Madrigal buys right to RNA-interfering agent that could be coupled with its MASH drug, Rezdriffa

Madrigal Pharmaceutical, the maker of Rezdiffra (resmetirom), has purchased the development rights to a small interfering RNA (iRNA) drug designed to silence a gene implicated as the upstream cause of moderate to advanced fibrosis in metabolic dysfunction-associated steatohepatitis (MASH).

Madrigal purchased the licensing rights to the siRNA drug, called ARO-PNPLA3, from Arrowhead Pharmaceuticals for an upfront payment of $25 million with additional payments that could total $975 million due if certain milestones are met.

“The addition of an siRNA program targeting PNPLA3 [patatin-like phospholipase domain-containing protein 3] reflects Madrigal’s commitment to shaping the future of MASH patient care,” Bill Sibold, CEO of Madrigal, said in a news release issued last week about the deal wiht Arrowhead

Madrigal currently has seven siRNA programs in its pipeline, according to that news release. The news release says that siRNA molecules can be delivered directly to liver cells where they can home in on and break down select messenger RNA that is instrumental in causing MASH.

By pairing this RNA blocker with Rezdiffra, Madrigal “aims to explore whether reducing drivers of disease at the genetic level can complement Rezdiffra’s therapeutic effects,” according to teh news release.

When the FDA approved Rezdiffra in 2024 for noncirrhotic MASH with moderate to advanced liver fibrosis, it was the only drug approved for the increasingly common liver condition, which is associated with obesity. In August 2025, the U.S. drug regulator added a MASH indication to the approvals of Wegovy (semaglutide), the weight-loss drug, setting off what might become a fierce competition between the two drugs.

ARO-PNPLA3 has had a somewhat circuitous path — including a name change — as it has wended through the development process. Arrowhead, which has a flight of siRNA agents under development, was developing ARO-PNPLA3 in partnership with Janssen Pharmaceuticals, which is part of Johnson & Johnson. During that phase of its development, the agent’s moniker was JNJ-75220795. But in 2023, Janssen ceded its development rights to the drug to Arrowhead, and now Arrowhead has sold rights to the drug to Madrigal.

In August 2024, Janssen researchers reported positive results from two, phase 1 trials of ARO-PNPLA3 in a letter in the New England Journal of Medicine (NEJM). In the letter, they referred to the agent by its Jansen name, JNJ-75220795.

Lead author Elisa Fabbrini, M.D., Ph.D., who was then at Janssen, and her colleagues noted in the NEJM letter that in preclinical studies, ARO-PNPLA3 was shown to selectively target PNPLA3 messenger RNA and to produce what they described as a “profound,” 70% decrease in PNPLA3 mRNA expression from baseline levels in the liver cells of nonhuman primates. The preclinical studies also showed that the response was durable.

The larger of the two trials discussed in the NJEM letter enrolled a total of 55 patients, 31 of whom were homozygous for PNPLA3 I148M variant that is associated with susceptibility to steatohepatitis, fibrosis, cirrhosis and liver cancer, and 24 of whom were heterozygous.

The other trial had 9 participants, all of whom were homozygous for PNPLA3 I148M variant.

Notably, 93% of the participants in the larger trial were Hispanic and Latino, a reflection of the high prevalence of the PNPLA3 risk allele in the Hispanic population, wrote Fabbrini and her colleagues.

The researchers randomly assigned the participants in the two trials to receive a single subcutaneous injection of ARO-PNPLA3 (45 participants) or a placebo (19 participants). Among the homozygous participants in the larger trial, the ARO-PNPLA3 injection was associated with a dose-dependent decrease in liver fat content up to 46% at 12 weeks. Fabbrini and her colleagues noted that the decrease was apparent at 6 weeks and was sustained at 24 weeks. They also noted that the effect on liver fat was not seen wiht lower doses (10 milligrams [mg] or 25 mg) or in heterozygous patients at any of the doses studied (75 mg, 200 mg or 400 mg).

The takeaway from Fabbrini and her colleagues was that ARO-PNPLA3 “reduced liver fat content in humans homozygous for the PNPLA3 I148M variant” and that the findings provided proof of concept for ARO-PNPL3 as a “precision medicine approach” for homozygous patients.