Madrigal Pharmaceuticals has licensed from Arrowhead Pharmaceuticals an RNA interference candidate that targets a genetic mutation present in around 30% of patients with MASH.
Madrigal Pharmaceuticals continues to build out its growing siRNA pipeline for the liver disease metabolic dysfunction-associated steatohepatitis, this time linking up with California’s Arrowhead Pharmaceuticals in a back-heavy licensing deal.
Under the terms of the agreement, announced Tuesday morning, Madrigal will front $25 million and pay up to $1 billion total to gain access to ARO-PNPLA3, an RNAi candidate that targets a major genetic driver of MASH.
ARO-PNPLA3 fits with Madrigal’s strategy of addressing “validated disease mechanisms and may complement Rezdiffra’s broad therapeutic effects,” Madrigal CMO David Soergel said in a prepared statement on Tuesday.
Rezdiffra, which became the first FDA-approved MASH therapy in March 2024, is a partial agonist of the thyroid hormone receptor-beta that works by reducing liver triglycerides and boosting lipid metabolism. Last year, the drug made $958.4 million.
ARO-PNPLA3 complements Rezdiffra’s mechanism by shooting for a different target: the PNPLA3 I148M mutation, which according to Madrigal is a “well-established genetic contributor to MASH progression.” Around 30% of patients have two copies of this variant. The genetic alteration is linked to liver fat buildup, inflammation, cirrhosis and fibrosis—all hallmarks of MASH.
Phase 1 data in patients with metabolic dysfunction-associated fatty liver disease showed that ARO-PNPLA3 treatment cut liver fat by up to 46% at 12 weeks, according to the announcement. ARO-PNPLA3’s benefits were evident as early as six weeks after dosing and persisted through 24 weeks of follow-up.
Madrigal is now in talks with the FDA to align on a design for ARO-PNPLA3’s Phase 2 program, though the biotech did not provide a specific timeline for when it expects mid-stage development to start.
The Wednesday agreement with Arrowhead is Madrigal’s latest move to deepen its expertise in MASH and build out a portfolio beyond Rezdiffra. In February, the company paid $60 million upfront and promised up to $4.4 billion to partner with China’s Suzhou Ribo Life Sciences and collaborate on six investigational siRNA therapies directed at the liver. Madrigal plans to test these assets in combination with Rezdiffra.
In January, Madrigal licensed the DGAT-2 blocker ervogastat from Pfizer, paying $50 million upfront. Ervogastat is in mid-stage development for MASH, in combination with Rezdiffra.
For Arrowhead, the asset made more sense in the hands of Madrigal, CEO Chris Anzalone said in a Tuesday press release. He credited his company’s platform as finding drugs for diseases that may not be the best fit for Arrowhead but good options for licensing partnerships.
“Today’s transaction with Madrigal underscores Arrowhead’s disciplined business development strategy, demonstrating our ability to partner high-potential, clinically validated programs with leading organizations in therapeutic areas beyond our core commercial cardiometabolic focus,” Anzalone said in a statement.
