-agent therapy, with no thrombotic events. Cost: 60 mg/0.4 mL vial $7,579.20.
Key Limitations
Single-arm with intra-patient historical comparison (no concurrent control); small subgroups for q2wk/q4wk dosing; pediatric population; high cost; assay interference complicates monitoring.
Clinical Context
Supported FDA approval of emicizumab in pediatric inhibitor-positive hemophilia A. Subcutaneous, infrequent dosing addresses venous-access challenges in young children; established as standard prophylaxis in this population.