Madrigal Pharmaceuticals has gained the global rights to Arrowhead Pharmaceuticals’ small interfering RNA (siRNA) asset for the treatment of metabolic dysfunction-associated steatohepatitis (MASH).
The licence agreement, which is worth up to $1bn, sees Madrigal assume development, manufacturing, and commercialisation duties for Arrowhead’s ARO-PNPLA3. The deal includes $25m upfront and up to $975m in milestone payments, along with royalties on sales if the drug is approved.
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ARO-PNPLA3 is an siRNA treatment targeting patatin-like phospholipase domain-containing protein 3 (PNPLA3), which Madrigal asserts is a “key genetic driver” of MASH. siRNA molecules are delivered directly into hepatocytes, where they silence targeted genes.
Just under a third of patients with the liver disease that has moderate to advanced fibrosis (consistent with stages F2 to F3 fibrosis) carry two identical copies of this variant. This genetic contributor, which is associated with several hepatic pathologies, is also highly prevalent in Hispanic populations.
The siRNA therapeutic has already demonstrated positive results in a Phase I trial. In patients with metabolic dysfunction-associated fatty liver disease (MAFLD) who were either homozygous or heterozygous carriers of the PNPLA3 I148M variant, ARO-PNPLA3 reduced liver fat by up to 46%. This efficacy was observed six weeks after treatment and sustained through at least 24 weeks.
Madrigal is considered the current leader in the MASH market. The US pharma company’s thyroid hormone receptor-beta agonist, Rezdiffra (resmetirom), became the first US Food and Drug Administration (FDA) approved drug for the disease in March 2024. The product has become a lucrative revenue generator for Madrigal, surging to around $960m in global sales in 2025.
With Arrowhead’s asset now in its pipeline courtesy of the licensing agreement, Madrigal is already eyeing a potential combination with its lead drug.
“By pairing this [siRNA approach] with Rezdiffra, the company aims to explore whether reducing drivers of disease at the genetic level can complement Rezdiffra’s therapeutic effects,” Madrigal said in a statement.
The company added that it will consult with the FDA on the design of a Phase II combination trial with Rezdiffra.
Madrigal’s chief medical officer, David Soergel, said: “This licensing agreement advances our R&D strategy of developing therapies that target validated disease mechanisms and may complement Rezdiffra’s broad therapeutic effects, especially in patient populations with specific needs.”
The licensing deal with Arrowhead marks the second billion-dollar transaction in the siRNA space for Madrigal in 2026. In February, the company outlaid $4.4bn in a development and commercialisation agreement with Chinese biotech Suzhou Ribo Life Science and its subsidiary Ribocure Pharmaceuticals. As with ARO-PNPLA3, Madrigal is looking to use Ribo’s assets in combination with Rezdiffra.
