Madrigal acquires ervogastat to help boost MASH treatment options
Rezdiffra maker plans to test the two therapies in combination
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Madrigal Pharmaceuticals, the maker of Rezdiffra (resmetiron), has acquired three new experimental treatments for metabolic dysfunction-associated steatohepatitis (MASH), a severe form of fatty liver disease, in a deal with Pfizer.
Under the deal, Madrigal gains an exclusive global license to develop, manufacture, and commercialize ervogastat, a therapy candidate that’s already in Phase 2 clinical testing, as well as two other unnamed candidates in preclinical development. In exchange, Pfizer will receive an upfront payment of $50 million, with the potential for additional payments based on regulatory milestones and royalties on sales.
“Madrigal is committed to building the industry-leading pipeline that will shape the future of MASH care and improve patient outcomes,” Bill Sibold, Madrigal’s CEO, said in a company press release. “As the next wave of innovation moves toward combination therapies, Rezdiffra’s strong profile as a liver-directed, well-tolerated, once-daily oral therapy positions it as the ideal foundation.”
Madrigal is now planning to conduct a study to examine how ervogastat interacts with Rezdiffra, which became the first therapy approved for MASH in 2024. The company also plans to consult with the U.S. Food and Drug Administration on plans for a Phase 2 trial that would test these two treatments in combination.
“Our global license agreement for ervogastat aligns with our long-term leadership ambition, and we believe Madrigal is uniquely positioned to advance this promising Phase 2 asset and unlock its full clinical and commercial value through a development program focused on combination therapy with Rezdiffra,” Sibold added.
Rezdiffra, ervogastat target different proteins
MASH is a severe form of fatty liver disease in which the buildup of liver fat leads to inflammation and scarring (fibrosis) in the liver, which can set the stage for life-threatening complications such as liver cancer and failure.
Rezdiffra is a daily oral therapy approved in the U.S. and European Union in combination with diet and exercise for adults with MASH who have moderate to advanced liver fibrosis but no cirrhosis, or irreversible liver scarring.
The therapy works by activating thyroid hormone receptor beta, a protein that helps regulate fat metabolism in liver cells. Essentially, it aims to reduce liver fat levels by increasing the rate at which liver cells burn fat, which is expected to slow the progression of liver inflammation and fibrosis.
Ervogastat (PF-06865571) is an investigational, liver-directed oral therapy that targets a different protein, diacylglycerol O-acyltransferase 2, that is involved in the production of triglycerides, a type of fatty molecule, in the liver. By blocking this protein, the therapy is expected to reduce liver fat accumulation.
There is a compelling scientific rationale for studying ervogastat in combination with Rezdiffra. Because Rezdiffra and ervogastat act on distinct yet complementary pathways that drive liver fat accumulation, this combination has potential to produce additive [anti-fat buildup] and antifibrotic efficacy.
Because Rezdiffra works to burn existing liver fat while ervogastat works to stop the buildup of new liver fat, there’s reason to think the two medicines might offer additive benefits if used together.
“There is a compelling scientific rationale for studying ervogastat in combination with Rezdiffra,” said Quentin Anstee, PhD, a lead investigator on a prior ervogastat Phase 2 study at Newcastle University. “Because Rezdiffra and ervogastat act on distinct yet complementary pathways that drive liver fat accumulation, this combination has potential to produce additive [anti-fat buildup] and antifibrotic efficacy.”
According to Madrigal, a previous Phase 2 clinical trial (NCT04321031) showed that 72% of MASH patients treated with ervogastat at a dose of 150 mg achieved at least a 30% reduction in liver fat, as measured by MRI scans.
Also, most patients (61%) achieved at least a 50% reduction in liver fat, which “is an important measure of efficacy that has been predictive of longer-term fibrosis improvement for other mechanisms, including Rezdiffra,” Anstee said.
Markers of liver damage and fibrosis were also reduced with ervogastat, which was overall tolerated well.
“MASH is a complex disease that will require multiple treatment approaches to address the full spectrum of patient needs,” said David Soergel, MD, chief medical officer of Madrigal. “With Rezdiffra as the anchor and a world-class R&D team, our broadened portfolio now spans several key pathways that will define the future of MASH treatment.”
