Madrigal Pharmaceuticals Inks $1 Billion Global Licensing Deal for ARO-PNPLA3 siRNA Therapy Targeting Genetic Driver of MASH

May 5，Madrigal Pharmaceuticals(NASDAQ:MDGL) announced withArrowhead PharmaceuticalsARO-PNLA3 reaches an exclusive global licensing agreement, ARO-PNPLA3 is a clinical-stage small interfering RNA (siRNA) asset targeting patatin-like phospholipase domain-containing protein 3 (PNPLA3), a key genetic driver of MASH.Arrowhead will receive a $25 million upfront payment, and if certain milestones are achieved, it will also be eligible for up to $975 million in additional payments as well as royalties on net sales.

The licensing of ARO-PNPLA3 expands Madrigal's ability to offer precision medicine approaches for high-risk MASH patients. PNPLA3 I148M is a recognized genetic factor in MASH progression, associated with increased liver fat, inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Approximately 30% of MASH patients with moderate to advanced fibrosis (consistent with F2 to F3 stage fibrosis) carry two identical copies of this variant (referred to as homozygous patients), which is particularly prevalent in the Hispanic population.

In 2023, Arrowhead acquired the rights to ARO-PNPLA3 (formerly known as JNJ-75220795) from Janssen, a subsidiary of Johnson & Johnson. In 2018, Johnson & Johnson entered into a $3.7 billion collaboration with Arrowhead to co-develop and promote the hepatitis B RNAi therapy ARO-HBV. Additionally, Janssen had the option to collaborate with Arrowhead on up to three other RNAi drugs targeting different diseases, one of which is ARO-PNPLA3.

Madrigal CEO Bill Sibold said:"Adding the PNPLA3 siRNA program to our pipeline reflects Madrigal's commitment to shaping the future of care for patients with MASH. MASH is a complex and 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 are particularly excited about the potential to advance research for Hispanic community members who are disproportionately affected by MASH."

Madrigal Chief Medical Officer David Soergel, M.D., stated:"We are pleased to add ARO-PNPLA3 to our product line as we continue to expand Madrigal's leadership in MASH. This licThe agreement advances our R&D strategy of developing therapies targeting validated disease mechanisms and may complementRezdiffra(resmetirom) The wideTreatmentTherapeutic effects, particularly in patient populations with specific needs. Encourage Phase 1 clinical data to support the continued development of this targeted approach for patients with clear genetic drivers of disease, and we will begin planning with Rez."Diffra's joint research."

Phase 1 trial provides proof-of-concept for ARO-PNPLA3 as a potential precision medicine approach in MASH

A Phase 1 first-in-human double-blind placebo-controlled trial of ARO-PNPLA3 was conducted in the United States among 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 the participants were Hispanic or Latino. Data from the study, published in The New England Journal of Medicine, showed:

Twelve weeks after a single dose at the highest tested dose level in PNPLA3 I148M homozygous patients, liver fat reduction reached up to 46% (measured by MRI-PDFF).

Rapid onset, reduction observed at 6 weeks, and sustained for at least 24 weeks.

No clinically significant adverse events were observed.

Liver fat content in heterozygous participants was not affected at any of the doses studied.

The results of the second Phase 1 trial (n=9) conducted in Japan support these findings.

siRNA: The Potential of an Effective Gene-Targeted Treatment

Small interfering RNA (siRNA) provides a precise method for gene silencing in MASH by selectively reducing the production of disease-driving proteins. When conjugated with a GalNAc ligand, siRNA molecules are directly delivered into hepatocytes, where they silence genes identified as key risk factors for MASH by degrading targeted mRNA. Through this preciseGene Silencing Methods andRezdiffraPairing, the company aims to explore whether reducing disease drivers at the genetic level can be complementary.RezdiffraThe therapeutic effect. Madrigal currently has 7 siRNA projects in preparation.

ARO-PNPLA3 is a GalNAc-conjugated siRNA designed to reduce the expression of PNPLA3, a genetically validated driver of MASH. Mutations in the PNPLA3 gene have been shown to impair the liver's ability to properly process fat. This leads to increased fat accumulation in hepatocytes and is closely associated with MASH progression and a high risk of developing hepatocellular carcinoma (HCC). Results from two Phase 1 trials demonstrated that a single dose of ARO-PNPLA3 reduced liver fat content in homozygous carriers of the PNPLA3 I148M variant, providing proof-of-concept for ARO-PNPLA3 as a precision medicine approach for this patient population. Madrigal will collaborate with the U.S. FDA.AndRezdiffraPhase 2 CombinationConsult on the design of the conformity test.

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