Prophylactic emicizumab for hemophilia A in the Asia‐Pacific region: A randomized study (HAVEN 5)

Abstract

Background Emicizumab is a subcutaneously administered humanized, bispecific, monoclonal antibody approved for prophylaxis in people with hemophilia A. Methods HAVEN 5 (NCT03315455) is a randomized, open‐label, phase 3 study of individuals aged ≥12 years with severe hemophilia A without factor VIII (FVIII) inhibitors, or hemophilia A of any severity with FVIII inhibitors, across the Asia‐Pacific region. Participants were randomly assigned (2:2:1) to receive emicizumab 1.5 mg/kg once weekly (arm A), emicizumab 6 mg/kg every 4 weeks (arm B), or no prophylaxis (arm C). The primary end point was annualized bleeding rate (ABR) for treated bleeds; ABRs were compared between people receiving emicizumab prophylaxis versus those with no prophylaxis. Secondary end points included ABR for treated target joint bleeds. Safety was also evaluated. Results From April 26, 2018, to January 4, 2019, 70 of 76 screened participants were enrolled and randomized (arm A, n = 29; arm B, n = 27; arm C, n = 14). ABRs (95% confidence interval) for treated bleeds and treated target joint bleeds, respectively, were: arm A, 1.0 (0.53‐1.85) and 0.4 (0.18‐1.09); arm B, 1.0 (0.50‐1.84) and 0.3 (0.12‐0.85); arm C, 27.0 (13.29‐54.91) and 8.6 (3.15‐23.42). The most common adverse event, upper respiratory tract infection, was reported for 14 of 56 (25.0%; emicizumab) and 2 of 14 (14.3%; no prophylaxis) participants. No thrombotic events, thrombotic microangiopathies, or deaths were reported. Conclusion Emicizumab 1.5 mg/kg once weekly and 6 mg/kg every 4 weeks demonstrated bleed control in this study population, was well tolerated, and could improve use of prophylaxis in people with hemophilia A.

Current and future therapies for haemophilia—Beyond factor replacement therapies

“…Standard‐dose FVIII replacement therapy in non‐inhibitor patients receiving emicizumab prophylaxis is recommended for severe breakthrough bleeds or surgical intervention 14–16,33 . The additive effect of FVIII in the presence of emicizumab was reported under in vitro conditions, 38,39 potentially reflecting no thrombosis with concomitant use.…”

Hemophilia a patients with inhibitors: Mechanistic insights and novel therapeutic implications

“…The efficacy, safety, and pharmaceutics of these treatments have been further studied in the phase 3 HAVEN 3-5 studies, which included adults/adolescents ≥ 12 years of age with and without inhibitors ( 100 – 102 ). These trials demonstrated that emicizumab prophylaxis achieved remarkable efficacy for bleeding control and was well tolerated in HA patients, regardless of FVIII inhibitor status.…”

“…Moreover, 0.33% (25/7500) of subjects produced an immune response to emicizumab ( 93 ). In the HAVEN trials, 2 out of 88 pediatric participants in HAVEN 2 ( 99 , 105 ) and 1 out of 64 evaluable participants in HAVEN 5 ( 102 ) developed anti-drug antibodies (ADAs) with neutralizing potential. Although this occurs infrequently, it is necessary to monitor the neutralizing ADAs to implement immunological surveillance in HA patients with emicizumab regimens.…”

Anti‐idiotype monoclonal antibodies against emicizumab enable accurate procoagulant and anticoagulant assays, irrespective of the test base, in the presence of emicizumab

“…6,7 Emicizumab can be administered subcutaneously, and it has a long plasma half-life of approximately 30 days, making regimens of once every 1-4 weeks possible. [8][9][10][11][12][13][14][15] Emicizumab has improved procoagulant potential in patients with severe HA to subnormal or mild HA patients, 16,17 irrespective of the presence of FVIII inhibitors. 4 The effectiveness of emicizumab in preventing repeated bleeding has been confirmed by global clinical phase 3(HAVEN 1-5 [10][11][12][13][14] and HOHOEMI studies 15 ) and real-world data for patients with HA.…”

“…This humanized bispecific monoclonal antibody (mAb) mimics the cofactor function of activated FVIII by spatially relocating FIXa/FIX and FX/FXa to the appropriate position in the tenase assembly 6,7 . Emicizumab can be administered subcutaneously, and it has a long plasma half‐life of approximately 30 days, making regimens of once every 1–4 weeks possible 8–15 . Emicizumab has improved procoagulant potential in patients with severe HA to subnormal or mild HA patients, 16,17 irrespective of the presence of FVIII inhibitors 4 .…”