MASH patients with high BMI, weight respond ‘slightly better’ to higher Rezdiffra dose
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Key takeaways:
- MASH resolution and fibrosis improvement were ‘slightly better’ in those weighing more than 100 kg receiving resmetirom 100 mg.
- This finding was similar in those receiving 100 mg with a BMI more than 35 kg/m².
Patients with metabolic dysfunction-associated steatohepatitis who weigh more than 100 kg or a BMI more than 35 kg/m² had “slightly better” response with a 100 mg dose of Rezdiffra, according to data presented at EASL Congress.
“MAESTRO-NASH was the pivotal phase 3 study supporting the first FDA-approved therapy for NASH, Rezdiffra (resmetirom, Madrigal Pharmaceuticals),” Mazen Noureddin, MD, MHSc, professor of medicine and hepatologist at Houston Methodist Hospital, told Healio. “At EASL, we presented an analysis of how patients’ weight and BMI impacted the response to Rezdiffra in MAESTRO-NASH, [which are] important because they support the weight-based dosing recommendations in the Rezdiffra prescribing information.”
He added: “For patients weighing less than 100 kg or 220 lbs, the recommended dosage is 80 mg orally once daily, and for patients weighing over 100 kg or 220 lbs, the recommended dosage is 100 mg orally once daily.”
To establish the relationship between resmetirom dose response, baseline body weight and BMI, Noureddin and colleagues performed a post-hoc analysis of the ongoing 54-month phase 3 MAESTRO-NASH trial, which evaluated the efficacy and safety of 80 mg and 100 mg doses of Rezdiffra among 966 adults with biopsy-proven MASH.
The researchers stratified efficacy and safety data based on baseline body weight ( 100 kg and > 100kg) and BMI (<35kg/m² and 35 k/mg²). This included coprimary endpoints from MAESTRO-NASH already achieved at week 52 by both doses: NASH resolution with no worsening of fibrosis and at least one-stage reduction in fibrosis with no worsening of the nonalcoholic fatty liver disease activity score.
Noureddin told EASL attendees that the response was not significantly different between resmetirom doses in patients weighing less than 100 kg; however, in patients weighing more than 100 kg, those who received resmetirom 100 mg vs. 80 mg had “slightly better” NASH resolution (36% vs. 27%) and fibrosis improvement (33% vs. 23%).
Similarly, in the placebo-adjusted, intention-to-treat analysis, Noureddin reported that patients receiving resmetirom 100 mg vs. 80 mg with a BMI more than 35 kg/m² had a “little bit better” NASH resolution (20% vs. 10%) and fibrosis improvement (11% vs. 7%).
According to study results, more patients who received 100 mg vs. 80 mg achieved targets for sex hormone binding globulin (defined by at least a 120% increase) and MRI-proton density fat fraction response (defined by more than 30% reduction), with a greater difference observed in patients weighing more than 100 kg (55% vs. 30%; 73% vs. 57%, respectively).
In addition, other biomarkers including alanine transaminase, FibroScan controlled attenuation parameter and vibration-controlled transient elastography at 80 mg and 100 mg showed similar improvements with resmetirom when compared with placebo. In those receiving resmetirom, responses on FibroScan were “durable out to 3 years of treatment” demonstrating improvement and less worsening compared with placebo, Noureddin reported.
“The longer term FibroScan data should provide clinicians with confidence that a large proportion of their patients will achieve improvement or stabilization of their disease over the course of 3 years of treatment with Rezdiffra,” Noureddin told Healio.
Resmetirom was well tolerated at both doses, Noureddin noted, although patients who received 100 mg with a baseline body weight less than 100 kg had “slightly higher” discontinuations compared with 80 mg due to gastrointestinal adverse events.
“These results reinforce the simple weight-based dosing recommendations in the Rezdiffra prescribing information,” he said.
Perspective
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Jamile' Wakim-Fleming, MD, FACG, FAASLD
MASH-related liver disease is associated with cirrhosis, liver cancer, obesity and complications from cardiovascular disease. MASH has become the leading cause of liver transplantation, along with alcoholic liver disease.
In March 2024, the FDA accelerated approval of resmetirom for the treatment of patients with MASH with moderate to advanced fibrosis. The recommended dosage is based on an individual’s body weight: 80 mg once daily for those who weigh less than 100 kg and 100 mg for those who weigh more than 100 kg.
In post-hoc analysis, the weight-based dosing of resmetirom showed slightly better results for MASH and fibrosis resolution among people who weigh more than100 kg or have a BMI greater than 35 kg/m2. Researchers expect that by the end of the trial at 52 months, a large proportion of patients may achieve these improvements.
Both weight-adjusted and fixed-dose regimens of drugs are practiced. The choice of either regimen depends on the disease, the drug prescribed, age and weight of the patient, efficacy and other factors. It has been recommended that weight-based dosing regimens should be practiced when the weight is measured accurately to avoid harmful effects.
For MASH-related liver disease, lifestyle modification is currently the backbone in management. Medications to lose weight were recently approved, but resmetirom is the first FDA-approved drug to treat liver fibrosis related to MASH. Higher doses are shown to be more efficacious for patients who weigh more than 100 kg or have a BMI greater than 35 kg/m2 at baseline without worsening side effects, but there was no difference between the two doses of resmetirom for individuals weighing less than 100 kg.
This is major progress in the treatment of a disease whose management had been stagnant for decades, and these results reinforce the weight-based dosing recommendations in the resmetirom prescribing information.
What remains to be determined is the side effect profile when larger populations that lose weight over time are involved. We hope that by the end of the trial at 3 years, these answers will be available and a simple dosing regimen of resmetirom 100 mg daily would be safe and efficacious in MASH-related liver disease.
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Schattenberg JM, et al. Assessment of resmetirom efficacy (80 mg vs. 100 mg) stratified by baseline body mass index and weight in patients from the MAESTRO-NASH trial, Presented at: EASL Congress; June 5-8,2024; Milan (hybrid meeting).
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