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

• DOI: 10.1182/blood.2020009217
• Publication Date: 2020-12-19T05:46:50Z
• Authors: Michael U. Callaghan; Claude Negrier; Ido Paz-Priel; Tiffany Chang; Sammy Chebon; Michaela Lehle; Johnny Mahlangu; Guy Young; Rebecca Kruse-Jarres; Maria Elisa Mancuso; Markus Niggli; Monet Howard; Nives Selak Bienz; Midori Shima; Victor Jiménez-Yuste; Christophe Schmitt; Elina Asikanius; Gallia G. Levy; Steven W. Pipe; Johannes Oldenburg
• Keywords: Adult; Male; Factor VIII; Adolescent; Hemorrhage; Middle Aged; Antibodies, Monoclonal, Humanized; Hemophilia A; 3. Good health; Young Adult; 03 medical and health sciences; Treatment Outcome; 0302 clinical medicine; Antibodies, Bispecific; Humans; Female; Child; Aged; Follow-Up 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.