Treatment of Bleeding Episodes with Efanesoctocog Alfa in Children with Severe Hemophilia A in the XTEND-Kids Phase 3 Study

Introduction Efanesoctocog alfa (formerly BIVV001) is a new class of high sustained factor VIII (FVIII) replacement therapy, composed of a single recombinant FVIII protein fused to dimeric Fc protein, 2 XTEN polypeptides, and the D'D3 domain of von Willebrand factor (VWF), designed to overcome the endogenous VWF-imposed half-life ceiling. The XTEND-Kids (NCT04759131) study demonstrated once-weekly efanesoctocog alfa was well tolerated and provided effective treatment of and protection from bleeds in previously treated patients <12 years old with severe hemophilia A. Here, we provide a detailed report on efanesoctocog alfa as a treatment for bleeds during XTEND-Kids. Methods Previously treated patients <12 years old (≥150 exposure days [EDs] for patients 6 to <12 years of age and ≥50 EDs for patients <6 years old) with severe hemophilia A (<1 IU/dL [<1%] endogenous FVIII activity or a documented genotype associated with severe hemophilia) received efanesoctocog alfa 50 IU/kg once weekly for 52 weeks. In line with the study protocol, bleeds were treated with a single dose of efanesoctocog alfa (50 IU/kg). Additional doses (30 or 50 IU/kg, every 2-3 days) could be considered if needed. For minor/moderate bleeds occurring within 2-3 days of a recent prophylactic dose, a 30 IU/kg dose could also be used. The number and location of bleeds, as well as dose and number of efanesoctocog alfa injections required to resolve them were recorded. Patient assessment of the response to the first injection for treating a bleed was evaluated using the 4-point International Society on Thrombosis and Haemostasis (ISTH) scale (excellent, good, moderate, and none). Results Of 74 patients in XTEND-Kids, 73 were included in these post hoc analyses, including 38 subjects <6 years of age. One subject in the 6 to <12 group was excluded from these analyses as he did not receive weekly prophylaxis treatment as specified in the protocol, instead receiving intense consolidation treatment (2-3 injections per week for ~4 months) following 2 traumatic self-reported hip bleeds (however, no signs of bleeding or joint damage were observed by magnetic resonance imaging during the consolidation treatment period). The mean (SD) total number of EDs was 52.3 (6.83) for the overall population. The mean (95% confidence interval [CI]) estimated annualized bleed rate (ABR) was 0.61 (0.42-0.90). The mean (95% CI) annualized spontaneous, traumatic, and joint bleed rates were 0.16 (0.08-0.31), 0.40 (0.24-0.65), and 0.30 (0.16-0.57), respectively. Eighty-six percent of participants (n=63) had ≤1 bleed, including 64% (n=47) with no overall bleeds; 88% (n=64) had no spontaneous bleeds and 84% (n=61) had no joint bleeds. There were 43 bleeds treated with efanesoctocog alfa, of which 11 were reported as spontaneous (26%), 28 as traumatic (65%), and 4 (9%) were of unknown etiology (Table). The most common locations for bleeds were the joints (n=21, 49%) and skin/mucosa (n=15, 35%). The rate of bleeding events per week throughout the study remained consistently low (Figure). The mean (SD) duration between a treated bleed and nearest injection taken prior to that bleed was 4.7 (1.95) days, with a mean of 4.5 (1.56) days for a spontaneous bleed and 4.8 (2.12) for traumatic bleeds. A single injection was sufficient to resolve 95% of bleeds, and no bleed required more than 2 injections for resolution. The median (interquartile range) total dose required to resolve a bleed was 52.6 (50.0-55.8) IU/kg. Among first injections for bleeding episodes with an evaluation of response by participants (n=37), the vast majority (n=36, 97%) were rated as excellent or good. Conclusions A single dose of efanesoctocog alfa 50 IU/kg resolved 95% of bleeds in children <12 years of age, regardless of type or location. The hemostatic efficacy of efanesoctocog alfa was rated as excellent or good for nearly all evaluated first injections (97%). Once-weekly efanesoctocog alfa provided efficient prophylaxis with no bleeds in 64% of participants, and consistently low ABRs among all types and locations of bleeds. Efanesoctocog alfa provided effective treatment and prevention of bleeds in previously treated children <12 years of age with severe hemophilia A.

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