Madrigal Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval to Rezdiffra (resmetirom) for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH), also known as metabolic dysfunction-associated steatohepatitis (MASH), with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). This approval marks a significant milestone as Rezdiffra becomes the first FDA-approved therapy for NASH. The drug is to be used in conjunction with diet and exercise.
The accelerated approval was based on data from the Phase 3 MAESTRO-NASH trial, which demonstrated that Rezdiffra improved liver fibrosis and resolved NASH in patients. Continued approval for this indication may be contingent upon verification and description of clinical benefit in ongoing confirmatory trials.
Clinical Efficacy and Safety
The Phase 3 MAESTRO-NASH trial enrolled 1,759 patients with biopsy-confirmed NASH. Patients were randomized to receive once-daily Rezdiffra at doses of 80 mg or 100 mg, or placebo. The trial achieved its primary endpoints at week 52, demonstrating NASH resolution with no worsening of fibrosis and an improvement in fibrosis by at least one stage with no worsening of the NAFLD activity score. A key secondary endpoint was the percent change from baseline in LDL cholesterol at week 24.
Both 80 mg and 100 mg doses of Rezdiffra showed statistically significant improvement compared to placebo in achieving NASH resolution and fibrosis improvement. These results were consistent across various subgroups, including age, gender, type 2 diabetes status, and fibrosis stage. The primary results of the trial were published in the New England Journal of Medicine in February 2024.
The most common adverse reactions reported in patients treated with Rezdiffra included diarrhea, nausea, pruritis, abdominal pain, vomiting, constipation, and dizziness. Diarrhea and nausea typically began early in treatment and were mild to moderate in severity.
Dosing and Availability
The recommended dosage of Rezdiffra is based on body weight. For patients weighing less than 100 kg (220 lbs), the recommended dose is 80 mg orally once daily. For patients weighing 100 kg (220 lbs) or more, the recommended dose is 100 mg orally once daily. Rezdiffra is expected to be available to patients in the U.S. in April and will be distributed through a limited specialty pharmacy network.
Madrigal is committed to helping appropriate patients access Rezdiffra through the Madrigal Patient Support program, which provides assistance with insurance navigation, affordability challenges, and co-pay support for eligible patients. A patient assistance program (PAP) has also been established to help patients with no insurance access the medication.
Ongoing Studies and Future Directions
The MAESTRO-NASH trial is ongoing as an outcomes study designed to generate confirmatory data to verify clinical benefit and potentially support full approval. This includes assessing progression to cirrhosis on biopsy and hepatic decompensation events, as well as all-cause mortality. A second ongoing outcomes trial is evaluating progression to liver decompensation events in patients with well-compensated NASH cirrhosis treated with Rezdiffra versus placebo.
Stephen Harrison, M.D., lead Principal Investigator of the MAESTRO studies, commented, "The approval of the first medication for NASH is a true game-changer for healthcare providers, the research community and, most importantly, patients living with this serious liver condition... I believe Rezdiffra will become the foundational therapy for patients with NASH with moderate to advanced liver fibrosis."
About NASH
NASH is a more advanced form of nonalcoholic fatty liver disease (NAFLD) and is a leading cause of liver-related mortality. It is characterized by liver inflammation and damage caused by a buildup of fat in the liver. Once patients progress to NASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis), the risk of adverse liver outcomes increases dramatically. NASH is rapidly becoming the leading cause of liver transplantation in the U.S.
NASH is also known as metabolic dysfunction-associated steatohepatitis (MASH). Patients with MASH have at least one related comorbid condition, such as obesity, hypertension, dyslipidemia, or type 2 diabetes.
