Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies

Abstract

Prophylaxis with emicizumab-a subcutaneously administered, bispecific, humanized, monoclonal antibody-promotes effective hemostasis in persons with hemophilia A (PwHA). The primary efficacy, safety and pharmacokinetics of emicizumab were reported previously, but long-term data were limited. Here, data from 401 pediatric and adult PwHA with/without factor VIII inhibitors who were enrolled in the Phase III HAVEN 1, HAVEN 2, HAVEN 3, and HAVEN 4 studies have been pooled to establish a long-term efficacy, safety and pharmacokinetic profile. Across a median (interquartile range) efficacy period of 120.4 (89.0-164.4) weeks (data cut-off May 15, 2020), the model-based treated annualized bleed rate (ABR) was 1.4 (95% confidence interval, 1.1-1.7). ABRs declined and then maintained at <1 in an analysis of 24-week treatment intervals; at Weeks 121-144 (n=170) the mean treated ABR was 0.7 (0-5.0). During Weeks 121-144, 82.4% of participants had zero treated bleeds, 97.6% had ≤3 treated bleeds, and 94.1% reported zero treated target joint bleeds. Bleeding into target joints decreased substantially. Emicizumab was well tolerated, and no participants discontinued due to adverse events beyond the five previously described. This data-cut includes the previously reported 3 thrombotic microangiopathies (1 in the PwHA with fatal rectal hemorrhage), and 2 thromboembolic events, all associated with activated prothrombin complex concentrate use; and additionally, a myocardial infarction and a venous device occlusion. With 970.3 patient-years of exposure, emicizumab prophylaxis maintained low bleed rates in PwHA of all ages with/without FVIII inhibitors and remains well tolerated, with no new safety concerns identified. Clinical trials registered as NCT02622321, NCT02795767, NCT02847637, NCT03020160.

Real‐world cost estimates of initiating emicizumab in US patients with haemophilia A

“…However, the study period centred around initiating emicizumab strengthens our conclusions regarding the direct impact of emicizumab on the estimated costs, as it likely minimizes other potential confounding changes such as improving or worsening joint disease. Likewise, though it is unknown whether the decrease in breakthrough bleeds observed in the relatively short study period after initiating emicizumab in the real world will continue for longer than 6 months, 5 recent reports of long‐term clinical trial data suggest such improvements may be sustained 16 …”

“…Likewise, though it is unknown whether the decrease in breakthrough bleeds observed in the relatively short study period after initiating emicizumab in the real world will continue for longer than 6 months, 5 recent reports of long-term clinical trial data suggest such improvements may be sustained. 16 We also relied on patient report and chart review to determine the haemostatic product consumptions, rather than pharmacy dispensing data; we were therefore unable to consider drug wastage in the estimated costs. We note that the minimal weight gain during the study (<10%) would increase the post-emicizumab costs.…”

Pharmacokinetics and Associated Efficacy of Emicizumab in Humans: A Systematic Review

“…Moreover, clinically unstable disease leads to numerous (spontaneous) bleeds, especially in the first weeks of emicizumab treatment, leading to overestimation of ABRs in shorter studies [43][44][45][46]. Recently, the analysis of pooled bleeding data from HAVEN 1−4 reported ABRs maintaining < 1 in 24-week intervals and an increase in the proportion of PwHA without treated bleeds from 70.8% in the first 6 months to 80.2% after 1 year of emicizumab treatment [52]. Consequently, predicted ABRs may be overestimated in our model.…”

Current therapeutic approaches in the management of hemophilia—a consensus view by the Romanian Society of Hematology

“…When looking at all HAVEN 1-4 studies, with data from 401 pediatric and adult HA patients with/without factor VIII inhibitors enrolled, as well as a 970.3 patient-years of exposure, emicizumab prophylaxis maintained low bleed rates in HA patients of all ages and remains well tolerated, with no new safety concerns identified (147).…”