In a pivotal step toward changing the landscape of non-alcoholic steatohepatitis (NASH) management, new data from the Phase 3 MAESTRO-NASH trial of resmetirom in patients with NASH and fibrosis show that thyroid hormone receptor Approved treatments for advanced liver disease suggest that beta-selective agonists may be poised to become the first drugs.1
was announced on New England Medical Journal, Results showed that a greater proportion of patients in the resmetilom 80 mg and 100 mg treatment groups achieved NASH resolution without worsening of fibrosis and non-alcoholic fatty liver disease compared to patients in the resmetilom 80 mg and 100 mg treatment groups. showed that fibrosis improvement of 1 grade or more was achieved without worsening of disease (NAFLD) activity scores. Those receiving a placebo.1
Data on the first 1,050 patients of the MAESTRO-NASH trial are based on the target PDUFA date assigned to resmetilom by the U.S. Food and Drug Administration (FDA) in response to Madrigal Pharmaceuticals’ acceptance of a new drug application (NDA). It was announced just over a month ago on April 14th. ) on September 13, 2023.2
“There is a really huge unmet need for NASH drugs, or MASH drugs to use the new term metabolic steatohepatitis,” said Dr. Stephen Harrison, medical director of Pinnacle Clinical Research, in an interview. emphasized. HCP Liveciting the increasing prevalence of liver disease in the United States and the current lack of proven treatments to treat it.
The safety and efficacy of resmetilom, an oral thyroid hormone receptor (THR)-β selective agonist designed to target the primary underlying cause of NASH in the liver, in adult NASH has been evaluated in Phase 2 and 3 studies. Proven in phase tests. MAESTRO-NASH, a phase 3, double-blind, randomized, placebo-controlled trial, is one of 18 studies in the resmetilom clinical development program to support the use of NDA in adult patients with NASH and fibrosis. .1, 2
Eligible patients must be 18 years of age or older, have 3 or more metabolic risk factors, have a controlled attenuation parameter (CAP) of 280 dB per meter or higher, and have a liver stiffness measurement of 8.5 kPa or higher within 3 months. That was required. Evaluation of registration by vibration-controlled transient elastography (VCTE). In addition, histological evidence of NASH and NAFLD activity score of 4 or higher and a score of 1 or higher for each component had to be included.1
A total of 1,050 patients were enrolled in the study, with 966 with fibrosis stage F1B, F2, or F3 at baseline receiving resmetirom 80 mg (patient n = 322), resmetirom 100 mg in a 1:1:1 ratio mg (patient) randomly assigned. n = 323), or placebo (n = 321). The mean age of the cohort was 56.6 years (standard deviation) [SD]10.9) years, and most patients were Caucasian (89.3%) with a higher incidence of metabolic risk factors such as hypertension (78.1%), dyslipidemia (71.3%), and type 2 diabetes (67.0%).1
“From a demographic standpoint, this population in this trial is very similar to the same demographics that we would see in the general population with this degree of underlying fibrosis,” Harrison said. I pointed this out in an interview. HCP Liveincreasing the generalizability of research results.
The researchers outlined two primary endpoints for the study, both measured at week 52. The first was NASH resolution, defined as achieving a reduction in hepatocellular ballooning score of 0, lobular inflammation score of 0 or 1, and NAFLD activity score of ≥ or greater. No worsening of fibrosis, 2 points. Second, his NAFLD activity score did not worsen and his fibrosis improved by more than one grade. Additionally, a key secondary endpoint was percent change from baseline in low-density lipoprotein (LDL) cholesterol at week 24.1
Results showed that resolution of NASH without worsening of fibrosis was achieved in 25.9% of patients in the resmetilom 80 mg group and 29.9% in the resmetilom 100 mg group, compared with 9.7% in the placebo group (P <.001). Improvement in fibrosis by one grade or more without worsening of NAFLD activity scores was also superior in the resmetilom 80 mg group (24.2%) and resmetilom 100 mg group (25.9%) compared with the placebo group (14.2%). P <.001).1
Dr. Harrison explained the importance of these findings, particularly regarding the progression of fibrosis: “Fibrosis portends a poor prognosis. The more scarring, the worse the condition in these people, and in this trial, 80% of patients at week 52 of biopsy had either reversal of fibrosis or slowed disease progression. I couldn’t see it.”
Furthermore, the change in LDL cholesterol levels from baseline to week 24 was −13.6% in the resmetilom 80 mg group and −16.3% in the resmetilom 100 mg group compared with 0.1% in the placebo group (P<.001). .1
Most adverse events in the resmetilom group (91.6% to 91.9%) and the placebo group (92.8%) were mild or moderate in severity. The most frequent adverse events were diarrhea and nausea, both of which occurred more frequently with resmetilom and COVID-19. Importantly, the researchers noted that the incidence of serious adverse events was similar across study groups: 10.9% in the resmetilome 80 mg group, 12.7% in the resmetilome 100 mg group, and 11.5% in the placebo group. Met.1
References:
- Harrison SA, Bedossa P, Guy CD A phase 3 randomized controlled trial of resmetirom in NASH with other liver fibrosis. N English J Medical doi:10.1056/NEJMoa2309000
- Madrigal Pharmaceuticals. Madrigal Pharmaceuticals announced NDA acceptance and priority review of its new drug application for resmetilom, a treatment for NASH associated with liver fibrosis. press release. September 13, 2023. Accessed February 6, 2024. https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-announces-nda-acceptance-and-priority
