Once-Weekly Efanesoctocog Alfa Prophylaxis Provided High Sustained Factor VIII Activity Levels, Independent of Blood Group, in Children <12 Years of Age with Severe Hemophilia A

Introduction Efanesoctocog alfa is a new class of factor VIII (FVIII) replacement therapy uniquely designed to overcome the von Willebrand factor-imposed FVIII half-life ceiling. In the Phase 3 XTEND-Kids study in previously treated children <12 years of age with severe hemophilia A, efanesoctocog alfa was well tolerated and FVIII inhibitor development was not detected. Furthermore, once-weekly efanesoctocog alfa 50 IU/kg provided highly effective bleed protection and treatment. These results are consistent with the results of the Phase 3 XTEND-1 study in adolescents and adults with severe hemophilia A. Objective To characterize the pharmacokinetics (PK) of efanesoctocog alfa in children <12 years of age with severe hemophilia A in the XTEND-Kids study (NCT04759131). Methods The XTEND-Kids study enrolled children with severe hemophilia A (<1 IU/dL endogenous FVIII activity) previously treated with FVIII replacement products or cryoprecipitate for ≥150 exposure days (6-<12 years) or ≥50 exposure days (<6 years). Participants received once-weekly efanesoctocog alfa 50 IU/kg for 52 weeks. FVIII activity levels were assessed using the activated partial thromboplastin time-based one-stage clotting assay with the reagent Actin FSL. PK parameters after the first dose were estimated for the 37 participants in the PK subgroup using non-compartmental analysis. Mean peak and trough FVIII activity levels were determined for all participants by visit. Time to FVIII activity levels at steady state (Week 26) was determined using population modelling. Results A total of 74 participants were enrolled in XTEND-Kids; of these, 37 were included in the PK subgroup (n=19, <6 years; n=18, ≥6-<12 years). At the end of the first weekly dosing interval, mean (standard deviation [SD]) FVIII activity levels were 5.73 (1.63) IU/dL in participants <6 years and 6.93 (1.76) IU/dL in those ≥6-<12 years (Figure). After the first dose of efanesoctocog alfa, mean (SD) half-life was 38.0 (3.72) and 42.4 (3.70) hours, and mean (SD) clearance was 0.742 (0.121) and 0.681 (0.139) mL/h/kg in participants <6 years and ≥6-<12 years, respectively (Table). Incremental recovery values remained consistent throughout the study, ranging from 2.12 to 2.35 IU/dL per IU/kg. Mean (SD) areas under the activity-time curve over the dosing interval (AUC 0-tau) were 6800 (1120) and 7190 (1450) h*IU/dL in participants <6 years and ≥6-<12 years, respectively. Mean (SD) clearance after first dose was similar between participants with blood group O and non-O, 0.76 (0.12) versus 0.68 (0.15) mL/h/kg (Table). Half-life was also similar; mean (SD) half-life was 40.2 (4.45) hours in participants with blood group O, and 40.0 (4.17) hours in those with a non-O group. In the overall study population, mean trough (pre-dose) FVIII activity levels ranged from 8.54 IU/dL at Week 4 to 13.7 IU/dL at Week 52. Across all visits mean FVIII activity levels 15 minutes post-dose were consistently below 150 IU/dL. Mean FVIII activity levels at steady state (Week 26) remained >40 IU/dL for 3 days and >10 IU/dL for ~7 days following a 50 IU/kg weekly dose of efanesoctocog alfa. Conclusions PK parameters and the mean FVIII activity-time profile were similar for participants <6 years and ≥6-<12 years of age. No clinically relevant differences in PK parameters were observed between participants with blood group O and non-O. At steady state (Week 26), FVIII activity levels were maintained in the normal to near-normal range (>40 IU/dL) for 3 days and remained >10 IU/dL for ~7 days following a 50 IU/kg dose of efanesoctocog alfa. Once-weekly prophylaxis with efanesoctocog alfa provided high sustained FVIII levels across the week for children <12 years of age in the XTEND-Kids study.