• Annette von Drygalski, Pratima Chowdary, Roshni Kulkarni, Sophie Susen, Barbara A Konkle, Johannes Oldenburg, Davide Matino, Robert Klamroth, Angela C Weyand, Victor Jimenez-Yuste, Keiji Nogami, Stacey Poloskey, Bent Winding, Annemieke Willemze, Karin Knobe, and XTEND-1 Trial Group.
• From the Division of Hematology and Oncology, Department of Medicine, University of California, San Diego, San Diego (A.D.); the Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London (P.C.); Michigan State University, East Lansing (R. Kulkarni); Centre Hospitalier Universitaire de Lille, Université de Lille, Lille (S.S.), and Sanofi, Chilly-Mazarin (K.K.) - both in France; the Washington Center for Bleeding Disorders and the University of Washington - both in Seattle (B.A.K.); the Institute of Experimental Hematology and Transfusion Medicine, Universitätsklinikum Bonn, Bonn (J.O.), and Vivantes Klinikum im Friedrichshain, Berlin (R. Klamroth) - both in Germany; the Division of Hematology and Thromboembolism, Department of Medicine, McMaster University, Hamilton, ON, Canada (D.M.); the Division of Hematology-Oncology, Department of Pediatrics, University of Michigan, Ann Arbor (A.C.W.); Hospital Universitario La Paz, Autónoma University, Madrid (V.J.-Y.); Nara Medical University, Nara, Japan (K.N.); Sanofi, Cambridge, MA (S.P.); Sobi, Stockholm (B.W.); and Sanofi, Amsterdam (A.W.).
• N. Engl. J. Med. 2023 Jan 26; 388 (4): 310318310-318.

BackgroundEfanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor-imposed half-life ceiling. The efficacy, safety, and pharmacokinetics of efanesoctocog alfa for prophylaxis and treatment of bleeding episodes in previously treated patients with severe hemophilia A are unclear.MethodsWe conducted a phase 3 study involving patients 12 years of age or older with severe hemophilia A. In group A, patients received once-weekly prophylaxis with efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. In group B, patients received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks. The primary end point was the mean annualized bleeding rate in group A; the key secondary end point was an intrapatient comparison of the annualized bleeding rate during prophylaxis in group A with the rate during prestudy factor VIII prophylaxis. Additional end points included treatment of bleeding episodes, safety, pharmacokinetics, and changes in physical health, pain, and joint health.ResultsIn group A (133 patients), the median annualized bleeding rate was 0 (interquartile range, 0 to 1.04), and the estimated mean annualized bleeding rate was 0.71 (95% confidence interval [CI], 0.52 to 0.97). The mean annualized bleeding rate decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11), a finding that showed superiority over prestudy factor VIII prophylaxis (P<0.001). A total of 26 patients were enrolled in group B. In the overall population, nearly all bleeding episodes (97%) resolved with one injection of efanesoctocog alfa. Weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU per deciliter for the majority of the week and of 15 IU per deciliter at day 7. Prophylaxis with efanesoctocog alfa for 52 weeks (group A) improved physical health (P<0.001), pain intensity (P = 0.03), and joint health (P = 0.01). In the overall study population, efanesoctocog alfa had an acceptable side-effect profile, and the development of inhibitors to factor VIII was not detected.ConclusionsIn patients with severe hemophilia A, once-weekly efanesoctocog alfa provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health. (Funded by Sanofi and Sobi; XTEND-1 ClinicalTrials.gov number, NCT04161495.).Copyright © 2023 Massachusetts Medical Society.

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