依因子VIII预防严重A型血友病患者

Efanesoctocog Alfa Prophylaxis for Patients with Severe Hemophilia A.

作者信息

von Drygalski Annette, Chowdary Pratima, Kulkarni Roshni, Susen Sophie, Konkle Barbara A, Oldenburg Johannes, Matino Davide, Klamroth Robert, Weyand Angela C, Jimenez-Yuste Victor, Nogami Keiji, Poloskey Stacey, Winding Bent, Willemze Annemieke, Knobe Karin

机构信息

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.).

出版信息

N Engl J Med. 2023 Jan 26;388(4):310-318. doi: 10.1056/NEJMoa2209226.

DOI:10.1056/NEJMoa2209226

PMID:36720133

Abstract

BACKGROUND

Efanesoctocog 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.

METHODS

We 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.

RESULTS

In 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.

CONCLUSIONS

In 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.).

摘要

背景

通过克服血管性血友病因子所设定的半衰期上限，依诺凝血素α可提供高持续水平的凝血因子VIII活性。依诺凝血素α用于既往接受过治疗的重度甲型血友病患者预防和治疗出血发作的疗效、安全性及药代动力学尚不清楚。

方法

我们开展了一项3期研究，纳入12岁及以上的重度甲型血友病患者。A组患者接受依诺凝血素α（每千克体重50 IU）每周一次的预防治疗，持续52周。B组患者接受依诺凝血素α按需治疗26周，随后接受依诺凝血素α每周一次的预防治疗26周。主要终点是A组的年化出血率均值；关键次要终点是A组患者预防治疗期间的年化出血率与研究前凝血因子VIII预防治疗期间的出血率进行患者内比较。其他终点包括出血发作的治疗、安全性、药代动力学以及身体健康、疼痛和关节健康的变化。

结果

A组（133例患者）的年化出血率中位数为0（四分位间距，0至1.04），估计年化出血率均值为0.71（95%置信区间[CI]，0.52至0.97）。年化出血率均值从2.96（95%CI，2.00至4.37）降至0.69（95%CI，0.43至1.11），这一结果显示优于研究前的凝血因子VIII预防治疗（P<0.001）。B组共纳入26例患者。在总体人群中，几乎所有出血发作（97%）通过注射一次依诺凝血素α即可缓解。依诺凝血素α每周预防治疗在一周的大部分时间内可使凝血因子VIII活性均值超过40 IU/分升，并在第7天时达到15 IU/分升。依诺凝血素α预防治疗52周（A组）可改善身体健康（P<0.001）、疼痛强度（P = 0.03）和关节健康（P = 0.01）。在整个研究人群中，依诺凝血素α具有可接受的副作用谱，且未检测到针对凝血因子VIII的抑制剂产生。