When Madrigal Pharmaceuticals achieved a first-in-disease approval for the MASH treatment Rezdiffra this year, the company had a clear head start in an emerging market that’s become a prime target for drugmakers.
Despite being the only pharma with an approved MASH drug, Madrigal’s entry into the space has also created a potential advantage for other companies looking for a way in.
“Madrigal is doing a lot of work for us,” said Frederic Cren, CEO of Inventiva Pharma, which has its own oral MASH drug candidate lanifibranor in phase 3 testing. “They are educating physicians. They are making the general population aware [of] the severity of this disease, and when we arrive with what we think will be a more efficacious drug, the market will be large and open to a new oral drug.”
Inventiva’s lanifibranor is a PPAR agonist designed to induce anti-fibrotic, anti-inflammatory and metabolic changes in MASH patients. With investor enthusiasm high in the cardiometabolic space, Inventiva raised $367 million in an October financing round.
Just how large is the MASH market?
Rezdiffra sales topped $62 million during the third quarter of 2024, well above analysts’ expectations of $36 million for the quarter. Plus, Madrigal said it was ahead in its goals for prescribing coverage.
Across the development landscape, several other pharmas and biotechs have MASH drugs in the clinic, including 89bio, Akero Therapeutics and Galectin Therapeutics.
But off in the distance, another class of treatments await their shot at MASH: GLP-1s.
GLP-1s for MASH
Novo Nordisk, the biggest seller in the GLP-1 market, announced earlier this month it was seeking regulatory approval for semaglutide — the active ingredient in its blockbuster weight loss and diabetes drugs Ozempic and Wegovy — in MASH. The news came with positive phase 3 trial results showing MASH patients with moderate to advanced liver fibrosis saw “improvement in liver fibrosis with no worsening of steatohepatitis,” or fat buildup in the liver, the company said.
GLP-1s are among the bestselling drugs in the past few years, and their impact in the MASH market could also be substantial. Eli Lilly is in phase 2 testing for MASH indications for tirzepatide, the ingredient in its GLP-1 blockbusters Mounjaro and Zepbound.
However, Cren isn’t worried the GLP-1s could eclipse market opportunities. Instead, he views their impact as potentially deepening the market for Inventiva’s lanifibranor and creating an opportunity for MASH drugs to be used alongside GLP-1s.
“It's great news for patients, but also great news for us, because it means that large pharma will be increasingly more interested,” Cren said. “But [GLP-1s] will need to be combined with another treatment that will provide additional efficacy and especially a direct activity on fibrosis.”
Cren also believes GLP-1s will be less suitable for long-term use due to their unpleasant gastrointestinal side effects. Madrigal also pointed out in its third-quarter earnings presentation that 70% of semaglutide users discontinued treatment after 12 months, underscoring the adherence issue.
Market differentiation
Even with Rezdiffra’s success, there’s likely plenty of room in the market for competitors. Like GLP-1s, Rezdiffra has potential GI side effects, which could impact its uptake, according to an April survey of gastroenterologists. Additionally, there may be some patients with moderate to severe liver fibrosis who don’t respond to Rezdiffra, the survey said.
One “key feature” of lanifibranor is its ability to reduce insulin resistance, as many patients with MASH also have type 2 diabetes and may have trouble controlling their blood sugar, said Cren. The drug also improves fatty liver. In Inventiva’s phase 2 trial, 83% of patients treated with lanifibranor showed “a reduction greater or equal to 30% of their hepatic fat.” Plus, patients saw reductions in fibrosis biomarkers. Inventiva is also betting that lanifibranor can rise above other PPAR agonists by targeting three PPAR isoforms rather than just one or two.
“It's a complex disease, so you need a drug that ultimately prevents a patient from becoming cirrhotic,” Cren said. “You want a drug that will regress your level of fibrosis — [it’s] really what everybody's looking for.”
The company is about 90% enrolled with its nearly 1,000-patient phase 3 trial, which will run for 18 months, according to Cren. But it hasn’t been all smooth sailing for Inventiva, which temporarily paused enrollment of its phase 3 study earlier this year after discovering elevated enzymes in a patient. The pharma plans to publish data from the study in the second half of 2026, Cren said.
