Madrigal Pharma is first over the MASH finish line

Madrigal Pharma has become the first drugmaker to claim FDA approval for a drug to treat metabolic dysfunction-associated steatohepatitis (MASH), an elusive target that has seen many other experimental therapies fall by the wayside.

The US regulator has cleared Madrigal’s oral THR β-selective agonist Rezdiffra (resmetirom) for adults with MASH – also known as non-alcoholic steatohepatitis (NASH) – who have moderate to advanced liver scarring (fibrosis), but who have not developed cirrhosis.

Importantly for Madrigal, it has not required a liver biopsy before treatment, which analysts have suggested could have been a barrier to take-up.

MASH is a form of non-alcoholic fatty liver disease (NAFLD) that affects between 6 million to 8 million people in the US alone and for some time has been billed as pharma’s next big growth area. Until now, efforts to bring a therapy to market had all failed, with drugs from Intercept, Gilead, Genfit, Albireo, CymaBay, Cirius, and NGM Biopharma among the abandoned projects.

The condition is largely associated with obesity and an unhealthy diet and lifestyle, and is on the rise in industrialised nations, leading to estimates it could present a market opportunity worth tens of billions of dollars worldwide.

“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, acting director of the FDA’s Office of Immunology and Inflammation, adding that Rezdiffra “will, for the first time, provide a treatment option for these patients, in addition to diet and exercise.”

The FDA’s accelerated approval is based mainly on two phase 3 trials, MAESTRO-NASH and MAESTRO-NAFLD-1, which showed that a higher proportion of patients treated with Rezdiffra achieved NASH resolution or an improvement in liver scarring compared to a placebo group.

In MAESTRO-NASH, after 52 weeks, NASH resolution was seen in 26% of the 80 mg group and 30% of those on 100 mg, with both results significantly better than the 10% rate seen with placebo.

Madrigal has set a list price of the Rezdiffra of $47,400 per year, ahead of any discounts or rebates, which lies within the $39,600 to $50,100 range that the influential Institute for Clinical and Economic Review (ICER) concluded would be cost-effective in its appraisal of the drug.

Analysts vary in their estimates for Rezdiffra’s peak sales potential, but plenty believe it could reach $2 billion to $3 billion a year, and some think that will make Madrigal a takeover target. Shares in the company rose 24% in after-hours trading, raising its market cap to $4.85 billion.

Chief executive Bill Sibold said that the approval was an “historic moment” and “a culmination of more than 15 years of research from [...] founder Dr Becky Taub and a small R&D team that took on one of the biggest challenges in drug development.”

It has also been warmly welcomed by the Fatty Liver Foundation, which represents patients with MASH and other related disorders.

“This is a day of celebration for patients with NASH who have been waiting many years for the first approved therapy,” said CEO Wayne Eskridge. “I believe this approval milestone will bring new energy and momentum to the NASH community, accelerating our efforts to improve disease education, build care pathways, and expand investment in NASH research.”