From Versiti Blood Research Institute, and the Division of Hematology and Oncology, Departments of Medicine and Pediatrics, Medical College of Wisconsin - both in Milwaukee (L.M.); IRCCS Ca' Granda Maggiore Hospital Foundation, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, and Università degli Studi di Milano, Department of Pathophysiology and Transplantation - both in Milan (F.P.); McMaster Children's Hospital, McMaster University, Hamilton, ON (A.K.C.C.), and the Division of Hematology-Oncology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto (M.C.) - both in Canada; Goethe University Frankfurt, University Hospital, Department of Pediatrics and Adolescent Medicine, Frankfurt, Germany (C.K.); the Department of Pediatric Hematology, Istanbul University Oncology Institute, Inherited Bleeding Disorders, Istanbul, Turkey (B.Z.); Sanofi, Cambridge, MA (H.Y., M.D.); Rush University Medical Center, Rush Hemophilia and Thrombophilia Center, Chicago (M.S.); Hospital Universitario La Paz, Autonoma University of Madrid, IdiPAZ, Madrid (M.T.Á.R.); University of Iowa Stead Family Children's Hospital, Carver College of Medicine, Department of Pediatrics, Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Iowa City (J.M.S.); the Division of Hematology, Oncology, and Blood and Marrow Transplant at Nationwide Children's Hospital and the Ohio State University College of Medicine, Columbus (A.L.D.); the Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan (S.-C.C.); Centre de Référence de l'Hémophilie et des Maladies Hémorragiques Constitutionnelles and Hémostase Inflammation Thrombose, Unité Mixte de Recherche S1176, INSERM, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Université Paris-Saclay, Le Kremlin-Bicêtre, France (R.O.); University Children's Hospital, Zurich (M.A.), and Sobi, Basel (E.S., L.A.-F.) - both in Switzerland; Sanofi, Bridgewater, NJ (A.Y., N.W., S.G.); and Amsterdam UMC, University of Amsterdam, Emma Children's Hospital, Pediatric Hematology, Amsterdam (K.F.).
N Engl J Med. 2024 Jul 18;391(3):235-246. doi: 10.1056/NEJMoa2312611.
Once-weekly efanesoctocog alfa provides high sustained factor VIII activity with superior bleeding prevention as compared with prestudy factor VIII prophylaxis in previously treated patients 12 years of age or older with severe hemophilia A. Data on outcomes of efanesoctocog alfa treatment in children younger than 12 years of age with severe hemophilia A are limited.
We conducted a phase 3, open-label study involving previously treated patients younger than 12 years of age with severe hemophilia A. Patients received prophylaxis with once-weekly efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. The primary end point was the occurrence of factor VIII inhibitors (neutralizing antibodies against factor VIII). Secondary end points included annualized rates of treated bleeding episodes, bleeding treatment, safety, and pharmacokinetics.
A total of 74 male patients were enrolled (38 with an age of <6 years and 36 with an age of 6 to <12 years). No factor VIII inhibitors developed. Most adverse events were nonserious. No serious adverse events that were assessed by the investigator as being related to efanesoctocog alfa were reported. In the 73 patients treated according to the protocol, the median and model-based mean annualized bleeding rates were 0.00 (interquartile range, 0.00 to 1.02) and 0.61 (95% confidence interval, 0.42 to 0.90), respectively. A total of 47 patients (64%) had no treated bleeding episodes, 65 (88%) had no spontaneous bleeding episodes, and 61 (82%) had no episodes of bleeding into joints. A total of 41 of 43 bleeding episodes (95%) resolved with one injection of efanesoctocog alfa. Mean factor VIII activity at steady state was more than 40 IU per deciliter for 3 days and more than 10 IU per deciliter for almost 7 days after dose administration. The geometric mean terminal half-life was 40.0 hours.
In children with severe hemophilia A, once-weekly prophylaxis with efanesoctocog alfa provided high sustained factor VIII activity in the normal to near-normal range (>40 IU per deciliter) for 3 days and more than 10 IU per deciliter for almost 7 days after administration, leading to effective bleeding prevention. Efanesoctocog alfa was associated with mainly nonserious adverse events. (Funded by Sanofi and Sobi; XTEND-Kids ClinicalTrials.gov number, NCT04759131.).
与既往治疗的 12 岁及以上重度 A 型血友病患者接受预研究因子 VIII 预防治疗相比，每周一次的 efanesoctocog alfa 可提供高且持续的因子 VIII 活性，具有更好的出血预防作用。关于年龄在 12 岁以下的重度 A 型血友病儿童接受 efanesoctocog alfa 治疗的结局数据有限。
我们开展了一项 3 期、开放标签研究，纳入了年龄在 12 岁以下的既往治疗的重度 A 型血友病患儿。患者接受每周一次的 efanesoctocog alfa（50IU/kg 体重）预防治疗 52 周。主要终点是因子 VIII 抑制剂（针对因子 VIII 的中和抗体）的发生情况。次要终点包括年化治疗出血发作率、出血治疗情况、安全性和药代动力学。
共纳入 74 例男性患者（年龄<6 岁 38 例，6 岁至<12 岁 36 例），未发生因子 VIII 抑制剂。大多数不良事件为非严重事件。研究者评估的与 efanesoctocog alfa 相关的严重不良事件无报告。在按方案治疗的 73 例患者中，中位和基于模型的年化出血率分别为 0.00（四分位距，0.00 至 1.02）和 0.61（95%置信区间，0.42 至 0.90）。47 例（64%）患者无治疗出血发作，65 例（88%）无自发性出血发作，61 例（82%）无关节出血发作。43 例出血发作中的 41 例（95%）接受一次 efanesoctocog alfa 注射后缓解。稳态时平均因子 VIII 活性在给药后 3 天内超过 40IU/dL，在给药后近 7 天内超过 10IU/dL。几何均数终末半衰期为 40.0 小时。
在重度 A 型血友病儿童中，每周一次的 efanesoctocog alfa 预防治疗可提供高且持续的因子 VIII 活性，在正常至接近正常范围内（>40IU/dL）持续 3 天，在给药后近 7 天内超过 10IU/dL，从而有效预防出血。efanesoctocog alfa 主要与非严重不良事件相关。（由 Sanofi 和 Sobi 资助；XTEND-Kids 临床试验.gov 编号，NCT04759131。）
