Background
Phase III RCT, N=152, congenital hemophilia A (endogenous FVIII activity <1%) without current FVIII inhibitors (<0.6 BU/mL), ≥12 y/o, previously on episodic (arms A, B, C) or prophylactic (arm D) FVIII. Emicizumab is a bispecific monoclonal antibody bridging factors IXa and X, mimicking missing FVIIIa cofactor activity.
Interventions and follow up
Arm A: emicizumab 1.5 mg/kg qwk*
Arm B: emicizumab 3.0 mg/kg q2wk*
Arm C: no emicizumab prophylaxis (episodic FVIII)
Arm D: prior FVIII prophylaxis switched to emicizumab 1.5 mg/kg qwk*
Primary endpoint: annualized rate of treated bleeding events over ≥24 weeks
*Loading: emicizumab 3.0 mg/kg qwk ×4 in all patients.
Arm B: emicizumab 3.0 mg/kg q2wk*
Arm C: no emicizumab prophylaxis (episodic FVIII)
Arm D: prior FVIII prophylaxis switched to emicizumab 1.5 mg/kg qwk*
Primary endpoint: annualized rate of treated bleeding events over ≥24 weeks
*Loading: emicizumab 3.0 mg/kg qwk ×4 in all patients.
Results
Annualized treated bleeding rate (A vs B vs C): 1.5 (0.9-2.5) vs 1.3 (0.8-2.3) vs 38.2 (22.9-63.8)
RR A vs C: 0.04, 95%CI 0.02-0.08, P<.001 (96% reduction)
RR B vs C: 0.03, 95%CI 0.02-0.07, P<.001 (97% reduction)
Median bleeding events (A vs B vs C): 0.0 (0.0-2.5) vs 0.0 (0.0-1.9) vs 40.4 (25.3-56.7)
Zero bleeds/yr (A vs B vs C): 56% vs 60% vs 0
Arm D intra-patient (emicizumab vs prior FVIII prophylaxis): 1.5 (1.0-2.3) vs 4.8 (3.2-7.1), RR 0.32 (0.20-0.51), P<.001
RR A vs C: 0.04, 95%CI 0.02-0.08, P<.001 (96% reduction)
RR B vs C: 0.03, 95%CI 0.02-0.07, P<.001 (97% reduction)
Median bleeding events (A vs B vs C): 0.0 (0.0-2.5) vs 0.0 (0.0-1.9) vs 40.4 (25.3-56.7)
Zero bleeds/yr (A vs B vs C): 56% vs 60% vs 0
Arm D intra-patient (emicizumab vs prior FVIII prophylaxis): 1.5 (1.0-2.3) vs 4.8 (3.2-7.1), RR 0.32 (0.20-0.51), P<.001
Adverse events
Injection-site reactions (A/B/C/D): 25% vs 20% vs 12% vs 32%
Arthralgia: 19% vs 17% vs 6% vs 22%
URI: 11% vs 11% vs 0% vs 13%
Headache: 8% vs 11% vs 6% vs 13%
Influenza: 3% vs 9% vs 0% vs 8%
Inhibitors: no new FVIII inhibitors on emicizumab. Boxed warning for thrombotic events/TMA (seen with concomitant aPCC/FEIBA in HAVEN 1/2, inhibitor patients).
Arthralgia: 19% vs 17% vs 6% vs 22%
URI: 11% vs 11% vs 0% vs 13%
Headache: 8% vs 11% vs 6% vs 13%
Influenza: 3% vs 9% vs 0% vs 8%
Inhibitors: no new FVIII inhibitors on emicizumab. Boxed warning for thrombotic events/TMA (seen with concomitant aPCC/FEIBA in HAVEN 1/2, inhibitor patients).
Conclusions
Emicizumab prophylaxis reduced bleeding by >95% vs no prophylaxis and was superior to prior FVIII prophylaxis in non-inhibitor hemophilia A. Cost: 60 mg/0.4 mL vial $7,579.20; ~$345,000-$690,000/yr depending on weight.
Key Limitations
Open-label; episodic-control arm (C) is small and reflects no prophylaxis; intra-patient comparison (arm D) is non-randomized; high acquisition cost; long-term thrombotic/TMA safety driven by concomitant bypassing agents.
Clinical Context
FDA approved emicizumab prophylaxis for hemophilia A without inhibitors (2018) based on HAVEN 3/4. Subcutaneous, every 1-4 week dosing makes it a standard prophylaxis option vs IV FVIII; chromogenic FVIII assays with bovine reagents required for monitoring.