Abstract
Introduction Efanesoctocog alfa is a first-in-class high-sustained factor VIII (FVIII) replacement therapy designed to decouple recombinant FVIII from endogenous von Willebrand factor. In the Phase 3 XTEND-1 (NCT04161495) and XTEND-Kids (NCT04759131) studies, once-weekly efanesoctocog alfa exhibited effective bleed protection, was well tolerated, providing FVIII activity within the normal to near-normal (>40%) range for 4 and 3 days, respectively, at steady state. We present the third interim analysis of the XTEND-ed (NCT04644575) long-term extension study examining the safety and efficacy of efanesoctocog alfa prophylaxis in patients with severe hemophilia A.
Methods Participants who completed XTEND-1 (≥12 years) and XTEND-Kids (<12 years), could continue once-weekly 50 IU/kg efanesoctocog alfa prophylaxis in the ongoing, multicenter, open-label, long-term XTEND-ed study. The primary endpoint was the incidence of FVIII inhibitor development and secondary endpoints included annualized bleed rates (ABRs), efficacy for bleed treatment, and safety. Data cut: February 21, 2025.
Results Among adults and adolescents, 146 participants rolled over from XTEND-1 to XTEND-ed baseline with a median (range) age of 37.0 (13.0–74.0) years. The median (range) treatment duration in XTEND-ed was 166.0 (14.1–192.7) weeks, comprising a median (range) of 167.0 (14.0–200.0) exposure days (EDs). The median (range) cumulative treatment duration from XTEND-1 baseline until XTEND-ed data cut was 212.2 (46.3–244.8) weeks, comprising a median (range) of 216.5 (47.0–254.0) EDs. No FVIII inhibitor development was observed. During XTEND-ed, the mean (SD) ABR for Day 1–Month 12 (n=146) was 0.70 (1.31), Months 12–24 (n=141) was 0.62 (1.23) and Months 24–36 (n=132) was 0.45 (1.24), with 96/146 (65.8%), 96/141 (68.1%), and 103/132 (78.0%) participants with zero bleeds, respectively. The mean (95% CI) model-based ABR for the efficacy period was 0.60 (0.47; 0.76) for overall treated bleeds, and 0.20 (0.15; 0.28) and 0.29 (0.22; 0.39) for spontaneous and traumatic bleeds, respectively. Of 252 treated bleeding episodes, 94.0% (237) were resolved with 1 efanesoctocog alfa injection; participants rated the response excellent/good for 87.8% (173/197) bleeds. The median (range) weekly efanesoctocog alfa consumption was 51.6 (39.4–58.9) IU/kg. In total, 126 participants (86.3%) experienced ≥1 treatment-emergent adverse event (TEAE), most commonly COVID-19 (26.7%), arthralgia (17.1%), influenza (15.1%), and nasopharyngitis (15.1%). Two participants had ≥1 treatment-related TEAE (facial paralysis and reduced FVIII levels); no treatment-related serious TEAEs were reported. TEAEs unrelated to study drug led to the death of 2 participants and treatment discontinuation in 3 participants.
Among children, 71 participants (<6 years, n=35; 6–<12 years, n=36) rolled over from XTEND-Kids to XTEND-ed, with the median (range) treatment duration of 116.7 (36.3–152.6) weeks, comprising a median (range) of 116.0 (11.0–153.0) EDs. The median (range) cumulative treatment duration from XTEND-Kids baseline until XTEND-ed data cut was 169.8 (88.2–204.7) weeks, with a median (range) of 171.0 (65.0–207.0) EDs. No FVIII inhibitors were observed. During XTEND-ed, the mean (SD) ABR evaluated for Day 1–Month 12 (n=71) was 0.68 (1.13) and Months 12–24 (n=62) was 0.49 (0.82), with 46/71 (64.8%) and 41/62 (66.1%) participants with zero bleeds, respectively. The mean (95% CI) model-based ABR was 0.64 (0.48; 0.85) for overall treated bleeds, and 0.08 (0.04; 0.15) and 0.44 (0.31; 0.62) for spontaneous and traumatic bleeds, respectively. Of 89 treated bleeding episodes, 91.0% (81) were resolved with 1 efanesoctocog alfa injection; participants rated the response excellent/good for 94.1% (64/68) bleeds. The median (range) weekly efanesoctocog alfa consumption was 54.0 (46.2–73.1) IU/kg. Overall, 60 (84.5%) participants experienced ≥1 TEAE; most commonly pyrexia (18.3%), upper respiratory tract infection (16.9%), arthralgia (15.5%), and cough (15.5%). Two participants had ≥1 treatment-related TEAE (asthma and post infusion pain and headache); no treatment-related serious TEAEs or treatment discontinuations were reported.
Conclusion Results from up to 4 years of the XTEND-ed study demonstrate that once-weekly efanesoctocog alfa continues to be well tolerated, providing highly effective bleed protection with no inhibitor development in adults, adolescents, and children with severe hemophilia A.
