Stephen Harrison, MD, provides insight into the use of resmetirom for NASH with fibrosis ahead of the thyroid hormone receptor-β selective agonist’s March 14 PDUFA date.
A paradigm shift might be underway for the management of liver disease with the prospect of a landmark US Food and Drug Administration (FDA) approval on the horizon as hepatologists and patients alike await the FDA’s decision for the use of resmetirom in nonalcoholic steatohepatitis (NASH).
If approved, resmetirom would become the first pharmacologic treatment for the progressive hepatic condition. Having earned Priority Review and being assigned a PDUFA date of March 14 upon the FDA’s acceptance of Madrigal Pharmaceuticals’ New Drug Application (NDA) in September of 2023, the recent publication of positive phase 3 data reinforces hope for the thyroid hormone receptor (THR)-β selective agonist’s indication in NASH.1
“This disease is mirroring the trend in obesity and diabetes, where we're seeing increases in both of those metabolic diseases, Stephen Harrison, MD, founder and chairman of Pinnacle Clinical Research and Summit Clinical Research, explained in an interview with HCPLive. “While we have treatments for diabetes and we have treatments for obesity, we have no proven therapy for NASH. So, this is a huge unmet medical need.”
The clinical development program for resmetirom is comprised of 18 clinical studies supporting the NDA, including 12 phase 1 studies, a pair of phase 2 studies, and 4 phase 3 studies. Data from the 52-week first 1000 patient portion of the phase 3, double-blind, randomized, placebo-controlled MAESTRO-NASH trial, together with data from MAESTRO-NAFLD-1, MAESTRO-NAFLD-OLE, as well as phase 2 and phase 1 data, formed the basis for the accelerated approval submission.2
Addressing potential questions as to why a thyroid hormone drug is being studied for the treatment of a liver disease, Harrison described the relative hypothyroidism of the liver and resmetirom’s ability to induce new mitochondrial formation allowing for improved beta-oxidation of fatty acids and the conversion of T4 to T3.
Earlier phase trials have demonstrated resmetirom’s ability to reduce liver fat, resolve steatohepatitis, and lower both low-density lipoprotein cholesterol and well as triglycerides. The 52-week biopsy assessment data, however, officially made MAESTRO-NASH the only phase 3 study in NASH to achieve both primary endpoints proposed by the FDA as reasonably likely to predict clinical benefit:
Indeed, study results published in the New England Journal of Medicine showed NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the resmetirom 80 mg group and 29.9% of those in the resmetirom 100 mg group, both significantly more than the 9.7% of patients who achieved this endpoint in the placebo group (P <.001). Additionally, fibrosis improvement by ≥ 1 stage with no worsening of the NAFLD activity score was also superior in the resmetirom 80 mg (24.2%) and resmetirom 100 mg (25.9%) groups versus the placebo group (14.2%; P <.001).3
Of note, the incidence of serious adverse events was similar across the treatment groups: 10.9%, 12.7%, and 11.5% in the resmetirom 80 mg, resmetirom 100 mg, and placebo groups, respectively.3
Given the positive findings from the 52-week biopsy assessment supporting resmetirom’s accelerated approval and the March 14 PDUFA date looming around the corner, the future of NASH treatment may get a lot brighter in the next few weeks.
Speculating questions clinicians may have about resmetirom before prescribing it if approved by the FDA, Harrison emphasized the specific patient population the thyroid hormone receptor (THR)-β selective agonist is intended for: patients with moderate to severe fibrosis.
“If you have a little fat [and minimal to no fibrosis] in your liver and you're obese and you're diabetic, this isn't a [ideal] drug for you, and the GLP-1 class of drugs is probably the drug to start with,” he explained, also noting resmetirom should not be used in patients with cirrhosis or no fibrosis at all because “that’s not what was studied, and we want to try to stick with what was studied.”