Nonalcoholic steatohepatitis (NASH) cirrhosis: a snapshot of therapeutic agents in clinical development and the optimal design for clinical trials

ABSTRACT

Introduction

Patients with nonalcoholic steatohepatitis (NASH)-associated cirrhosis have the highest rates of major adverse liver outcomes (MALO) within the fatty liver disease spectrum and therefore have the highest unmet need for effective therapeutic agents. Several drugs are being tested for patients with NASH cirrhosis with different mechanisms of action and endpoints.

Areas covered

This article summarizes the available data on the natural history of NASH cirrhosis and the rates of developing MALO. We provide examples of ongoing clinical trials for NASH cirrhosis including the study design and endpoints. We then discuss the FDA-guidance on acceptable endpoints for NASH cirrhosis trials that will lead to approval.

Expert opinion

Metabolic and antifibrotic drugs are currently in phase 2b trials for NASH cirrhosis with outcomes ranging from histologic improvement on liver biopsy to the development of varices or MALO. We provide the readers with pragmatic advice on trial design for phase 2B and 3 NASH cirrhosis trials. The data presented in the article justify further development and investigation of therapeutic agents for the treatment of NASH cirrhosis.

KEYWORDS:

• Nonalcoholic steatohepatitis (NASH)
• cirrhosis
• clinical trials
• natural history
• obeticholic acid
• aldafermin
• resmetirom
• clinical trials

Article highlights

• Presently, there are no FDA-approved therapies for NASH cirrhosis. However, there are several recently completed and ongoing clinical trials that are reviewed in this manuscript.

• While many trials focus on histologic endpoints such as NASH resolution with or without fibrosis regression, the FDA recommends clinical outcomes endpoints in trials for patients with NASH cirrhosis.

• The FDA already has a list of major adverse liver outcomes (MALO) that are suitable clinical endpoints for clinical trials: ascites, variceal hemorrhage, hepatic encephalopathy, worsening MELD score, liver transplant, or all-cause mortality.

• Another reasonable endpoint for NASH cirrhosis trials may be endoscopic endpoints or serial measurement of clinically significant portal hypertension.

• Non-invasive tests including serum biomarkers and radiologic assessments such as magnetic resonance elastography also provide suitable alternatives for clinical outcome measures and may reasonably replace liver biopsy as the gold standard in the future.

• We envision increased uniformity among patients enrolled in clinical trials along with decreased utilization of liver biopsy and increased utilization of noninvasive testing and clinical outcomes as primary endpoints in clinical trials.

This box summarizes key points contained in the article.

Declaration of interest

N Alkhouri served on advisory boards for 89Bio, Allergan, Gilead, Intercept, Madrigal, Pfizer, and Zydus; he has served as a speaker for AbbVie, Alexion, Gilead, Intercept, and Simply Speaking; and has received research support from 89 Bio, Akero, Albireo, Allergan, Axcella, Enyo, Galectin, Genentech, Genfit, Gilead, Hepion, Intercept, Madrigal, Metacrine, NGM Bio, Novartis, Novo Nordisk, Northsea, Pfizer, Viking, 89 Bio.

M Noureddin has been on the advisory board for 89BIO, Gilead, Intercept, Pfizer, Novo Nordisk, Blade, EchoSens, Fractyl, Terns, Siemens and Roche diagnostic and has received research support from Allergan, BMS, Gilead, Galmed, Galectin, Genfit, Conatus, Enanta.

S Harrison is Scientific advisor or consultant for Akero, Alentis, Altimmune, Arrowhead, Axcella, BMS, Echosens, Fibronostics, Forest Labs, Galectin, Gilead, Hepion, Hepagene, HistoIndex, Intercept, Madrigal, Medpace, Metacrine, NGM Bio, Northsea, Novartis, Novo Nordisk, PathAI, Poxel, Liminal, Sagimet, Terns, Viking. He has stock options in Akero, Cirius, Galectin, Genfit, Hepion, HistoIndex, PathAI, Metacrine, NGM Bio, Northsea. Grant/Research support: Akero, Axcella, BMS, Cirius, CiVi Biopharma, Conatus, Cymabay, Enyo, Galectin, Genentech, Genfit, Gilead, Hepion, Hightide, Intercept, Madrigal, Metacrine, NGM Bio, Novartis, Novo Nordisk, Northsea, Pfizer, Sagimet, Viking, 89 Bio.

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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Review disclosure

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

Additional information

Funding

This paper was not funded.