Efficacy of Efanesoctocog Alfa on Physical Functioning: Results from the XTEND-1 Phase 3 Clinical Trial in Previously Treated Patients with Hemophilia A

Background: Adults with severe hemophilia A may have reduced levels of physical functioning significantly impacting their health-related quality of life (HRQoL). Results from the Phase 3 XTEND-1 study demonstrated that once-weekly efanesoctocog alfa prophylaxis was well-tolerated and provided superior bleed protection compared with prior factor VIII (FVIII) prophylaxis.

Objective: To evaluate the efficacy of once-weekly efanesoctocog alfa prophylaxis on physical functioning in adults and adolescents (≥12 years of age) with severe hemophilia A who were previously treated with standard of care FVIII prophylaxis.

Methods: XTEND-1 (NCT04161495) was a phase 3, open-label, multicenter trial in previously treated patients (≥12 years of age) with severe hemophilia A. Patients received once-weekly prophylactic efanesoctocog alfa, 50 IU/kg for 52 weeks (Arm A) or on-demand efanesoctocog alfa, 50 IU/kg for 26 weeks followed by 26 weeks of once-weekly prophylaxis ([50 IU/kg]; Arm B). Physical functioning was assessed as a secondary endpoint using hemophilia-specific HRQoL questionnaire for adults (Haem-A-QoL; in patients ≥17 years of age), Patient-Reported Outcomes Measurement Information System (PROMIS)-Short Form v2.0 physical function (PF; in patients ≥18 years of age), and as exploratory endpoints using Hemophilia Activities List (HAL; in patients ≥18 years of age), and EuroQol- 5 Dimension-5 Level (EQ-5D-5L; mobility and usual activities domains). Exit interviews, ActiGraph Activity Monitors (worn for 8 consecutive days at intervals throughout the study period), and post-hoc analysis (including psychometric analyses) were also used to evaluate physical functioning. The mean change from baseline to Week 52 in Haem-A-QoL Physical Health (PH) score, PROMIS PF 6b T-score, and HAL overall score, along with 95% confidence interval (CI) were estimated by a mixed-effect model with repeated measures. Here we report results for patients in Arm A. Results of the exit interviews and Actigraphy were evaluated in the overall patients included in the trial (Arms A and B).

Results: A total of 159 patients (Arm A, N=133; Arm B, N=26) were included in the XTEND-1 trial. At baseline, the Haem-A-QoL PH score (mean [standard deviation, SD]) was 37.02 (23.83), while the overall HAL score was 76.11 [20.73]. A total of 18% (22/122) and 9% (11/122) patients reported moderate to severe problems with mobility and usual activities, respectively, at baseline, as per EQ-5D-5L. Prophylactic treatment with efanesoctocog alfa resulted in significant improvement in physical health: least square (LS) mean change in the Haem-A-QoL PH score from baseline to Week 52 was -6.74 (95% CI: -10.13 to -3.36; P=0.0001). Psychometric analyses reported meaningful within-group change for Haem-A-QoL PH score of 6.8 (range: 4.8-6.8) defined in the context used in the study. Numerical improvement was observed in PROMIS PF 6b T-score (LS mean change from baseline: 0.56 [95% CI: -0.38 to 1.50] and in HAL overall score at Week 52 (LS mean change: 0.67 [95% CI: -2.03 to 3.38]). A total of 23.5% (27/115) patients reported an improvement in at least 1 category in mobility at Week 52, while usual activities improved in 19.1% (22/115) patients in the EQ-5D-5L scale. These improvements in physical functioning on various instruments were aligned with the results from the exit interviews (N=29, including 17 patients in Arm A) reporting improvement in physical functioning in most patients (26/29). In addition, trends of improved physical activity were also observed in the Actigraphy data (mean [SD]: 5376 [3796] steps/day at baseline versus 5758 [4472] steps/day at Week 52; overall patients, N=158, including 132 patients in Arm A).

Conclusions: Once-weekly prophylaxis with efanesoctocog alfa resulted in improvement in physical functioning in patients with hemophilia A, positively impacting daily living activities, in patients who were on prior standard of care FVIII prophylaxis.

Wilson:Sanofi: Current Employment. Kragh:Sobi (Swedish Orphan Biovitrum AB ): Current Employment. Dumont:Sanofi: Current Employment. Mshijid:Sanofi: Current Employment, Current holder of stock options in a privately-held company. Willemze:Sanofi: Current Employment, Current holder of stock options in a privately-held company. Bystricka:Sobi (Swedish Orphan Biovitrum AB ): Current Employment. Zhang:Sanofi: Current Employment. Weyand:Bayer: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Research Funding; Spark: Consultancy; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Fischer:CSL Behring: Honoraria; NovoNordisk: Honoraria; CSL Behring: Consultancy; Freeline: Consultancy; NovoNordisk: Consultancy; Roche: Consultancy; Sobi: Consultancy. Jimenez-Yuste:Pfizer: Consultancy; Novo Nordisk: Consultancy; Shire: Consultancy; Grifols: Consultancy; Sobi (Swedish Orphan Biovitrum AB ): Consultancy; CSL Behring: Consultancy; Bayer: Consultancy; F. Hoffmann-La Roche: Consultancy, Other: lecture fees.