Plasma emicizumab concentrations and bleeding rates in children and adults with severe hemophilia A.

BACKGROUND: Emicizumab has been in clinical use for less than 10 years. Real-world experience is still needed to guide its use for optimal safety, efficacy, and resource efficiency. Recent data suggest that conventional weight-based dosing may be excessive for many patients. More data on the correlation between bleeding events and plasma emicizumab concentation will help to clarify optimal dosing regimens. OBJECTIVES: To determine bleeding rates and their correlation with drug levels in patients without inhibitors using prophylactic emicizumab. METHODS: We conducted an observational study in a large cohort of adult and pediatric persons with severe hemophilia A without inhibitors to determine the rate of bleeding events during emicizumab prophylaxis and the correlation between plasma emicizumab concentration and bleeding rates. RESULTS: Among the 73 patients followed for a mean of 69.0 weeks, 47.9% had 0 treated bleeds and 80.8% had 0 spontaneous bleeds. The mean and median annualized treated bleed rates were 1.12 and 0.57, and the mean and median annualized joint bleed rates were 0.51 and 0. The mean factor VIII concentrate used to treat bleeds was 63.0 IU/kg/y per patient (median, 23.1 IU/kg/y). Steady-state plasma emicizumab concentration did not correlate with total or spontaneous annualized treated bleed rate and annualized joint bleed rate or with patient age at enrolment, body weight, or body mass index. Dose capping at 150 mg/wk did not result in lower emicizumab concentrations in the 9 patients with body weight >100 kg. CONCLUSION: Emicizumab provided highly effective prophylaxis in persons with severe hemophilia A across the age spectrum. The lack of correlation of bleed outcomes with plasma emicizumab concentration suggests that minimal effective drug concentrations should be reconsidered. Studies to rationalize and personalize therapy should be explored.