New Drug
Lauren Howell, PharmD
In March 2024, FDA approved the first treatment option for adults with liver scarring due to fatty liver disease. Rezdiffra (resmetirom–Madrigal Pharmaceuticals) provides an option for patients with liver scarring, who previously did not have a medication option that would address liver damage.
FDA approved Rezdiffra under an accelerated pathway, which allows drugs that treat serious conditions and address unmet medical needs to be approved earlier than the usual pathway to approval. Continued approval of the medication is contingent upon clinical benefit in confirmatory trials.
Rezdiffra is a thyroid hormone receptor-b agonist that is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis. By partially activating a thyroid hormone receptor in the liver, Rezdiffra reduces liver fat accumulation.
Recommended dosage and administration
Rezdiffra is available in 60 mg, 80 mg, and 100 mg tablets. Dosing is based on actual body weight. For patients weighing less than 100 kg, the recommended dosage is 80 mg orally once daily. For patients weighing greater than or equal to 100 kg, the recommended dosage is 100 mg orally once daily. Rezdiffra can be administered with or without food.
Concomitant use of Rezdiffra with strong CYP2C8 inhibitors is not recommended and the Rezdiffra dosage should be reduced if it is used with moderate CYP2C8 inhibitors. Concomitant use with OATP1B1 and OATP1B3 inhibitors is also not recommended. If atorvastatin, pravastatin, rosuvastatin, or simvastatin are used alongside Rezdiffra, the daily dosage of the statin should be limited. Patients taking CYP2C8 substrates should be monitored frequently for substrate-related adverse reactions.
Warnings, precautions, and adverse effects
The most common adverse reactions reported in clinical trials for Rezdiffra are diarrhea, nausea, pruritus, vomiting, constipation, abdominal pain, and dizziness. The use of Rezdiffra should be avoided in patients with decompensated cirrhosis or moderate to severe hepatic impairment.
During treatment, patients should be monitored for elevations in liver enzymes as hepatotoxicity may occur. If hepatotoxicity is suspected, Rezdiffra should be discontinued. During clinical trials, cholelithiasis and cholecystitis were observed more frequently in patients treated with Rezdiffra.
Clinical trials
The efficacy of Rezdiffra was evaluated in a randomized, double-blind, placebo-controlled trial. Although this trial will last for a total of 54 months, FDA approval was granted based on an efficacy analysis at Month 12. The efficacy endpoints were resolution of steatohepatitis without worsening of fibrosis and one stage improvement in fibrosis without worsening of steatohepatitis on post-baseline liver biopsies collected at 12 months.
Patients were randomized to receive placebo, Rezdiffra 80 mg once daily, or Rezdiffra 100 mg once daily. Two pathologists independently read the liver biopsies for each patient at Month 12. Both the 80 mg and 100 mg daily dosages demonstrated statistically significant improvement on the efficacy endpoints at Month 12 compared to placebo.
A total of 26% to 27% of individuals who received 80 mg of Rezdiffra and 24% to 36% of individuals who received 100 mg of Rezdiffra experienced NASH resolution and no worsening of liver scarring, compared to 9% to 13% in the placebo group. A total of 23% of individuals who received 80 mg of Rezdiffra and 24% to 28% of individuals who received 100 mg of Rezdiffra experienced an improvement in liver scarring and no worsening of NASH, compared to 13% to 15% of those in the placebo group. ■