近日，悉尼医学与健康学院John E.J. Rasko团队对Fidanacogene Elaparvove治疗血友病B进行了一项多年随访研究。2025年4月17日出版的《新英格兰医学杂志》发表了这一最新研究成果。

在一项临床1-2a期研究中，研究组使用重组腺相关病毒（AAV）载体fidanacogene elaparvovic治疗血友病B，导致高活性因子IX变体（FIX-R38L或FIX Padua）的持续表达。这种治疗的长期安全性和有效性尚不清楚。

在一项为期12个月的研究中，15名患有严重或中度血友病B（凝血因子IX活性≤正常值的2%）的参与者接受了fidanacogene elaparvovic治疗，剂量为每公斤体重5×10¹¹个载体基因组（vg）；之后，参与者可以参加一项为期5年的随访研究。安全终点包括不良事件和实验室措施的变化。疗效终点包括治疗出血事件的年化率（年化出血率）和因子IX活性。

共有14名参与者表示同意并完成了至少3年的随访（中位数为5.5；范围为3至6）；数据截止时，8人仍在参与。在第1年后，没有参与者报告与治疗相关的不良事件。在整个随访过程中，4名参与者出现了9起严重不良事件；无血栓形成或治疗相关。未检测到因子IX抑制剂。在整个随访过程中，因子IX的平均活性在轻度血友病范围内；平均年出血率小于1，10名参与者没有治疗过出血事件。从第1年开始的监测肝脏超声显示没有癌症的证据，但在4名体重增加和转氨酶水平升高的参与者中显示脂肪变性（最大丙氨酸转氨酶水平，77U/升）。一名有丙型肝炎、乙型肝炎、人类免疫缺陷病毒感染史和体重指数升高的参与者出现了潜在的晚期肝纤维化进展。8名参与者共进行了13次手术；在10次手术中给予外源性因子IX，没有发生相关的意外出血并发症。

研究结果表明，在3至6年的时间里，Fidanacogene elaparvovic与无不良反应或仅轻度不良反应有关。长期疗效维持在每公斤5×10¹¹ vg，这是用于任何适应症的最低静脉注射AAV剂量之一。

附：英文原文

Title: Fidanacogene Elaparvovec for Hemophilia B — A Multiyear Follow-up Study

Author: John E.J. Rasko, Benjamin J. Samelson-Jones, Lindsey A. George, Adam Giermasz, Jonathan M. Ducore, Jerome M. Teitel, Catherine E. McGuinn, Katherine A. High, Ype P. de Jong, Amit Chhabra, Amanda O’Brien, Lynne M. Smith, Ian Winburn, Jeremy Rupon

Issue&Volume: 2025-04-17

Abstract:

BACKGROUND

Treatment with fidanacogene elaparvovec, a recombinant adeno-associated virus (AAV) vector developed for the treatment of hemophilia B, led to sustained expression of the high-activity factor IX variant (FIX-R338L, or FIX-Padua) in a phase 1–2a study. The long-term safety and efficacy of this treatment are not known.

METHODS

In a 12-month study, 15 participants with severe or moderately severe hemophilia B (factor IX coagulant activity, ≤2% of the normal value) received fidanacogene elaparvovec at a dose of 5×1011 vector genomes (vg) per kilogram of body weight; thereafter, participants could enroll in a 5-year follow-up study. Safety end points included adverse events and changes in laboratory measures. Efficacy end points included the annualized rate of treated bleeding events (annualized bleeding rate) and factor IX activity.

RESULTS

A total of 14 participants provided consent and completed at least 3 years of follow-up (median, 5.5; range 3 to 6); participation was ongoing among 8 at the data cutoff. None of the participants reported treatment-related adverse events after year 1. Throughout follow-up, nine serious adverse events were noted in 4 participants; none were thrombotic or treatment-related. No factor IX inhibitors were detected. Throughout follow-up, mean factor IX activity was in the mild hemophilia range; the mean annualized bleeding rate was less than 1, and 10 participants had no treated bleeding episodes. Surveillance liver ultrasounds obtained from year 1 onward showed no evidence of cancer but showed steatosis in 4 participants who had weight gain and elevated aminotransferase levels (maximum alanine aminotransferase level, 77 U per liter). One participant with a history of hepatitis C, hepatitis B, human immunodeficiency virus infection, and an elevated body-mass index had progression of underlying advanced liver fibrosis. A total of 13 surgical procedures were performed in 8 participants; exogenous factor IX was administered for 10 procedures, and no associated unexpected bleeding complications occurred.

CONCLUSIONS

Fidanacogene elaparvovec was associated with no or only low-grade adverse effects over a period of 3 to 6 years. Efficacy was maintained in the long term at 5×1011 vg per kilogram, one of the lowest intravenous doses of AAV used for any indication.

DOI: NJ202504173921509

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2307159