Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
Summit Clinical Research, San Antonio, Texas, USA.
J Hepatol. 2024 Nov;81(5):886-894. doi: 10.1016/j.jhep.2024.06.008. Epub 2024 Jun 13.
During recent decades, the metabolic dysfunction-associated steatohepatitis (MASH) field has witnessed several paradigm shifts, including the recognition of liver fibrosis as the main predictor of major adverse liver outcomes. Throughout this evolution, liver histology has been recognised as one of the main hurdles in MASH drug development due to its invasive nature, associated cost, and high inter- and intra-reader variability. Collective experience demonstrates the importance of consistency in the central reading process, where consensus methods have emerged as appropriate ways to mitigate against well-known challenges. Using crystalized knowledge in the field, stakeholders should collectively work towards the next paradigm shift, where non-invasive biomarkers will be considered surrogate endpoints for accelerated approval. In this review, we provide an overview of the evolution of the regulatory histology endpoints and the liver biopsy reading process, within the MASH trial landscape, over recent decades; we then review the biggest challenges associated with liver biopsy endpoints. Finally, we discuss and provide recommendations on the best practices for liver biopsy evaluation in MASH drug development.
在最近几十年，代谢相关脂肪性肝炎（MASH）领域发生了几次范式转变，包括认识到肝纤维化是主要不良肝脏结局的主要预测因素。在这一演变过程中，由于其侵袭性、相关成本以及较高的观察者内和观察者间变异性，肝组织学被认为是 MASH 药物开发的主要障碍之一。集体经验表明，在中央阅读过程中保持一致性非常重要，共识方法已成为减轻众所周知的挑战的适当方法。利益相关者应利用该领域的既定知识，共同努力实现下一个范式转变，即将非侵入性生物标志物视为加速批准的替代终点。在这篇综述中，我们概述了在过去几十年中，MASH 试验领域中监管组织学终点和肝活检阅读过程的演变；然后我们回顾了与肝活检终点相关的最大挑战。最后，我们讨论并就 MASH 药物开发中肝活检评估的最佳实践提供了建议。
