Resmetirom significantly reduces LDL-C and restores thyroid hormones in NASH fibrosis patients

Resmelon may be able to restore thyroid hormone levels,¹ and reducing and maintaining lipid/lipoprotein levels in patients with non-alcoholic steatohepatitis (NASH),² Based on the results of two Phase 3 evaluations.

This weekend, the American Association for the Study of Liver Diseases (AASLD) published 2 separate abstracts at the 2023 Liver Meeting in Boston, including Phase 3 MAESTRO-NASH data demonstrating multi-hormonal and cardiovascular benefits of remerol in patients with NASH and fibrosis benefit. The latest results from the late-stage trial come two months after Madrigal Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) had received New Drug Acceptance (NDA) for remerol to treat NASH and liver fibrosis.³

Resmetirom is an oral, liver-targeted thyroid hormone receptor (THR)-beta selective agonist. In accepting the NDA in September, Madrigal chief medical officer and president of research and development Dr. Becky Taub said the drug was supported by a “compelling data package” supporting its clinical benefit in patients with NASH and liver fibrosis.

“The NDA is supported by the positive efficacy results observed in our pivotal Phase 3 trial, the large safety database we have established through the MAESTRO program, and two ongoing outcome studies designed to validate the potential accelerated post-approval clinical benefits,” Taub noted.

cardiovascular benefits

The first abstract, submitted by Naim Alkhouri, MD, Chief Medical Officer, Chief of Transplant Hepatology, and Director of the Fatty Liver Program at Arizona Liver Health Center, analyzes 54 months of MAESTRO-NASH data to demonstrate the impact of 2 doses of remetron on Atherogenic effects on lipid and lipoprotein levels.²

Remelon has previously been shown to significantly improve lipid profile in patients with suspected NASH. In this analysis, Alkhouri and colleagues analyzed patients with metabolic risk factors, cirrhosis, liver disease, biopsy-proven F1B-F3 fibrotic NASH, and nonalcoholic fatty liver disease (NAFLD) activity score (NAS) >4.

Patients were randomly assigned in a 1:1:1 ratio to receive 80 mg or 100 mg of resmetirom orally once daily or placebo. The key endpoint of the analysis was the percent change from baseline to week 24 in LDL-C, while the tertiary endpoint included patients’ percent change from baseline in triglycerides, apoB, apoCIII, and Lp(a).

The mean LDL-C in patients treated with Remerol 80 mg and 100 mg was 106.6 mg/dL and 102.9 mg/dL, respectively. At week 24, researchers observed a decrease in mean LDL-C score of 13.6 mg/dL in patients who received the 80 mg dose and a decrease of 16.3 mg/dL in those who received the 100 mg dose, compared with placebo. Mean LDL-C scores increased by 0.1 mg/dL among patients receiving the dose.

The treatment difference in LDL-C lowering was -13.7 mg/dL (95% CI, -17.5 to -10.0; ask <.0001) 80 mg Remelon versus placebo. For patients on the 100 mg dose, the difference was even greater (-16.4 mg/dL; 95% CI, -20.1 to -12.6; ask <.0001).

Over 52 weeks, researchers observed that patients taking the 80 mg dose maintained a difference in LDL-C reduction rates (-13.3 mg/dL; 95% CI, -17.3 to -9.3; 95% CI, -17.3 to – 9.3; ask <.0001) and the 100 mg dose (-19.0 mg/dL; 95% CI, -23.0 to -15.1; ask <.0001) compared to placebo.

Alkhouri and colleagues also observed significant reductions in mean triglycerides, ApoB, ApoCIII, and Lp(a) at both remetron doses compared with placebo at 24 and 52 weeks.

“The impact of potential NASH therapies on cardiovascular risk factors, including atherogenic lipids/lipoproteins, is important because cardiovascular disease is a common cause of death in patients with NASH and fibrosis,” the team concluded.

hormonal benefits

In a second abstract presented by Stephen A. Harrison, MD, medical director of clinical research at Pinnacle, researchers analyzed MAESTRO-NASH data to understand the effects of 80 mg and 100 mg of once-daily remerol on thyroid hormone levels over 52 weeks. Influence. The team noted that (THR)-β is responsible for regulating multiple metabolic pathways in the liver. 1

“However, hepatic THR-β signaling in patients with NASH is attenuated (due to reduced conversion of the prohormone T4 to the active hormone T3 in favor of increased conversion of T4 to the inactive metabolite reverse T3 (rT3)),” they wrote. “Resmetirom…may address this underlying pathophysiology.”

Harrison and colleagues evaluated circulating thyroid hormone levels, including thyroid-stimulating hormone (TSH), FT3, FT4, at week 52 in 3 cohorts from the MAESTRO-NASH population (overall patients, thyroxine-treated patients, and euthyroid patients) and rT3.

Researchers reported significant reductions in FT4 and rT3 levels in both remetron treatment groups at week 52 compared with placebo (ask <.0001), and a significant increase in the Ft3/rT3 ratio in both treatment groups compared with placebo (ask <.0001). Similar effects were observed in the overall population, in the thyroxine-treated population, and in the euthyroid population.

However, at 52 weeks, the research team did not observe any significant changes in TSH or FT3 levels at either dose of Remeirox compared with placebo. Nonetheless, the researchers rated the results of the analysis positively.

“Resmetirom treatment significantly reduced FT4 and rT3 levels, consistent with increased conversion of T4 to the active hormone T3 and decreased conversion of T4 to the inactive metabolite rT3. Overall, these data suggest that resmetirom treatment can restore liver function in patients with NASH. Thyroid hormone levels, fibrosis.”

refer to

1. ^{Bedossa P, Guy CD, Schattenburg JM, Loompa R, et al. 2463-C: RESMETIROM treatment helps restore thyroid hormone levels in patients with non-alcoholic steatohepatitis: 52-week data from the MAESTRO-NASH Phase 3 trial. Paper presented at: Liver Conference. Boston, MA. November 10-14, 2023.}
2. ^{Bedossa P, Guy CD, Schattenburg JM, Loompa R, et al. 2462-C: RESMETIROM improves atherogenic lipid/lipoprotein signatures in patients with non-alcoholic steatohepatitis: 52-week data from the MAESTRO-NASH Phase 3 trial. Paper presented at: Liver Conference. Boston, MA. November 10-14, 2023.}
3. ^{Madrigal Pharmaceuticals. Madrigal Pharmaceuticals announced that its New Drug Application for Resmetirom for the treatment of NASH liver fibrosis has been accepted as an NDA and is undergoing priority review. Press release. Published September 13, 2023. https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-announces-nda-acceptance-and-priority}