MASLD: Promising Treatments for a Newly Renamed Disease

Sujit V. Janardhan, MD, PhD; Nancy Reau, MD


September 14, 2023

In June 2023, a multisociety group agreed to change the name of the disease formerly known as nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction–associated steatotic liver disease (MASLD).

In the week leading up to this, Intercept Pharmaceuticals announced that their program to develop obeticholic acid (OCA) as a first-to-market, long-awaited potential drug therapy for metabolic dysfunction–associated steatohepatitis (MASH), the more pathogenic form of this disease, was being abandoned after the US Food and Drug Administration (FDA) Gastrointestinal Drugs Advisory Committee voted against accelerated approval of the drug. This decision was made in large part owing to data showing modest efficacy coupled with multiple drug-related side effects, including worsening metabolic dysfunction.

The juxtaposition of these two events highlights what could be a fundamental change in perspective when it comes to the management of patients with MASLD and the development of therapies for this disease.

A More Precise Nomenclature for a Broad-Spectrum Disease

The updating of the NAFLD nomenclature to MASLD represents an important change in the way that the medical community is being asked to view and approach the disease of "fatty liver."

The previous nomenclature clarified that pathogenic liver steatosis can exist in the absence of alcohol. However, it failed to define the primary drivers of the most common form of NAFLD: that is, metabolic syndrome diseases. The new nomenclature not only better defines the broad spectrum of steatotic liver diseases (alcohol, metabolic, drug/genetic, cryptogenic) but also refocuses the attention of providers on the fundamental basis of MASLD as a critical member of the metabolic syndrome spectrum of diseases.

This is in line with the recently updated American Association for the Study of Liver Disease Practice Guidelines for NAFLD (now MASLD), which focus on active screening to identify patients at risk for advanced MASLD, in particular those with medically complicated obesity or high-risk metabolic characteristics such as diabetes. This is a change from previous versions of the guidelines that were cautious to recommend broad screening guidelines in part owing to the lack of "available therapies."

The increasing clinical burden of MASH has led to the recognition that patients do not have the luxury of waiting for "anticipated therapies" that have frequently shown only marginal or insignificant efficacy. As a result, some providers have refocused their efforts on the development of care pathways that can efficiently provide comprehensive lifestyle interventions to treat MASH and related metabolic comorbidities within hepatology or other subspecialty clinics.

Learning From OCA's Limitations

The approach to drug development for MASH seems to be shifting in a similar, metabolic syndrome–focused way.

The risk-benefit analysis from the FDA advisory committee evaluating OCA noted that the drug provided only modest (albeit statistically significant) benefits over placebo in achieving one of two primary clinical endpoints (improvement in fibrosis by one stage without worsening of NASH), but was associated with toxicity as well as significant drug-related side effects, including new or worsening dyslipidemia, accelerated progression to prediabetes or diabetes, and worsening glycemic control in patients with diabetes.

Worsening clinical markers of metabolic health were an important factor in the advisory committee's decision to not provide accelerated approval of OCA. This informs the criteria upon which future MASH therapies will be evaluated for approval: that an ideal agent for MASH not only will have a significant impact on MASH pathophysiology but will also provide benefit for (or at least not worsen) the metabolic comorbidities associated with MASH.

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, vs 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 low-density lipoprotein 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 glucagon-like 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 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 vs 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 high-density lipoprotein 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.

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