Pasadena, CA — May 5, 2026 — Leads & Copy — Arrowhead Pharmaceuticals Inc. (NASDAQ: ARWR) announced an exclusive worldwide license agreement with Madrigal Pharmaceuticals (NASDAQ: MDGL) for ARO-PNPLA3, Arrowhead’s clinical stage RNA interference (RNAi) therapeutic designed to reduce liver expression of patatin-like phospholipase domain containing 3 (PNPLA3) as a potential treatment for patients with metabolic dysfunction-associated steatohepatitis (MASH).
Under the terms of the agreement, Madrigal will receive an exclusive global license to develop, manufacture, and commercialize ARO-PNPLA3, a clinical stage program that utilizes Arrowhead’s TRiMTM platform designed to silence hepatocyte expression of PNPLA3 as a potential treatment for patients with MASH.
Madrigal will make a $25 million upfront payment to Arrowhead upon closing. Arrowhead is also eligible to receive development, regulatory, and sales milestone payments of up to $975 million. Arrowhead is further eligible to receive tiered royalties on commercial sales ranging from high-single digits to the mid-teens.
Christopher Anzalone, Ph.D., President and CEO at Arrowhead, said that the early clinical data for ARO-PNPLA3 have been quite compelling and demonstrate reductions in liver fat up to 46% following a single dose in patients homozygous for the PNPLA3 I148M mutation. He added that Madrigal’s leadership in the MASH space makes them a natural and attractive partner to advance ARO-PNPLA3.
Anzalone noted that Arrowhead’s proprietary TRiMTM platform enables broad targeting of diseases and genes expressed throughout the body generating a deep pipeline of candidates, many of which are well suited for strategic partnerships to accelerate development and commercialization. He also stated that the transaction with Madrigal underscores Arrowhead’s disciplined business development strategy, demonstrating their ability to partner high-potential, clinically validated programs with leading organizations in therapeutic areas beyond their core commercial cardiometabolic focus.
PNPLA3 has strong genetic and preclinical validation as a driver of fat accumulation and damage in the livers of patients who carry the I148M mutation. The I148M genetic variant is involved with the underlying pathophysiology and is a known risk factor for hepatic steatosis, steatohepatitis, elevated plasma liver enzyme levels, hepatic fibrosis, and cirrhosis.
A Phase 1, first-in-human, double-blind, placebo-controlled trial of ARO-PNPLA3 was conducted in the United States in 55 patients with Metabolic dysfunction-associated fatty liver disease (MAFLD) who were either homozygous or heterozygous carriers of the PNPLA3 I148M variant. Approximately 93% of participants were Hispanic or Latino. Data from this study, published in The New England Journal of Medicine, demonstrated:
- Reductions in liver fat up to 46% (as measured by MRI-PDFF) at 12 weeks following a single dose at the highest dose level tested in PNPLA3 I148M homozygous patients
- Rapid onset of effect, with reductions observed at six weeks and sustained through at least 24 weeks
- No clinically meaningful adverse events were observed
- No effect on liver fat content was observed in heterozygous participants at any of the doses studied
Results from a second Phase 1 trial conducted in Japan (n=9) support these findings.
Arrowhead Pharmaceuticals (NASDAQ: ARWR) is a commercial-stage pharmaceutical company developing medicines that treat intractable diseases by silencing the genes that cause them, harnessing the natural RNA interference (RNAi) mechanism. The company has built a broad portfolio of clinical and commercial RNAi therapeutics through its industry-leading targeted RNAi molecule (TRiM™) platform, which can precisely silence genes in a wide range of cell types, including liver, lung, muscle, adipose, and central nervous system tissue. At Arrowhead, they rapidly advance potential best- and first-in-class RNAi treatments for diseases with significant unmet medical need, because every day matters to the patients they serve.
Source: Arrowhead Pharmaceuticals
