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原因，特别是那些由罕见基因缺陷引发的、可能危及生命或导致严重衰弱的问题。尽管近年来基因疗法开发取得了显著进展，但由于缺乏关于长期结局的数据（尤其是在其上市早期阶段），理解其长期有效性仍面临挑战。为了解决无需等待冗长临床试验完成即可评估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。该框架从外部来源（通常是拥有更全面纵向疗效数据的早期临床试验）中筛选相关数据，从而可能改进对长期疗效结局的推断。我们将这一方法应用于预测HEMGENIX（etranacogene dezaparvovec，首个获FDA批准用于治疗成人重度血友病B的基因疗法）在III期研究中的长期因子IX（FIX）水平。我们的应用展示了该框架在评估HEMGENIX治疗后5年FIX水平的能力，证明了HEMGENIX输注诱导的持续FIX水平。此外，我们通过建立该方法的后验收敛性质，为其提供了理论层面的深入见解。