Drug development of nonalcoholic fatty liver disease: challenges in research, regulatory pathways, and study endpoints

ABSTRACT

Introduction

The growing prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and its association with obesity as a metabolic disease contributes to harmful outcomes and healthcare resource burden worldwide. For this reason, there is an urgent need to develop new therapies. Identification of treatment targets, research design, endpoints definitions and assessments, and supportive regulatory pathways for drug approval all play prominent roles in shaping efforts in drug discovery, investigation, and approval.

Areas covered

In this perspective, the authors enumerate key challenges of NAFLD clinical research and offer a conceptual framework to address these issues which arise during clinical trials.

Expert opinion

With the anticipated significant healthcare and costs burden that NAFLD will impose throughout the world, the diagnostics and drug development processes need to be accelerated. Important measures to improve clinical trial research include standardization of case definitions, comprehensive and granular covariate data collection, quality study development incorporating novel trial designs, and quality data reporting. The authors believe that these actions will accelerate understanding, development, and ultimately approval of efficacious treatments.

KEYWORDS:

• Fatty liver
• nonalcoholic steatohepatitis
• metabolic associated fatty liver disease
• clinical trials
• drug development
• study design

Article highlights

• Clinical trials for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are urgently needed, but there are multiple issues which lead to difficulty in conducting quality research, including patient, disease, and methodological factors.

• Knowledge of granular NAFLD and NASH phenotypes is poorly understood, which leads to a heterogenous study group and thus large variation in patient outcomes, which confounds interpretation of clinical trial results.

• The reliance on histologic outcomes for primary trial endpoints underscores limitations of liver biopsy as an imperfect gold-standard test and as a barrier to patient enrollment.

• The ideal clinical trial outcomes in patients with NAFLD and NASH (incident cirrhosis, cirrhosis decompensation, hepatocellular carcinoma, liver transplantation, mortality) are impractical for trials due to long latency periods, thus necessitating surrogate endpoints.

• Standardization of case definitions, comprehensive covariate data collection, novel trial designs, and data reporting are needed to ensure high-quality research data.

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Declaration of interest

JK Lim report research contracts (via their institution) from Allergan, Conatus, Genfit, Gilead Sciences, and Intercept while WZ Mehal reports research contracts (via their institution) from Pfizer Inc and Intercept. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.