New treatments on the horizon
Fortunately, several new MASH therapeutics in development seem to have promising metabolic profiles.
In the phase 3 MAESTRO-NASH biopsy trial, treatment with resmetirom, a thyroid hormone receptor–beta selective agonist versus placebo resulted in a clinically significant improvement in liver fibrosis by one stage or more (26% vs. 14%) and NASH resolution (30% vs. 10%). Unlike OCA, resmetirom was associated with a clinically significant reduction in LDL cholesterol (–16% compared with placebo).
Resmetirom has received a breakthrough therapy designation, and Madrigal Pharmaceuticals recently completed submission of a new drug application for accelerated approval of this agent to the FDA.
Semaglutide is a glucagonlike peptide–1 receptor agonist that is already FDA approved for treatment of diabetes and obesity and is being studied in a phase 3 analysis for NASH.
In a phase 2 trial, daily dosing of semaglutide vs placebo led to clinically significant improvement in NASH resolution (59% vs. 17%) but not significant improvement in fibrosis (43% vs 33%). Although it is impossible to make a meaningful comparison in outcomes between clinical trials, it should be noted that the absolute rate of response in this trial was higher than is routinely seen in other NASH trials and that the placebo rate for improvement in fibrosis was higher than expected, a common problem with NASH trials.
As expected, treatment with semaglutide was associated with dose-dependent reduction in body weight and hemoglobin A1c, highlighting the global metabolic benefit of this agent.
Another major class of agents being studied for NASH treatment are the fibroblast growth factor (FGF) 21 analogs.
In the recently published phase 2b ENLIVEN trial, treatment with the FGF21 analog pegozafermin versus placebo led to a statistically significant improvement in liver fibrosis by one stage (27% vs. 7%) and a numerical improvement in NASH resolution (26% vs. 2%).
In addition to its effects directly in the liver, FGF21 has been associated with promoting positive global metabolic effects, including improved peripheral insulin sensitivity and amelioration of dyslipidemia. Consistent with this, treatment with pegozafermin resulted in a decrease in serum triglycerides and an increase in serum HDL cholesterol and adiponectin levels.
Ultimately, the best therapeutic strategy for MASH may be one that uses combination therapy to maximize liver-directed effects and also ameliorate concomitant or contributing metabolic dysfunction. This approach is already being investigated. What seems clear, however, is that MASH therapy without concurrent treatment of metabolic comorbidities is probably destined to be ineffective, if not counterproductive.
So, what’s in a name? When it comes to MASLD, it seems quite a bit.
Dr. Janardhan is an assistant professor, department of internal medicine, at Rush University Medical Center, Chicago. Dr. Reau is a professor, department of internal medicine, Rush University. Dr. Janardhan reported conflicts of interest with Target RWE, Novo Nordisk, Intercept, and Enanta. Dr. Reau reported conflicts of interest with AbbVie, Gilead, and AASLD.
A version of this article appeared on Medscape.com.