Madrigal Pharmaceuticals Inc. (NASDAQ: MDGL) announced an exclusive global licensing agreement with Arrowhead Pharmaceuticals for ARO-PNPLA3, a clinical-stage small interfering RNA asset targeting a genetic driver of metabolic dysfunction-associated steatohepatitis.

The siRNA targets the PNPLA3 gene, which contains a mutation present in approximately 30% of MASH patients with moderate to advanced fibrosis. The mutation is particularly prevalent in Hispanic populations and is associated with increased liver fat, inflammation, fibrosis, cirrhosis and hepatocellular carcinoma.

Phase 1 trial data published in The New England Journal of Medicine showed ARO-PNPLA3 reduced liver fat by up to 46% in patients with two copies of the PNPLA3 I148M variant. The study included 55 patients in the United States, with approximately 93% being Hispanic or Latino. Effects were observed at six weeks and sustained through 24 weeks following a single dose, with no clinically meaningful adverse events reported.

Under the agreement terms, Arrowhead will receive $25 million upfront, up to $975 million in milestone payments, and royalties on net sales. Madrigal plans to consult with the FDA on designing a Phase 2 combination trial with its approved MASH treatment Rezdiffra.

ARO-PNPLA3 uses GalNAc-conjugated siRNA technology to deliver the therapeutic directly into liver cells, where it silences the PNPLA3 gene by breaking down targeted mRNA. Madrigal currently has seven siRNA programs in its pipeline alongside Rezdiffra, which was the first medication approved by the FDA and European Commission for treating MASH with moderate to advanced fibrosis.