Histological Endpoints for Nonalcoholic Steatohepatitis Trials: Lights and Shadows

Abstract

Nonalcoholic steatohepatitis (NASH) with liver fibrosis is an increasingly important cause of liver-related morbidity and mortality. A diagnosis of NASH can only be made using liver biopsy. Liver histology also forms the endpoint for the expedited licensing strategies that have been approved by regulators to allow patients with NASH access to treatment before the impact of these on clinical outcomes is known. Validation of these histological surrogate endpoints is critical for the ongoing development of new therapies for NASH. The use of liver biopsy to define both trial entry and endpoints raises questions about the use of treatments for NASH in practice when the effectiveness of treatment will likely depend, at least in part, on the use of histology for patient selection in the real world.

Endpoints in NASH Clinical Trials: Are We Blind in One Eye?

“…Although NASH is defined histologically, liver biopsy poses various challenges impacting patient enrollment, observers’ agreement, and extension to the clinical practice of trial findings [ 172 ]. Moreover, the intrinsic imprecision of liver biopsy makes currently adopted histological endpoints in NASH clinical trials both fallacious and overambitious and strongly advises in favor of identifying noninvasive biomarkers and criteria for entry into NASH trials and evaluating drug efficacy [ 34 ].…”