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.
Physicians typically feel comfortable diagnosing MASH with noninvasive tools such as the FibroScan and therefore don’t routinely perform biopsies, Madrigal CEO Bill Sibold said in an interview with Fierce Pharma ahead of the approval. Plus, the biopsy procedure isn’t perfect for MASH because it only takes a thin slice of the liver, and it also comes with safety risks.
With that considered, Madrigal wasn’t expecting a biopsy requirement from the FDA, or pushback from payers in reimbursement discussions, Sibold said.
Based on a sans-biopsy-requirement label, analysts at Evercore ISI recently estimated that Rezdiffra could reach about $2.6 billion in global sales in 2030 and $5.5 billion at peak. That’s based on Madrigal’s estimate that about 315,000 U.S. patients who have MASH with significant fibrosis at stage 2 or 3 (F2 and F3) are currently being treated by specialists.
Those F2 and F3 patients—plus about 5,000 to 7,000 high-volume, top-tier hepatologists and gastroenterologists—will be Madrigal’s key focus for the launch of Rezdiffra, Sibold said.
A specialty launch
Sibold joined Madrigal in September after spending 12 years at Sanofi, most recently as executive vice president of specialty care and president of the French pharma’s North America business.
Sibold compared Rezdiffra to Dupixent, the blockbuster inflammatory disease drug that he managed, which delivered Sanofi 10.7 billion euros ($11.7 billion) in revenue last year.
In Dupixent’s case, the dual inhibitor of IL-4/13 was the first biologic medicine approved for atopic dermatitis. Now, Rezdiffra is the first drug for MASH, another major market opportunity with significant unmet need.
“Since there hasn’t been [a drug], we really get to shape the market and shape how you engage with the various stakeholders, and I love doing that,” Sibold said.
Because Rezdiffra is the first MASH drug to hit the market, Madrigal has a lot of prep work to do. In a Feb. 29 note to clients, Evercore’s analysts said they expect to see a meaningful sales acceleration in the second year of the launch, after an initial phase for establishing infrastructure.
“Just remember, there’s never, in the history of the country, a script been written for NASH,” Sibold said. “So there’s this notion of creating a pathway for patients to get through that.”
In one important consideration, doctors will need to figure out how to process their existing patients. Initially, Madrigal will focus on educating doctors on both the disease and its medicine. The company will also work to have reimbursement policies in place and help practices navigate the prescription steps.
“That is not a barrier to the ultimate success of the product, but it’s just a prerequisite for getting to that […] more established pathway,” Sibold said.
By the CEO's estimate, it will take about 12 months before Madrigal can finish establishing the commercial foundation for Rezdiffra to ensure a “real rapid uptake," he said.
Prospect competitors behind the pioneer
While Rezdiffra enjoys its first-mover advantage, other therapies have turned up promising preliminary clinical data in the hope of snatching meaningful market share.
An estimated 100 million patients are projected to live with NASH in the U.S., France, Germany, Italy, Spain, the U.K., China and Japan by 2030. But researchers remain uncertain about how the disease’s prevalence will translate into a market for therapeutics, leading to wide variations in market size estimates, ranging from above $10 billion to more than $100 billion by 2030, according to a recent white paper from analytics firm IQVIA.
Viking Therapeutics has VK2809, which, like Rezdiffra, is an oral thyroid receptor-beta agonist. In a midstage study, the drug led to an average relative change in liver fat of 51.7% after 12 weeks of treatment. The company has yet to report 52-week data on histologic response.
Meanwhile, both 89bio’s pegozafermin and Akero Therapeutics’ efruxifermin are FGF21 analogs given subcutaneously. Both have shown promising anti-fibrosis results in patients with F2 and F3 MASH, and phase 3 trials are either already underway or about to start.
Just before Rezdiffra’s approval, Ionis on Wednesday said a high dose of its antisense candidate ION224 helped 32% patients achieve a one-stage improvement in liver fibrosis without worsening steatohepatitis at week 51 in a phase 2 trial, compared to just 12.5% who received placebo.
And then there’s the GLP-1 agonist class. Lilly in February reported positive phase 2 MASH data for its GIP/GLP-1 dual agonist tirzepatide in overweight or obese people, although the study wasn’t statistically powered to measure improvement in fibrosis. That drug is already approved in diabetes as Mounjaro and obesity as Zepbound.
A few days ago, Boehringer Ingelheim touted what it called the best-in-class potential of its Zealand Pharma-partnered glucagon/GLP-1 agonist survodutide for MASH based on a phase 2 win. Detailed trial findings on the drug's statistically significant improvement in fibrosis remain under wraps.
Sibold touted Rezdiffra’s advantage as a liver-directed medicine versus the more systemic approach with the GLP-1s, especially in patients with significant fibrosis. Madrigal plans to use its lead to establish deep roots in the community “in a way that will make it difficult for others to follow,” Sibold said.
Eventually, Sibold expects Rezdiffra to be a foundational therapy which others will want to utilize in combinations rather than replace. While the company recognizes that combination treatments will be the future, it is right now focused on completing Rezdiffra’s existing trials, he said.
As part of the accelerated approval, Madrigal has agreed to provide further evidence to confirm Rezdiffra’s benefits. That plan includes running the ongoing 54-month extension of MAESTRO-NASH that will measure disease progression and other outcomes such as liver transplants and development of cirrhosis. In addition, another study called MAESTRO-NASH Outcomes is evaluating Rezdiffra in patients with well-compensated NASH cirrhosis, which is a more advanced stage of the disease.
If positive, the study could support the full approval of Rezdiffra and expand its patient base. Sibold said it’s hard to predict an exact timeline for a readout because the trial is event-driven, but he put it as a 2026 or 2027 event.
While the long-term follow-up of MAESTRO-NASH lasts for 54 months, Sibold said Rezdiffra is expected to be a chronic treatment that patients continue to take until signs of the patient’s disease are gone and all the contributing factors such as obesity are removed.
Editor's Note: The story has been updated with Rezdiffra's price.