Arrowhead Pharmaceuticals, Inc. announced an exclusive worldwide license agreement with Madrigal Pharmaceuticals 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). 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.

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. Upon closing, Madrigal will make a $25 million upfront payment to Arrowhead. 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.