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 Food and Drug Administration 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.