During Monday’s ISTH 2017 Abstract Symposia Session, ISTH President Johannes Oldenburg, M.D., Ph.D., presented results from the pivotal HAVEN 1 clinical trial—a randomized, multicenter, phase 3 study evaluating the efficacy, safety, and pharmacokinetics of once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with inhibitors (PwHAwl).
- Emicizumab prophylaxis was found to be safe and reduced bleeds in PwHAwI:
- The annualized bleeding rate was 0 for patients treated with emicizumab vs. 18.8 for patients not receiving emicizumab prophylaxis
- 62.9% of patients treated with emicizumab had no bleeds vs. 5.6% of patients not receiving emicizumab prophylaxis
- Statistically significant improvements were also observed in health-related quality of life (HRQoL) and health status.
The phase 3 HAVEN 1 study is the first pivotal study of the novel agent emicizumab designed to address an unmet medical need in PwHAwI, a difficult-to-treat clinical setting. This study assessed the efficacy, safety, and pharmacokinetics (PK) of once-weekly subcutaneous emicizumab prophylaxis (Px) in PwHAwl. Emicizumab is a subcutaneously administered bispecific humanized monoclonal antibody which bridges factor IXa (FIXa) and FX to replace the function of missing FVIII, with resultant downstream thrombin generation and clot formation.
The study included PwHAwI 12 years of age or older, allocated to 4 arms. One hundred nine (109) PwHAwI were enrolled; the median age was 28 years (range: 12-75 years). Statistical significance was achieved in all primary and secondary endpoints. Clinically meaningful reductions were observed in treated (87% reduction, P < 0.0001), all, spontaneous, joint, and target joint bleeds with emicizumab Px (Arm A) vs. no Px (Arm B). A 79% reduction in treated bleeds was seen with emicizumab Px (Arm C) vs. bypassing agent Px prior to study entry (intra-person comparison).
Overall, 62.9% of PwHAwI on emicizumab Px had 0 treated bleeds compared with 5.6% of those receiving bypassing agents. Statistically significant improvements in HRQoL and health status were also seen for Arm A vs. B. Emicizumab was well tolerated: the most common adverse event (AE) was injection-site reaction (15%). Two people each experienced thrombotic microangiopathy or thromboembolic serious AEs; all events occurred when repeated high aPCC therapy (> 100 IU/kg/day for more than 24 h) was used concurrently with emicizumab; the 2 persons resumed emicizumab without sequelae. No antidrug antibodies were reported. Mean emicizumab concentrations >50 µg/mL were achieved after 4 weeks and sustained.
Emicizumab Px prevented or reduced bleeds in PwHAwI, with acceptable safety and meaningfully improved HRQoL. PK levels were sustained and no excess thrombotic risk was observed in the absence of concomitant aPCC. These data suggest a genuine paradigm shift in the management of PwHAwI.