Efanesoctocog Alfa Population Pharmacokinetics and Repeated Time‐To‐Event Analysis of Bleeds in Adults, Adolescents, and Children with Severe Hemophilia A

• DOI: 10.1002/jcph.70008
• Publication Date: 2025-03-24T08:40:56Z
• Authors: Nancy Wong; Pratik Bhagunde; Joakim Nyberg; Suresh Katragadda; Marek Demissie; Annemieke Willemze; Craig Benson; Sreeraj Macha

AbstractEfanesoctocog alfa is a first‐in‐class high‐sustained factor VIII (HSF) replacement therapy for treatment of hemophilia A. This article presents population pharmacokinetics (PopPK) of efanesoctocog alfa and repeated time‐to‐event (RTTE) analysis of bleeding episodes in adults/adolescents (≥12 years of age) and children (<12 years). The final PopPK dataset contained pooled data from 277 patients (4405 post‐dose factor VIII [FVIII] activity records) from two Phase 1/2a studies (NCT03205163; EudraCT 2018‐001535‐51), and three Phase 3 studies, XTEND‐1 (NCT04161495), XTEND‐Kids (NCT04759131), and XTEND‐ed (NCT04644575). The PopPK model developed was a linear one‐compartment model including body weight effect on clearance and volume of central compartment; Asian race was identified as a statistically significant covariate on clearance. The final PopPK model adequately described the FVIII activity–time profiles in adults, adolescents, and children with once‐weekly (QW) efanesoctocog alfa 50 IU/kg, consistent with experience in XTEND‐1 and XTEND‐Kids. Bleeding episodes in participants in XTEND‐1 and XTEND‐Kids were characterized by an RTTE model with a Weibull base hazard and effect of FVIII activity modeled by a power effect. The RTTE model showed the probability of being bleed‐free in 1 year with efanesoctocog alfa 50 IU/kg QW regimen was >70% across all age groups, consistent with the observed clinical outcomes in the Phase 3 trials of highly effective protection from bleeding episodes in patients with severe hemophilia A, which validates the model's prediction of the long‐term bleed hazard.