Department of Gastroenterology and Hepatology, Radboud University Medical Centre , Nijmegen, The Netherlands.
Department of Medicine, University Medical Centre of the Johannes Gutenberg-University , Mainz, Germany.
Expert Opin Investig Drugs. 2020 Dec;29(12):1365-1375. doi: 10.1080/13543784.2020.1839888. Epub 2020 Oct 27.
Numerous pharmacological compounds that target the different molecular targets involved in the pathobiology of nonalcoholic steatohepatitis (NASH) are currently in clinical testing. So far, there are no regulatory approvals.
This paper sheds light on the molecular pathways involved in NASH and the drugs targeting these pathways. We have identified 10 compounds whose clinical development program has been halted. Moreover, we explore early phase clinical trials and dissect the reasons for termination of development.
The main goal of NASH pharmacotherapy is to halt or reverse hepatic fibrosis or to achieve the resolution of steatohepatitis. There is an intense competition to develop compounds with disease-modulating properties with a focus on anti-metabolic, anti-inflammatory or anti-fibrotic properties. Numerous study programs, even in late-phase trials, have been halted because of lack of efficacy, safety concerns or drug-drug interactions. This underscores the urgent need to provide robust preclinical data and an extensive clinical trial program that builds on reliable data generated in earlier stages of clinical development before moving into late stage development.
目前有许多针对非酒精性脂肪性肝炎（NASH）发病生物学中涉及的不同分子靶点的药理学化合物正在进行临床测试。但到目前为止，还没有获得监管批准。
本文阐明了 NASH 涉及的分子途径以及针对这些途径的药物。我们已经确定了 10 种已停止临床开发计划的化合物。此外，我们还探讨了早期临床试验，并剖析了开发终止的原因。
NASH 药物治疗的主要目标是阻止或逆转肝纤维化或实现脂肪性肝炎的消退。目前，人们竞相开发具有疾病调节特性的化合物，重点是抗代谢、抗炎或抗纤维化特性。由于缺乏疗效、安全性问题或药物相互作用，许多研究项目，甚至在后期试验中，都已停止。这突显了迫切需要提供强大的临床前数据和广泛的临床试验计划，该计划应建立在早期临床开发阶段生成的可靠数据基础上，然后再进入后期开发阶段。
