Madrigal expands MASH pipeline with US$1B licensing deal for Arrowhead’s siRNA therapy

USA—Madrigal Pharmaceuticals has acquired exclusive global rights to an experimental siRNA therapy from Arrowhead Pharmaceuticals in a deal worth up to US$1 billion, enhancing its position in the growing market for metabolic dysfunction-associated steatohepatitis (MASH).

Under the agreement, Madrigal will take over the development, manufacturing, and commercialisation of Arrowhead’s investigational therapy, ARO-PNPLA3.

Arrowhead will receive an upfront payment of US$25 million, with additional milestone payments potentially reaching US$975 million, along with tiered royalties if the therapy reaches the market.

Precision medicine approach for MASH

ARO-PNPLA3 targets patatin-like phospholipase domain-containing protein 3 (PNPLA3), a gene strongly associated with the progression of MASH and liver fibrosis.

The therapy uses RNA interference technology to silence the disease-driving gene directly inside liver cells.

Madrigal said the therapy could support a more personalised treatment strategy for patients with genetically driven forms of the disease.

Approximately 30% of MASH patients with moderate-to-advanced fibrosis carry two copies of the PNPLA3 I148M mutation, which is particularly common in Hispanic populations.

The company added that the mutation is linked to increased liver fat accumulation, inflammation, cirrhosis, and hepatocellular carcinoma, making it an attractive therapeutic target.

Early clinical results show promise

The licensing deal follows encouraging Phase I data for ARO-PNPLA3.

In the first-in-human trial involving 55 patients with metabolic dysfunction-associated fatty liver disease (MAFLD), the therapy achieved liver fat reductions of up to 46% in patients carrying the PNPLA3 mutation after a single dose.

Researchers observed the effect within six weeks, and the reductions remained durable for at least 24 weeks.

The study also demonstrated a favourable safety and tolerability profile.

Around 93% of trial participants were Hispanic or Latino.

David Soergel, chief medical officer at Madrigal, said the agreement aligns with the company’s research strategy of developing therapies that target validated disease mechanisms while complementing Rezdiffra’s broad therapeutic activity.

Madrigal confirmed it plans to consult the US Food and Drug Administration (FDA) regarding a Phase II study combining ARO-PNPLA3 with Rezdiffra, its flagship MASH therapy.

Rezdiffra continues strong commercial growth

The latest deal comes as Rezdiffra continues to gain momentum in the market following its March 2024 FDA approval as the first treatment for MASH.

In its recently released first-quarter 2026 financial update, Madrigal reported Rezdiffra net sales of US$311.3 million, representing 127% year-over-year growth.

The company also disclosed that more than 42,000 patients were receiving the therapy as of March 2026.

Madrigal said its broader MASH pipeline now includes more than 10 programmes spanning several stages of development, including genetically targeted siRNA therapies and combination treatment approaches.

The Arrowhead agreement marks Madrigal’s second major siRNA-focused transaction this year.

In February 2026, the company signed a US$4.4 billion development and commercialization partnership with Chinese biotech firms Suzhou Ribo Life Science and Ribocure Pharmaceuticals to expand its next-generation MASH treatment pipeline.