Madrigal bolsters MASH pipeline with Arrowhead’s PNPLA3-targeting siRNA

Madrigal Pharmaceuticals has signed an exclusive global licensing deal with Arrowhead Pharmaceuticals for ARO-PNPLA3, a clinical-stage small interfering RNA (siRNA) therapy aimed at a key genetic driver of metabolic dysfunction-associated steatohepatitis (MASH). The asset targets patatin-like phospholipase domain-containing protein 3 (PNPLA3), broadening Madrigal’s portfolio into precision medicine territory.

The PNPLA3 I148M variant is a well-documented contributor to MASH progression, linked to elevated liver fat, inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Roughly 30% of MASH patients with moderate-to-advanced fibrosis (F2–F3) are homozygous for the variant, and the mutation is notably common in Hispanic populations — a group disproportionately burdened by the disease.

CEO Bill Sibold framed the deal as part of the company’s broader strategy: “The addition of an siRNA program targeting PNPLA3 to our pipeline reflects Madrigal’s commitment to shaping the future of MASH patient care. MASH is a complex, heterogeneous disease, and we believe patients will benefit from personalized treatment strategies targeting key genetic risk factors that drive disease progression and adverse outcomes. We’re particularly excited about the potential to advance research for members of the Hispanic community, who are disproportionately affected by MASH.”

Chief Medical Officer David Soergel pointed to the asset’s fit alongside Madrigal’s flagship therapy Rezdiffra (resmetirom): “We are pleased to add ARO-PNPLA3 to our pipeline as we continue to expand Madrigal’s leadership in MASH. 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. Encouraging Phase 1 data support continued development of this targeted approach for patients with a well-defined genetic driver of disease, and we will begin planning for combination studies with Rezdiffra.”

The Phase 1 readout

Published in The New England Journal of Medicine, the U.S.-based Phase 1 study enrolled 55 patients with metabolic dysfunction-associated fatty liver disease (MAFLD) carrying one or two copies of the PNPLA3 I148M variant. Roughly 93% of enrolled participants were Hispanic or Latino. Key findings included:

• Liver fat reductions of up to 46% (measured via MRI-PDFF) at 12 weeks after a single high-dose administration in homozygous patients
• Effects emerging by week six and holding through at least 24 weeks
• A clean safety profile with no clinically meaningful adverse events
• No liver fat changes in heterozygous patients across any dose tested

A smaller Japanese Phase 1 study produced consistent results.

Why siRNA, and why now

siRNA therapeutics silence disease-driving genes by degrading their messenger RNA. When conjugated to a GalNAc ligand, these molecules are shuttled directly into liver hepatocytes — making them well-suited for MASH targets. ARO-PNPLA3 follows this design, suppressing a gene whose mutation impairs the liver’s fat-processing machinery and drives both MASH progression and elevated HCC risk.

The acquisition deepens Madrigal’s siRNA bench, which now includes seven programs, and slots into a broader pipeline of more than 10 assets anchored by Rezdiffra. The company plans to consult with the FDA on a Phase 2 combination trial pairing ARO-PNPLA3 with Rezdiffra.

---

---

Related Topics and Keywords

madrigal, mash, PNPLA3-Targeting, PNPLA3-Targeting siRNA, siRNA