Abstract
INTRODUCTION: Emicizumab promotes effective haemostasis in people with haemophilia A (PwHA). It is indicated for routine prophylaxis of bleeding episodes in PwHA with or without factor (F)VIII inhibitors. AIM: To investigate the effect of emicizumab dose up-titration in PwHA with suboptimal bleeding control. METHODS: Data from seven completed or ongoing phase III studies were pooled. Pharmacokinetics, pharmacodynamics and bleeding events were evaluated before and after dose up-titration. Adverse events (AEs) were compared between PwHA with and without dose up-titration. RESULTS: Of 675 PwHA evaluable for the analysis, 24 (3.6%) had their maintenance dose up-titrated to 3 mg/kg once weekly (QW). Two participants had neutralising antibodies (nAbs) associated with decreased emicizumab exposure, and dose increase did not compensate for the effect of nAbs. In the other 22 participants, mean emicizumab steady-state trough concentrations increased from 44.0 to 86.2 μg/mL after up-titration. The median (interquartile range [IQR]) efficacy period prior to up-titration was 24.6 (24.0-32.0) weeks. The model-based annualised bleed rate for 'treated bleeds' and 'all bleeds' decreased by 70.2% and 72.9%, respectively, after a median (IQR) follow-up of 97.1 (48.4-123.3) weeks in the up-titration period. Incidences of injection-site reactions and serious AEs were higher in PwHA with up-titration; however, this was already observed in these participants before the dose up-titration. Overall, the safety profile appeared similar between PwHA with and without up-titration. CONCLUSION: The dose up-titration to 3 mg/kg QW was well tolerated. Bleed control improved in most participants whose bleeding tendency was inadequately controlled during clinical trials.