麻豆传媒

No FDA-approved therapy exists for metabolic dysfunction-associated steatohepatitis (MASH; formerly nonalcoholic steatohepatitis, or NASH), but the pipeline is full of potential candidates.

Hirsh Trivedi, MD, of Cedars-Sinai Medical Center in Los Angeles, said he's optimistic about the promise of multiple types of agents in phase II/III trials -- including glucagon-like peptide-1 (GLP-1) receptor agonists, thyroid hormone receptor (THR)-β selective agonists, FGF21 analogs, peroxisome proliferator-activated receptor (PPAR) agonists, and .

"There's definitely a race to the finish line to see which one gets approved first," he told 麻豆传媒.

Other than lifestyle modification, vitamin E from food sources and pioglitazone, a PPAR, are the only therapeutic in MASH.

However, authors of a noted that despite those modest benefits, their use "has been limited by concern of increased hemorrhagic stroke risk and prostate cancer with long-term synthetic vitamin E use, and weight gain, small bone fracture risk, and, rarely, hypoglycemia with pioglitazone."

These highlight "the need for a long-term NASH therapeutic agent to have an exceptional safety profile," wrote Meena Bansal, MD, of the Icahn School of Medicine at Mount Sinai, and Rohit Nathani, MD, of Mount Sinai West/Morningside Hospital, both in New York City.

MASH is characterized by hepatocyte ballooning and lobular inflammation, and patients who develop clinically significant liver fibrosis (stages F2 and F3) have a high risk of progression to cirrhosis, and thus, increased odds of hepatocellular carcinoma, liver decompensation, and death.

Antifibrotic treatments cenicriviroc and simtuzumab may hold promise for MASH, and resmetirom -- a once-daily, oral THR-β selective agonist -- may be the most promising agent in the pipeline, said Jamile Wakim-Fleming, MD, director of the Center for Metabolic Steatosis of the Liver at the Cleveland Clinic.

Resmetirom, which is "designed to target key underlying causes of MASH in the liver and stabilize or improve fibrosis, is currently in a phase III clinical trial in patients with NASH and fibrosis () and hopefully will be approved in 2024," she told 麻豆传媒.

Primary findings from MAESTRO-NASH were reported earlier this year. They showed resolution of inflammation, ballooning, and disease activity in 26% of people on an 80-mg dose of resmetirom and 30% with a 100-mg dose, as compared with 10% of placebo patients (P<0.0001).

Also, liver fibrosis improved by at least one stage without a worsening of nonalcoholic fatty liver disease (NAFLD) activity in 24%, 26%, and 14%, respectively (P=0.0002 and P<0.0001 for the resmetirom vs placebo comparisons). The most common adverse event with the investigational drug was mild and transient diarrhea.

Semaglutide (Ozempic, Wegovy), a GLP-1 receptor agonist approved for type 2 diabetes and obesity (conditions linked with increased risk for NAFLD and NASH), has shown some potential in mid-stage NASH trials and is currently being tested in the for patients with non-cirrhotic disease.

Lanifibranor represents another promising agent for NASH and is now being tested for patients with stages F2 and F3 fibrosis. In the phase IIb NATIVE trial, a 1,200-mg dose of the first-in-class pan-PPAR agonist was associated with significant improvement in patients' Steatosis, Activity, and Fibrosis score at 24 weeks compared with placebo.

Treatment with lanifibranor at the 1,200-mg dose, and at an 800-mg dose, also met secondary endpoints over placebo in improving NASH without worsening of fibrosis; improving fibrosis by at least one stage without worsening of NASH; and improving both NASH and fibrosis by at least one stage. However, a dose-dependent increase in weight was seen with the agent.

"Approval of at least one NASH therapeutic will be a critical advance for the field, as the bar will be set and provide a road map for additional therapies," concluded Bansal and Nathani. "Given NASH heterogeneity, no one drug will work for all patients, so having a rich pipeline will allow for a personalized approach and optimal patient care."

What about MASH in younger patients?

"Some weight-loss medications, such as the GLP-1 [receptor agonists], have been tried in pediatric subjects but appear not to be more effective than diet and exercise," said pediatricians Susan Baker, MD, PhD, and Robert Baker, MD, PhD, of the University at Buffalo in New York. Furthermore, "their lifetime accumulation of side effects is not known."

Baker and Baker noted that for children with severe obesity (a body mass index over 35), "bariatric surgery results in significant weight loss and improvement in MASH." But as no long-term data exists, "surgery should be approached with extreme caution," they said, referencing the American Academy of Pediatrics 2023 clinical practice guideline for the evaluation and treatment of children and adolescents with obesity.

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