携带预防性糖皮质激素的valoctocogene roxaparvovec的安全性和有效性：3b期单臂开放标签GENEr8-3研究的1年结果

Safety and efficacy of valoctocogene roxaparvovec with prophylactic glucocorticoids: 1-year results from the phase 3b, single-arm, open-label GENEr8-3 study.

作者信息

Ozelo Margareth C, Mason Jane, Dunn Amy L, Villaça Paula Ribeiro, Shen Ming-Ching, Agarwal Suresh, Imtiaz Urooj, Liu Hai, Robinson Tara M

机构信息

Department of Internal Medicine, Hemocentro UNICAMP, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.

Queensland Haemophilia Centre, Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; University of Queensland, Brisbane, Queensland, Australia.

出版信息

J Thromb Haemost. 2025 May;23(5):1496-1506. doi: 10.1016/j.jtha.2024.12.038. Epub 2025 Jan 10.

DOI:10.1016/j.jtha.2024.12.038

PMID:39800255

Abstract

BACKGROUND

Valoctocogene roxaparvovec, an adeno-associated virus vector that transfers a human factor (F)VIII (FVIII) coding sequence to hepatocytes, provides bleeding protection for people with severe hemophilia A.

OBJECTIVES

Determine the efficacy and safety of valoctocogene roxaparvovec with concomitant prophylactic glucocorticoids in the open-label, single-arm, phase 3b GENEr8-3 trial.

METHODS

Participants with severe hemophilia A who were using hemophilia A prophylaxis received one 6 × 10 vg/kg infusion of valoctocogene roxaparvovec concomitantly with daily prophylactic glucocorticoids (40 mg prednisolone equivalent/d weeks 0-8; taper to 5 mg/d weeks 9-19). The primary efficacy endpoint was change from baseline in FVIII activity (chromogenic substrate assay) at week 52. Secondary efficacy endpoints included annualized rate of FVIII use and annualized bleeding rate for treated bleeds. Safety was assessed by adverse events (AEs). Analysis populations were intent-to-treat (ITT; received valoctocogene roxaparvovec) for safety analyses and modified ITT (≥52 FVIII infusions in the year before dosing) for efficacy analyses.

RESULTS

Overall, 22 participants with severe hemophilia A received valoctocogene roxaparvovec. In the modified ITT population (n = 21), mean week 52 FVIII activity increased from baseline (imputed as 1 IU/dL) to 16.1 IU/dL (SD, 22.4; P = .0057); posthemophilia A prophylaxis, mean treated annualized bleeding rate and mean annualized FVIII use decreased 67.1% and 91.6% from baseline, respectively (P < .05). The most common AE was alanine aminotransferase elevation (20/22 participants). Glucocorticoid-related AEs occurred in 19 of 22 participants. No participants discontinued the study.

CONCLUSION

Based on cross-trial comparisons, prophylactic glucocorticoids do not confer safety or efficacy benefits compared with reactive glucocorticoid regimens.

摘要

背景

valoctocogene roxaparvovec是一种腺相关病毒载体，可将人因子VIII（FVIII）编码序列转移至肝细胞，为重度A型血友病患者提供出血保护。

目的

在开放标签、单臂3b期GENEr8-3试验中确定valoctocogene roxaparvovec联合预防性糖皮质激素的疗效和安全性。

方法

正在接受A型血友病预防治疗的重度A型血友病参与者接受一次6×10 vg/kg的valoctocogene roxaparvovec输注，同时每日接受预防性糖皮质激素治疗（第0-8周40 mg泼尼松等效剂量/天；第9-19周逐渐减量至5 mg/天）。主要疗效终点是第52周时FVIII活性（发色底物法）相对于基线的变化。次要疗效终点包括FVIII使用的年化率和治疗出血的年化出血率。通过不良事件（AE）评估安全性。分析人群在安全性分析中为意向性治疗（ITT；接受valoctocogene roxaparvovec），在疗效分析中为改良ITT（给药前一年≥52次FVIII输注）。

结果

总体而言，22名重度A型血友病参与者接受了valoctocogene roxaparvovec。在改良ITT人群（n = 21）中，第52周时FVIII平均活性从基线（推算为1 IU/dL）增加至16.1 IU/dL（标准差，22.4；P = 0.0057）；在进行A型血友病预防治疗后，治疗出血的平均年化率和FVIII的平均年化使用率分别较基线下降了67.1%和91.6%（P < 0.05）。最常见的AE是丙氨酸转氨酶升高（20/22名参与者）。22名参与者中有19名出现了与糖皮质激素相关的AE。没有参与者退出研究。