Gene therapies aim to address the root causes of diseases, particularly those stemming from rare genetic defects that can be life-threatening or severely debilitating. While there has been notable progress in the development of gene therapies in recent years, understanding their long-term effectiveness remains challenging due to a lack of data on long-term outcomes, especially during the early stages of their introduction to the market. To address the critical question of estimating long-term efficacy without waiting for the completion of lengthy clinical trials, we propose a novel Bayesian framework. This framework selects pertinent data from external sources, often early-phase clinical trials with more comprehensive longitudinal efficacy data that could lead to an improved inference of the long-term efficacy outcome. We apply this methodology to predict the long-term factor IX (FIX) levels of HEMGENIX (etranacogene dezaparvovec), the first FDA-approved gene therapy to treat adults with severe Hemophilia B, in a phase 3 study. Our application showcases the capability of the framework to estimate the 5-year FIX levels following HEMGENIX therapy, demonstrating sustained FIX levels induced by HEMGENIX infusion. Additionally, we provide theoretical insights into the methodology by establishing its posterior convergence properties.

翻译：摘要：基因疗法旨在解决疾病的根本病因，特别是针对那些由罕见基因缺陷引发的危及生命或严重致残的疾病。尽管近年来基因疗法开发取得了显著进展，但由于长期结局数据的缺乏（尤其是在其上市初期），评估其长期有效性仍面临挑战。为解决无需等待漫长临床试验完成即可估计长期疗效这一关键问题，我们提出了一种新颖的贝叶斯框架。该框架可从外部来源（通常为具有更全面纵向疗效数据的早期临床试验）中筛选相关数据，从而改进对长期疗效结局的推断。我们将该方法应用于一项III期研究，预测首个获FDA批准用于治疗成人重度血友病B的基因疗法HEMGENIX（etranacogene dezaparvovec）的长期因子IX（FIX）水平。实际应用表明，该框架可估计HEMGENIX治疗后5年的FIX水平，证实了HEMGENIX输注诱导的持续FIX水平。此外，我们通过建立后验收敛性为该方法提供了理论支撑。