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 (PwHAs). The primary efficacy, safety, and pharmacokinetics of emicizumab were reported previously, but long-term data were limited. Here, data from 401 pediatric and adult PwHAs with/without factor VIII (FVIII) inhibitors who were enrolled in the phase 3 HAVEN 1, HAVEN 2, HAVEN 3, and HAVEN 4 studies (NCT02622321, NCT02795767, NCT02847637, NCT03020160) have been pooled to establish a long-term efficacy, safety, and pharmacokinetics profile. Across a median efficacy period of 120.4 weeks (interquartile range, 89.0-164.4) (data cutoff 15 May 2020), the model-based treated annualized bleed rate (ABR) was 1.4 (95% confidence interval [CI], 1.1-1.7). ABRs declined and then stabilized at <1 in an analysis of 24-week treatment intervals; at weeks 121 to 144 (n = 170), the mean treated ABR was 0.7 (95% CI, 0-5.0). During weeks 121 to 144, 82.4% of participants had 0 treated bleeds, 97.6% had ≤3 treated bleeds, and 94.1% reported no treated target joint bleeds. Bleeding into target joints decreased substantially. Emicizumab was well tolerated, and no participant discontinued because of adverse events beyond the 5 previously described. This data cutoff includes the previously reported 3 thrombotic microangiopathies (one in the PwHA with fatal rectal hemorrhage) and 2 thromboembolic events, all associated with activated prothrombin complex concentrate use, as well as a myocardial infarction and a venous device occlusion. With 970.3 patient-years of exposure, emicizumab prophylaxis maintained low bleed rates in PwHAs of all ages with/without FVIII inhibitors and remains well tolerated, with no new safety concerns identified.

Graphical abstract

Figure 1.

Study overview for HAVEN 1, HAVEN 2, HAVEN 3, and HAVEN 4.^- *Participants receiving episodic bypassing agents prior to study entry were randomized to emicizumab prophylaxis (arm A) or no emicizumab (arm B, control), and those receiving prophylactic bypassing agents prior to study entry received emicizumab prophylaxis (arm C). After completing the first 24 weeks of the trial, participants in the control arm (arm B) could receive emicizumab prophylaxis. A fourth arm also receiving emicizumab prophylaxis (arm D) consisted of participants enrolled after arms A through C closed. †Participants receiving episodic FVIII prior to study entry were randomized (2:2:1) to emicizumab once weekly (arm A), emicizumab every 2 weeks (arm B) or no prophylaxis (arm C, control), and those receiving prophylactic FVIII prior to study entry received emicizumab once weekly (arm D). ‡Maintenance doses. With the exception of the HAVEN 4 PK run-in cohort (n = 7), all maintenance doses were preceded by loading doses of 3.0 mg/kg once weekly for 4 weeks. §Adolescents aged 12 to 17 years were also eligible to enroll in HAVEN 2 if they weighed <40 kg; 3 participants were aged 12 to 17 years. QW, once weekly; Q2W, once every 2 weeks; Q4W, once every 4 weeks.

Figure 2.

Participant disposition (total population).

Figure 3.

Pooled treated ABR and by HAVEN study across 24-week treatment intervals. 95% CI for the mean were calculated via the exact Poisson method. A treated bleed was defined as a bleed followed by treatment of a bleed; bleeds due to surgery/procedures were excluded. Only data for time intervals with ≥10 participants are reported; for inclusion within a time window, participants needed to have completed the entire 24-week interval (without uptitration). *Based on the calculated ABR for bleeds treated with coagulation factors. NE, not estimated.

Figure 4.

Proportion of participants with 0 or 1 to 3 treated bleeds by HAVEN study across 24-week treatment intervals. A treated bleed was defined as a bleed followed by treatment of a bleed; bleeds due to surgery/procedures were excluded. Only data for time intervals with ≥10 participants are reported; for inclusion within a time window, participants needed to have completed the entire 24-week interval (without uptitration). NE, not estimated.