FDA approved Rezdiffra (resmetirom) for Noncirrhotic NASH with Moderate to Advanced FibrosisFDA approved new drug Rezdiffra for fatty liver disease with scarring.

Rezdiffra is a thyroid hormone receptor-beta (THR-beta) agonist.

Rezdiffra is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). This indication is approved under accelerated approval based on improvement of NASH and fibrosis. Limitations of Use: Avoid use in patients with decompensated cirrhosis.

The recommended dosage is based on actual body weight. For patients weighing <100 kg, the recommended dosage is 80 mg orally once daily. For patients weighing ≥100 kg, the recommended dosage is 100 mg orally once daily. Administer with or without food. Swallow tablets whole; do not split, crush, or chew. If a dose is missed, do not take the missed dose and resume with the next scheduled dose. Concomitant use with strong CYP2C8 inhibitors (e.g., gemfibrozil) is not recommended. If used with a moderate CYP2C8 inhibitor (e.g., clopidogrel), reduce the dosage: <100 kg to 60 mg once daily; ≥100 kg to 80 mg once daily.

Efficacy was evaluated based on an efficacy analysis at Month 12 in Trial 1 (NCT03900429), a 54-month, randomized, double-blind, placebo-controlled trial. Enrolled patients had metabolic risk factors and a baseline or recent liver biopsy showing NASH with fibrosis stage 2 or 3 and a NAFLD Activity Score (NAS) of at least 4. The Month 12 analysis included 888 F2 and F3 patients randomized 1:1:1 to placebo (n=294), Rezdiffra 80 mg once daily (n=298), or Rezdiffra 100 mg once daily (n=296), in addition to lifestyle counseling. Baseline characteristics: median age 58 years, 56% female, 89% White, 2% Black or African American, 3% Asian, 21% Hispanic; median BMI 35 kg/m2; median body weight 99 kg; 68% had type 2 diabetes; 63% had F3 fibrosis. The primary endpoints were resolution of steatohepatitis without worsening of fibrosis and at least one stage improvement in fibrosis without worsening of steatohepatitis at Month 12. Both doses demonstrated improvement on these endpoints compared to placebo, with statistical significance achieved in an analysis incorporating two independent pathologists' readings. Examination of age, gender, diabetes status, and fibrosis stage subgroups did not identify differences in response.

Avoid use in patients with decompensated cirrhosis. Concomitant use with strong CYP2C8 inhibitors is not recommended. Dosage reduction is required with moderate CYP2C8 inhibitors.

Rezdiffra is a first-in-class THR-beta agonist approved for noncirrhotic NASH with F2 to F3 fibrosis under accelerated approval. It should be used in conjunction with diet and exercise. Clinicians should note the accelerated approval status and the need for confirmatory trials. Avoid use in decompensated cirrhosis.