Tailored prophylaxis in severe hemophilia A: Real-world experience with efanesoctocog alfa

Abstract Hemophilia A is an X-linked recessive genetic hemorrhagic disorder characterized by deficient or absent plasma clotting factor VIII (FVIII), leading to impaired blood coagulation and bleeding manifestations. According to the latest WFH report, the prevalence is 17 per 100,000 male births. Severe hemophilia A, defined by FVIII activity <1%, is associated with a high risk of spontaneous bleeding, joint damage, and chronic pain, significantly impacting quality of life (WHF 3rd edition,2020). Despite the availability of standard half-life (SHL) and extended half-life (EHL) FVIII therapies, maintaining sufficient FVIII levels requires frequent intravenous infusions, resulting in treatment burden and suboptimal adherence. The addition of pharmacokinetic (PK) profiling to the management of hemophilia enables more accurate determination of an individual's FVIII clearance rate and, by extension, enables more tailored prophylactic dosing. This can, in turn, result in an improvement in FVIII trough levels and a decreased risk of bleeding. (Bertamino et al. 2017) Efanesoctocog alfa is a novel recombinant FVIII replacement therapy with an extended half-life due to decoupling from von Willebrand factor, offering once-weekly dosing with sustained FVIII activity. We describe two cases of severe hemophilia A managed at the National Center for Cancer Care and Research (NCCCR), Doha, Qatar. Methods and results Case 1: A 26-year-old male, diagnosed in childhood when he presented with central nervous system (CNS) bleeding, a FVIII level of <0.04% and F8 inversion intron 22 mutation. He was transferred to adult care while on SHL prophylaxis three times per week, with established deforming hemophilic arthropathy, poor compliance with therapy and a body mass index (BMI) of 34 kg/m2. He subsequently switched to EHL prophylaxis but still had an annualized bleeding rate (ABR) of 4–6, with improved but still suboptimal adherence. He underwent multiple joint radioactive synovectomies and was still largely inactive, with poor quality of life as assessed by Hema-A QoL. He was then switched to efanesoctocog alfa 4500 IU (51 IU/kg) weekly, achieving excellent clinical outcomes with zero ABR, a more active lifestyle, and a BMI of 27 kg/m2, and a good quality of life as assessed by Hema-A QoL. His new PK evaluation using showed an estimated peak FVIII level of 119% at 3 hours post-infusion, with sustained FVIII activity of 10.7% after 7 days. Case 2: A 23-year-old male, the brother of Case 1, was diagnosed earlier in life due to the family history. He underwent the same transition between different FVIII prophylaxis regimens. At the time of transition to adult care, he was on SHL with single joint arthropathy and a BMI of 29 kg/m2. He was changed to EHL FVIII every 4 days (per patient preference), was more compliant, and was assessed to have moderate impairment based on Hema-A QoL. His PK profile while on EHL FVIII, using WAPPS-Hemo, showed FVIII 75% peak and 0.63% trough at 4 days, with an ABR of 2–4. He would take extra doses during sports activities. He was switched to efanesoctocog alfa 3500 IU (44 IU/kg) weekly, achieving significant improvement in quality of life, no bleeding events (ABR of zero) and a BMI of 24 kg/m2. Pharmacokinetic reassessment showed a new estimated peak FVIII level of 86% and FVIII activity of 7.3% after 7 days. Both patients reported reduced infusion frequency, improved adherence, and better joint health, consistent with real-world findings from the XTEND-1 trial. Conclusion These cases highlight the real-world benefits of once weekly efanesoctocog alfa prophylaxis in severe hemophilia A, including higher trough FVIII levels, reduced treatment burden, and improved clinical outcomes. Personalized, PK-guided care supported successful transitions and aligns with clinical trial data, reinforcing its role in modern hemophilia management.