PDF(Pubmed)
Abstract：
UNASSIGNED: The US Food and Drug Administration (FDA)\'s authorization of etranacogene dezaparvovec (Hemgenix) is a significant milestone, constituting not only the first FDA approval of a gene therapy for hemophilia but also the first approval of a liver-targeted adeno-associated virus vector gene therapy. This review summarizes the nonclinical studies and clinical development that supported regulatory clearance. Similar to other gene therapies for single gene disorders, both the short-term safety and the phenotypic improvement were unequivocal, justifying the modest-sized safety and efficacy database, which included 57 participants across the phase 2b (3 participants) and phase 3 (54 participants) studies. The most common adverse reactions included liver enzyme elevation, headache, flu-like symptoms, infusion-related reactions, creatine kinase elevation, malaise, and fatigue; these were mostly transient. One participant had hepatocellular carcinoma on a study-mandated liver ultrasound conducted 1 year after vector infusion; molecular analysis of the resected tumor showed no evidence of vector-related insertional mutagenesis as the etiology. A remarkable 96% of participants in the phase 3 trial were able to stop factor IX (FIX) prophylaxis, with the study demonstrating noninferiority to FIX prophylaxis in terms of the primary end point, annualized bleeding rate. Key secondary end points such as the annualized infusion rate, which declined by 97%, and the plasma FIX activity level at 18 months after infusion, with least squares mean increase of 34.3 percentage points compared with baseline, were both clinically and statistically significant. The FDA\'s landmark approval of Hemgenix as a pioneering treatment for hemophilia stands on the shoulders of >20 years of gene therapy clinical research and heralds a promising future for genomic medicines.
摘要：
■美国食品和药物管理局（FDA）的授权是一个重要的里程碑，这不仅是FDA首次批准血友病基因疗法，也是首次批准肝脏靶向腺相关病毒载体基因疗法。这篇综述总结了支持监管清除的非临床研究和临床开发。类似于其他针对单基因疾病的基因疗法，短期安全性和表型改善都是明确的，证明适度大小的安全性和有效性数据库，其中包括2b期(3名参与者)和3期(54名参与者)研究的57名参与者.最常见的不良反应包括肝酶升高，头痛,流感样症状,输液相关反应,肌酸激酶升高，萎靡不振,和疲劳；这些大多是短暂的。一名参与者在载体输注后1年进行的研究强制肝超声检查中患有肝细胞癌；切除肿瘤的分子分析没有证据表明载体相关的插入突变是病因。在3期试验中，有96％的参与者能够停止因子IX（FIX）预防，研究表明，就主要终点而言，对FIX预防具有非劣效性，年化出血率。关键的次要终点，如年度输液率，下降了97%，以及输注后18个月的血浆FIX活性水平，与基线相比，最小二乘均值增加了34.3个百分点，具有临床和统计学意义。FDA具有里程碑意义的批准Hemgenix作为血友病的开创性治疗方法，站在20多年的基因治疗临床研究的肩膀上，预示着基因组药物的前景。
