Madrigal Pharmaceuticals has entered into a licensing agreement with Arrowhead Pharmaceuticals to obtain rights to ARO-PNPLA3, an RNA interference (RNAi) therapy targeting a genetic mutation associated with metabolic dysfunction-associated steatohepatitis (MASH). The arrangement includes an upfront payment of $25 million, with additional development, regulatory, and commercial milestone payments that could bring the total value close to $1 billion.
The candidate therapy, ARO-PNPLA3, is designed to reduce the expression of patatin-like phospholipase domain-containing 3 (PNPLA3), specifically addressing the I148M mutation. This mutation is considered a contributor to the progression of MASH and is present in approximately 30% of patients, particularly those with moderate to advanced fibrosis. The genetic variation is associated with liver fat buildup, inflammation, fibrosis, and cirrhosis, which are commonly observed features of the disease.
Madrigal’s Chief Medical Officer, David Soergel, stated that the therapy aligns with the company’s focus on validated disease mechanisms and may complement the effects of its existing treatment, Rezdiffra. Rezdiffra, approved by the U.S. Food and Drug Administration in March 2024, acts as a partial agonist of the thyroid hormone receptor-beta, reducing liver triglycerides and boosting lipid metabolism. The drug generated $958.4 million last year, reflecting its role in the treatment landscape.
Clinical data from Phase 1 trials indicate that ARO-PNPLA3 demonstrated reductions in liver fat. In a U.S.-based study involving 55 patients with metabolic dysfunction-associated fatty liver disease, liver fat levels declined by up to 46% at 12 weeks. Effects were observed as early as six weeks after dosing and were maintained through 24 weeks of follow-up. A separate Phase 1 study conducted in Japan with nine participants supported these findings and showed consistent results across patient groups.
Madrigal has initiated discussions with the FDA to determine the design of a Phase 2 trial for ARO-PNPLA3, though no timeline for the next stage of development has been provided at this stage.
The agreement marks another step in Madrigal’s efforts to expand its pipeline beyond Rezdiffra. In February, the company entered a partnership with Suzhou Ribo Life Sciences and its affiliate Ribocure Pharmaceuticals, committing $60 million upfront and up to $4.4 billion in milestone payments for six investigational siRNA programs targeting the liver. These therapies are intended to be evaluated in combination with Rezdiffra. In January, Madrigal licensed the DGAT-2 inhibitor ervogastat from Pfizer, paying $50 million upfront. That candidate is in mid-stage development for MASH in combination with Rezdiffra.
ARO-PNPLA3 had previously been part of a broader collaboration between Arrowhead and Johnson & Johnson but was returned to Arrowhead in 2023 following restructuring within the Janssen unit.
“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,” Madrigal CEO Bill Sibold said in a statement.
Arrowhead CEO Christopher Anzalone stated that the agreement reflects the company’s strategy of partnering programs with other organizations and noted that Madrigal is positioned to advance ARO-PNPLA3 further through its development pipeline.
Madrigal Pharmaceuticals has entered a major licensing agreement with Arrowhead Pharmaceuticals for the investigational therapy ARO-PNPLA3. The agreement, valued at up to $1 billion, strengthens Madrigal’s position in liver disease therapeutics and expands the company’s long-term growth strategy.
Overview of the Madrigal-Arrowhead Agreement
Under the terms of the deal, Madrigal gains exclusive rights to develop and commercialize ARO-PNPLA3, an RNA interference (RNAi) therapy targeting liver diseases linked to PNPLA3 genetic mutations.
The partnership highlights Madrigal’s commitment to advancing innovative therapies for metabolic and liver-related disorders. By adding ARO-PNPLA3 to its pipeline, Madrigal aims to address significant unmet medical needs in patients with chronic liver disease.
Why Madrigal Chose ARO-PNPLA3
Targeting Genetic Drivers of Liver Disease
Madrigal sees strong potential in ARO-PNPLA3 because it directly targets a key genetic mutation associated with fatty liver disease and fibrosis progression.
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