Exploratory analysis from HAVEN 1–4 to further contextualize injection-site reactions among people with hemophilia A receiving emicizumab

Abstract Background: Long-term data with subcutaneous emicizumab prophylaxis in people with hemophilia A (PwHA) with or without factor (F)VIII inhibitors indicated low bleed rates and that emicizumab was well tolerated across the Phase III HAVEN 1–4 clinical studies (NCT02622321/NCT02795767/NCT02847637/NCT03020160; Callaghan et al. Blood 2021). Over a median emicizumab duration of 130.3 weeks (range: 3.4–221.1), the most common treatment-related adverse events were injection-site reactions (ISRs). Almost all were mild and occurred during the first 24 weeks, with the proportion of participants with ISRs declining over time to <1% of the safety population. This exploratory analysis further contextualizes ISRs across HAVEN 1–4, informing on the tolerability of emicizumab injections. Methods: This analysis includes PwHA who received emicizumab in the HAVEN 1–4 clinical studies. The study populations in the four Phase III studies included PwHA ≥12 years old with FVIII inhibitors (HAVEN 1 and 4), PwHA ≥12 years old without FVIII inhibitors (HAVEN 3 and 4), and PwHA <12 years old with FVIII inhibitors (HAVEN 2). Maintenance doses of emicizumab in the studies included 1.5mg/kg once weekly (HAVEN 1, 2, and 3), 3.0mg/kg every 2 weeks (HAVEN 2 and 3), or 6.0mg/kg every 4 weeks (HAVEN 2 and 4). The schedule of clinic visits during the HAVEN 1–4 studies was identical across the studies until Week 49 (HAVEN 2) or Week 73 (HAVEN 1, 3 and 4); following this, the schedule of follow-up visits was similar across the studies, with clinic visits every 12 weeks (HAVEN 1, 2 and 4) or every 24 weeks (HAVEN 3). Exploratory outcomes were assessed in the total safety population, and included the proportion of participants with ISRs over 24-week intervals, and the proportion of total emicizumab injections associated with an ISR (total ISRs divided by [mean number of doses per participant multiplied by the number of treated participants]). ISR events considered here are those reported as localized ISR with associated symptoms. Results: The safety population totaled 399 PwHA, including 132 participants (33.1%) aged <18 years old. The median emicizumab duration was 130.3 weeks (range: 3.4–221.1), and 389 participants (97.5%) had a duration >52 weeks. A total of 112 participants (28.1%) had ≥1 ISR. In the overall population, the median number of ISRs per participant was 0 (range: 0–23). The proportion of participants with ISRs declined over time from 23.3% in the first 24 weeks, 4.8% at 25–48 weeks, 2.5% at 49–72 weeks, 1.3% at 73–96 weeks, and <1% thereafter. In total, 317 ISRs occurred out of over 42,000 injections, reflecting that 0.75% of injections were associated with a reported ISR. When split by study, the percentage of ISRs by total injections was 0.42% in HAVEN 1, 0.98% in HAVEN 2, 0.65% in HAVEN 3, and 3.29% in HAVEN 4. No participant discontinued emicizumab because of an ISR. The top three most common recorded symptoms associated with ISRs were: erythema, occurring in 52 participants (46.4% of the total 112 participants with an ISR); pain, occurring in 18 participants (16.1%); and swelling, which occurred in 16 participants (14.3%). Type and incidence of symptoms associated with ISR were similar irrespective of emicizumab dosing regimen. Symptoms associated with ISRs trended down over time intervals across all four clinical studies and across all emicizumab dosing regimens. Conclusions: These data in PwHA receiving emicizumab prophylaxis across the four Phase III HAVEN 1–4 clinical studies show that the proportion of participants that experienced ISRs declined over time to <1%, with 0.75% of over 42,000 injections being associated with an ISR. However, it is important to acknowledge that changes in visit schedules beyond the main phase of the studies may introduce a reporting bias. The results from this analysis expand our understanding of the tolerability of emicizumab injections in PwHA.