Resmetirom Granted Priority Review for NASH With Liver Fibrosis

The Food and Drug Administration (FDA) has accepted for Priority Review the New Drug Application (NDA) for resmetirom, an oral thyroid hormone receptor (THR)-β selective agonist, for the treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis.

The application is supported by a clinical development program consisting of four phase 3 clinical studies, including the pivotal MAESTRO-NASH study (ClinicalTrials.gov Identifier: NCT03900429), which evaluated the efficacy and safety of resmetirom in more than 1000 patients with biopsy-proven NASH and fibrosis.

Study participants were randomly assigned to receive resmetirom 80mg (n=316), resmetirom 100mg (n=321), or placebo (n=318) once daily. The dual primary surrogate endpoints on biopsy were NASH resolution with at least a 2-point reduction in nonalcoholic fatty liver disease activity score (NAS), and with no worsening of fibrosis or at least a 1-stage improvement in fibrosis with no worsening of NAS after 52 weeks of treatment. 

Findings showed that 26% and 30% of patients treated with resmetirom 80mg and 100mg, respectively, achieved NASH resolution with at least a 2-point reduction in NAS and no worsening of fibrosis compared with 10% of those who received placebo (both P <.0001). Moreover, 24% (P =.0002) and 26% (P <.0001) of patients treated with resmetirom 80mg and 100mg, respectively, achieved at least a 1-stage improvement in fibrosis with no worsening of NAS vs 14% of the placebo group.

Patients treated with resmetirom 80mg and 100mg also met the following secondary endpoints vs placebo, respectively:

• Two-stage fibrosis improvement in the modified intent-to-treat (mITT) population: 8% and 10% vs 3% (P <.0001);
• NASH resolution and ≥1-stage improvement in fibrosis in the mITT population: 14% and 16% vs 5% (P <.0001);
• NASH resolution with ≥2-point reduction in NAS and no worsening of fibrosis in patients with both a baseline and week 52 biopsy: 32% and 39% vs 11% (P <.0001);
• ≥1-stage fibrosis improvement with no worsening of NAS in patients with both a baseline and week 52 biopsy: 30% and 34% vs 16% (P <.0001); and
• NASH resolution or ≥1-stage fibrosis improvement in patients with both a baseline and week 52 biopsy: 42% and  50% vs 19% (P <.0001).

The most common adverse events reported with treatment included mild and transient diarrhea and nausea at the start of the therapy.

“Resmetirom is a liver-directed therapy that has demonstrated the potential to treat the liver fibrosis that is associated with these negative outcomes, while resolving the underlying steatohepatitis that drives the disease,” said Bill Sibold, Chief Executive Officer of Madrigal. “The FDA’s acceptance of our NDA with priority review is an important step forward as we pursue our goal of delivering the first approved treatment to patients with NASH with liver fibrosis.”