Clesacostat

The plan for this year is to conduct a drug-to-drug interaction study of ervogastat with Rezdiffra as well as consult with the FDA on the design of a phase 2 combination trial.\n Madrigal has paid Pfizer $50 million for the rights to a DGAT2i inhibitor with the intention of combining the drug with its approved liver disease med Rezdiffra.Madrigal’s thyroid hormone receptor-beta (THR-beta) agonist Rezdiffra became the first-ever drug to be approved by the FDA for metabolic dysfunction-associated steatohepatitis (MASH) back in 2024. The therapy has proven a hit for the company, which is expecting full-year sales for 2025 to top $1 billion.The idea behind acquiring Pfizer’s DGAT2i inhibitor, called ervogastat, is to expand Rezdiffra’s potential. The plan for this year is to conduct a drug-to-drug interaction study of ervogastat and Rezdiffra as well as consult with the FDA on the design of a phase 2 trial for a combination treatment of both drugs.DGAT-2 inhibitors block the final step in triglyceride assembly and storage, resulting in lower hepatic triglycerides, reduced lipotoxic fat and decreased inflammation, Madrigal explained in the Jan. 9 release.“This differentiated mechanism offers the potential for additive clinical benefit when combined with Rezdiffra, a THR-β agonist that increases the cell’s ability to process fat via mitochondrial biogenesis,” the biopharma added.Madrigal also pointed to phase 2 data showing that 72% of patients treated with 150 mg ervogastat achieved at least a 30% reduction in liver fat, while 61% achieved at least a 50% reduction.Ervogastat was an asset in need of a good home. In November, Pfizer announced it was ending work on a MASH combination treatment of ervogastat and an acetyl-CoA carboxylase inhibitor called clesacostat. While Pfizer continued to list ervogastat in its pipeline as a monotherapy, there didn’t appear to be any further trials planned for the drug. In return for the license to ervogastat—along with the rights to two undisclosed early-stage MASH assets—Madrigal has handed over $50 million upfront. While potential milestone payments are also attached to the deal, the companies didn’t share those details.“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,” Madrigal CEO Bill Sibold said in this morning’s release.Madrigal may have been the first to score an approval for the tricky indication of MASH, but there is plenty of competition on the horizon—including from Novo Nordisk’s GLP-1 Wegovy, which gained an FDA label expansion for the disease last year.“MASH is a complex disease that will require multiple treatment approaches to address the full spectrum of patient needs,” Madrigal’s Chief Medical Officer David Soergel, M.D., said in today’s release.“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,” Soergel added. “Along with studies of our oral GLP-1 receptor agonist, we look forward to adding ervogastat to our growing clinical program.\"

Already at the head of the metabolic dysfunction-associated steatohepatitis (MASH) pack, Madrigal Pharmaceuticals is looking to firm up its position with a new deal for a pipeline asset recently cast aside by Pfizer.On Friday, Madrigal said it struck an exclusive global licensing agreement with Pfizer for ervogastat, a Phase II oral DGAT-2 inhibitor that had previously been part of the latter's internal MASH programme and was being developed as a combination with clesacostat, a liver-targeted inhibitor of acetyl-CoA carboxylase (ACC), before being shelved late last year.Madrigal will pay Pfizer $50 million upfront, with additional unspecified milestone payments and royalties tied to future development and sales.Madrigal's Rezdiffra (resmetirom) was the first FDA-approved treatment for non-cirrhotic MASH patients when it was cleared in 2024. The THR-β selective agonist, also approved in Europe, generated $287.3 million in its most recently reported quarter and is tracking toward $1 billion in annual revenues, CEO Bill Sibold has said."With Rezdiffra as the anchor…our broadened portfolio now spans several key pathways that will define the future of MASH treatment," David Soergel, chief medical officer, said in a release Friday. "Along with studies of our oral GLP-1 receptor agonist, we look forward to adding ervogastat to our growing clinical programme."Combo possibilitiesErvogastat targets the final stage of how the liver assembles and stores triglycerides, interrupting the process before toxic fat can accumulate, trigger inflammation and damage liver tissue. Madrigal cited a published Phase II study where 72% of patients treated with a 150-mg dose of ervogastat saw their liver fat drop by at least nearly a third, while 61% achieved reductions of half or more, as measured by MRI-PDFF scans. Patients also showed better liver enzyme levels and reduced liver stiffness on vibration-controlled transient elastography, and all active doses were well tolerated."Because Rezdiffra and ervogastat act on distinct yet complementary pathways that drive liver fat accumulation, this combination has potential to produce additive antisteatotic and antifibrotic efficacy," said Quentin Anstee, lead investigator on the Phase II study.Madrigal plans to conduct a drug-to-drug interaction study with Rezdiffra this year and consult with the FDA on the design of a possible Phase II combination trial.Last July, Madrigal bet up to $2.1 billion for exclusive worldwide rights to a GLP-1 agonist called SYH2086 under an agreement with CSPC Pharmaceutical in a bid to create a best-in-class oral combination therapy for MASH.Despite being first with a marketed treatment for MASH, Madrigal is no longer alone after Novo Nordisk's Wegovy (semaglutide) was granted an accelerated FDA approval — a first for a GLP-1 drug in the disease — last August (see – KOL Views Q&A: Wegovy and Rezdiffra could be friends with mutual benefits in MASH). Eli Lilly has also been trying to capture a piece of the MASH pie with its dual GLP-1/GIP drug tirzepatide.