The decades-long wait for an effective treatment for metabolic dysfunction-associated steatohepatitis (MASH) has ended, as the FDA has approved the first drug for the fatty liver disease.
After a long and winding drug development path for the common disease, Madrigal Pharmaceuticals’ resmetirom, to be sold under the brand name Rezdiffra, has become the first MASH therapy to clear the FDA finish line. Thursday, the FDA approved the tablet drug for the treatment of MASH, also known as nonalcoholic steatohepatitis (NASH), with moderate or severe liver scarring, or fibrosis, consistent with stage F2 and F3 disease, according to a product label (PDF) posted on the FDA’s website.
Rezdiffra emerged successful from a notorious drug development graveyard about four decades after the term NASH was first coined by researchers at Mayo Clinic. Its approval sets the bar for many other companies that are also eying the field, which is estimated to affect about 5% of adults in the U.S.
“Previously, patients with NASH who also have notable liver scarring did not have a medication that could directly address their liver damage,” said Nikolay Nikolov, M.D., acting director of the Office of Immunology and Inflammation in the FDA’s Center for Drug Evaluation and Research. “Today’s approval of Rezdiffra will, for the first time, provide a treatment option for these patients, in addition to diet and exercise.”
Madrigal is pricing Rezdiffra at the wholesale acquisition cost of $47,400 before any discounts. Previously, the influential cost watchdogs at the Institute for Clinical and Economic Review figured the drug would be cost-effective under common thresholds if its net price falls between $39,600 and $50,100 per year.
In a major win for Madrigal, the FDA isn’t requiring a liver biopsy to determine a patient’s eligibility for Rezdiffra. Before the approval, a potential biopsy requirement served as a key point of debate among investors because the cumbersome and invasive procedure would have limited access to Rezdiffra.
A clinical feat
Rezdiffra was the first drug to have met both goals of MASH resolution and fibrosis improvement in a phase 3 trial. Prior to Rezdiffra’s breakthrough, Intercept’s Ocaliva looked closest to being that first drug for MASH until the FDA struck it down for a second time in June 2023. The vast sea of MASH drug development had previously also sunk ships from the likes of Pfizer, Bristol Myers Squibb, Genfit, NGM Biopharmaceuticals, and others.
The current approval was based on an analysis of about 900 patients with biopsy-confirmed MASH and liver fibrosis who enrolled in the MAESTRO-NASH trial. In the study, Rezdiffra, given at either 80mg or 100mg once daily, cleared MASH with no worsening of fibrosis in 25.9% and 29.9% of patients, respectively, versus 9.7% for those who received placebo, according to data published in the New England Journal of Medicine.
In addition, 24.2% and 25.9% of patients on the two Rezdiffra doses enjoyed fibrosis improvement of at least one stage, with no worsening on a fatty liver disease activity score. The rates were significantly more than the 14.2% seen in the placebo group.
In the FDA’s approved label, Rezdiffra’s efficacy for each endpoint was presented by ruling from two pathologists. For improvement in liver fibrosis and no worsening of steatohepatitis, pathologist A found a 13% placebo-adjusted difference for Rezdiffra at 100mg, and the rate was 11% for pathologist B.
Under the FDA approval, patients will get different dosages of Rezdiffra based on their body weight. For those weighing less than 100kg (220lbs.), the recommended dosage is 80mg. The other patients are supposed to take the 100 mg strength.
Madrigal also provided additional safety data from the MAESTRO-NAFLD-1 trial, which the company believes resembles a real-world situation in which patients’ diagnoses are not confirmed by biopsies but instead noninvasive measures. There, the drug was found to be well tolerated, and offered significant improvements on some biomarkers such as liver fat and triglycerides.
Reference: https://www.fiercepharma.com/pharma/fda-approves-first-mash-drug-madrigal-breasts-tape-resmetirom
