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General Information
Rezdiffra (resmetirom) is a thyroid hormone receptor-beta (THR-beta) agonist.
Rezdiffra is specifically 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Rezdiffra is supplied as tablets for oral administration. 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 Rezdiffra with or without food.
See drug label for dosing modifications with concomitant use of moderate CYP2C8 inhibitors.
Mechanism of Action
Rezdiffra (resmetirom) is a partial agonist of the thyroid hormone receptor-beta (THR-β). Resmetirom produced 83.8% of the maximum response compared to triiodothyronine (T3), with an EC50 of 0.21 µM in an in vitro functional assay for THR-β activation. The same functional assay for thyroid hormone receptoralpha (THR-α) agonism showed 48.6% efficacy for resmetirom relative to T3, with an EC50 of 3.74 µM. THR-β is the major form of THR in the liver, and stimulation of THR-β in the liver reduces intrahepatic triglycerides, whereas actions of thyroid hormone outside the liver, including in heart and bone, are largely mediated through THR-α.
Side Effects
Adverse effects associated with the use of Rezdiffra may include, but are not limited to, the following:
- diarrhea
- nausea
- pruritus
- vomiting
- constipation
- abdominal pain
- dizziness
Clinical Trial Results
The FDA approval of Rezdiffra was based on an analysis of a surrogate endpoint at month 12 in a 54-month, randomized, double-blind placebo-controlled trial (MAESTRO-NASH). The surrogate endpoint measured the extent of liver inflammation and scarring. Patients enrolled in the trial needed to have a liver biopsy showing inflammation due to NASH with moderate or advanced liver scarring. In the trial, 888 subjects were randomly assigned to receive one of the following: placebo (294 subjects); 80 milligrams of Rezdiffra (298 subjects); or 100 milligrams of Rezdiffra (296 subjects); once daily, in addition to standard care for NASH, which includes counseling for healthy diet and exercise.
At 12 months, liver biopsies showed that a greater proportion of subjects who were treated with Rezdiffra achieved NASH resolution or an improvement in liver scarring as compared with those who received the placebo. A total of 26% to 27% of subjects who received 80 milligrams of Rezdiffra and 24% to 36% of subjects who received 100 milligrams of Rezdiffra experienced NASH resolution and no worsening of liver scarring, compared to 9% to 13% of those who received placebo and counseling on diet and exercise. In addition, a total of 23% of subjects who received 80 milligrams of Rezdiffra and 24% to 28% of subjects who received 100 milligrams of Rezdiffra experienced an improvement in liver scarring and no worsening of NASH, compared to 13% to 15% of those who received placebo, depending on each pathologist’s readings.
Continued approval will be based on verifying Rezdiffra’s clinical benefit, which will be done through completing the MAESTRO-NASH 54-month study.
Approval Date: 2024-03-01
Company Name: Madrigal Pharmaceuticals