Emicizumab prophylaxis in infants with hemophilia A (HAVEN 7): primary analysis of a phase 3b open-label trial

Abstract

Subcutaneous emicizumab enables prophylaxis for people with hemophilia A (HA) from birth, potentially reducing risk of bleeding and intracranial hemorrhage (ICH). HAVEN 7 (NCT04431726) is the first clinical trial of emicizumab dedicated to infants, designed to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab in those aged ≤12 months with severe HA without factor VIII (FVIII) inhibitors. Participants in this phase 3b trial received emicizumab 3 mg/kg maintenance dose every 2 weeks for 52 weeks and are continuing emicizumab during the 7-year long-term follow-up. Efficacy end points included annualized bleed rate (ABR): treated, all, treated spontaneous, and treated joint bleeds. Safety end points included adverse events (AEs), thromboembolic events (TEs), thrombotic microangiopathies (TMAs), and immunogenicity (anti-emicizumab antibodies [ADAs] and FVIII inhibitors). At primary analysis, 55 male participants had received emicizumab (median treatment duration: 100.3; range, 52-118 weeks). Median age at informed consent was 4.0 months (range, 9 days to 11 months 30 days). Model-based ABR for treated bleeds was 0.4 (95% confidence interval, 0.30-0.63), with 54.5% of participants (n = 30) having zero treated bleeds. No ICH occurred. All 42 treated bleeds in 25 participants (45.5%) were traumatic. Nine participants (16.4%) had ≥1 emicizumab-related AE (all grade 1 injection-site reactions). No AE led to treatment changes. No deaths, TEs, or TMAs occurred. No participant tested positive for ADAs. Two participants were confirmed positive for FVIII inhibitors. This primary analysis of HAVEN 7 indicates that emicizumab is efficacious and well tolerated in infants with severe HA without FVIII inhibitors.

Graphical abstract

Figure 1.

Participant disposition. ∗ indicates that emicizumab dose was up-titrated in 1 participant on day 374 while starting the long-term follow-up period. Up-titration was per investigator request based on locally assessed decreasing emicizumab levels (confirmed retrospectively to be 6.6 μg/mL in a central assessment). This participant experienced 3 treated and 2 untreated bleeds (all traumatic) before and after up-titration, respectively. † indicates that bleed end points consider data before up-titration only. Q2W, every 2 weeks; Q4W, every 4 weeks; QW, weekly.

Figure 2.

Pharmacokinetics of emicizumab prophylaxis. Mean (95% CI) emicizumab trough concentration at visit (A) over time and (B) based on age at visit during the maintenance period. For the participant whose dose was up-titrated, only data before up-titration are included. For the analysis according to the age, only samples from week 5 onwards (maintenance period) were considered.