Mazen Noureddin, MD: Differences in Resmetirom Efficacy Based on Body Weight, BMI

New research is providing clinicians with an overview of the association between resmetirom (Rezdiffra) dosing, body weight, and body mass index (BMI) in patients with metabolic dysfunction-associated steatohepatitis (MASH).¹

The posthoc analysis of the phase 3 MAESTRO-NASH trial was presented by Mazen Noureddin, MD, MHSc, a professor of medicine and transplant hepatologist at Houston Methodist and director of the Houston Research Institute, at the American College of Gastroenterology (ACG) 2024 Scientific Sessions. Results showed resmetirom 100 mg was more effective than 80 mg for the achievement of the dual primary endpoints in patients with greater baseline body weight and BMI but suggested both doses were equally efficacious in patients with a lower BMI.¹

On March 14, 2024, the US Food and Drug Administration (FDA) granted accelerated approval to resmetirom for the treatment of noncirrhotic MASH, formerly known as nonalcoholic steatohepatitis (NASH), with moderate to advanced fibrosis. The decision marked the first and only FDA approval for the progressive liver disease.²

“Many [patients] already started showing what we saw in clinical trials: improvement in liver enzymes, transient elastography, even, interestingly, some symptoms,” Noureddin explained to HCPLive, saying the field of hepatology made “huge progress” in 2024. “Patients are happy that they finally have options. For years, the only options we had for them were clinical trials, so it has been great.”

Of note, resmetirom's prescribing information does not include a liver biopsy requirement for diagnosis and the recommended dosage is based on actual body weight.²

“That decision was made during the discussion with the FDA and after the trial was done,” Noureddin said. “When we did the trial, patients were randomized to 80 versus 100 milligrams versus placebo, regardless of the body weight. So the investigators looked into post hoc analyses to stratify the relationship between weight and the dose as well as total efficacy.”

Investigators stratified resmetirom efficacy data on the dual endpoints, NASH resolution with no worsening of fibrosis and fibrosis improvement by ≥ 1 stage with no worsening of the nonalcoholic fatty liver disease (NAFLD) activity score, based on baseline patient body weight (≤100 and >100 kg) and BMI (≥35 and < 35 kg/m2).¹

For patients treated with resmetirom 80 mg who weighed ≤100 kg, results showed the 30% proton density fat fraction (PDFF) response was 66.9%. In patients with a week 52 biopsy, 35.4% showed fibrosis improvement compared with 32% who showed no worsening of fibrosis. In patients >100 kg, the 30% PDFF response was 56.7%; fibrosis improvement was 22.5%; and no worsening of fibrosis was 27%.¹

For patients who received resmetirom 100 mg who were ≤100 kg, the 30% PDFF response was 71.7%; fibrosis improvement was 33.6% and no worsening of fibrosis was 35.8%; for patients >100 kg, PDFF was 72.5%; fibrosis improvement was 32.5%; and no worsening of fibrosis was 35.8%.¹

Increases in fibrosis improvement were noted relative to placebo for patients who received resmetirom 80 mg who had BMI < 35. Increases were also noted relative to placebo for patients who received 100 mg of resmetirom who had a BMI < 35.¹

“Everyone’s also looking at the pipeline down the road, because, as you know, we think this disease is a combination therapy,” Noureddin said. “We're already combining resmetirom with other GLP-1s, not for the treatment of MASH in particular, but to address weight and type 2 diabetes through a holistic approach, until we see the data in phase 3 trials from the GLP-1s and the duals.”

Editors’ note: Noureddin has relevant disclosures with Altimmune, Madrigal Pharmaceuticals, Merck, Takeda, Terns, and others.

References

1. ^{Brooks A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed November 5, 2024. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash}
2. ^{Noureddin M, Schattenberg JM, Taub R, et al. 58 - Assessment of Resmetirom Efficacy (80 mg vs 100 mg) Stratified by Baseline Body Mass Index and Weight in Patients From the MAESTRO-NASH Trial. Paper presented at: American College of Gastroenterology (ACG) 2024 Scientific Sessions. Philadelphia, PA. October 25 – 30, 2024.}