Madrigal Pharmaceuticals’ hunger for fresh metabolic dysfunction-associated steatohepatitis (MASH) drugs shows no sign of being satiated, with the biopharma paying $25 million upfront to Arrowhead Pharmaceuticals for an asset that failed to win over Johnson & Johnson.
The backloaded deal will see Arrowhead in line for development, regulatory and sales milestone payments that could total $975 million, according to a May 5 release.
In return, Madrigal gains the exclusive rights to ARO-PNPLA3, an RNA interference (RNAi) therapeutic aimed at reducing liver expression of patatin-like phospholipase domain-containing 3 (PNPLA3). Phase 1 data have shown a 46% reduction in liver fat after a single dose in patients homozygous for the PNPLA3 I148M mutation, a genetic contributor to MASH progression.
According to Madrigal, 30% of MASH patients with moderate to advanced fibrosis have two identical copies of the PNPLA3 I148M mutation, which is highly prevalent in Hispanic populations.
“Madrigal’s leadership in the MASH space makes them a natural and attractive partner to advance ARO-PNPLA3,” Arrowhead CEO Christopher Anzalone, Ph.D., said in the release.
ARO-PNPLA3 has already been studied in a phase 1 trial of 55 patients in the U.S., which demonstrated fat reductions within six weeks that were maintained for at least 24 weeks. A second phase 1 trial involving nine patients in Japan supported these findings, Madrigal explained in the release.
Those data weren’t enough to maintain J&J’s interest, however. The pharma handed ARO-PNPLA3 back to Arrowhead amid a pipeline restructuring of the drugmaker’s Janssen unit back in 2023. The MASH drug had been just one element of a wider, $3.7- billion-biobucks partnership with Arrowhead.
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Madrigal hasn’t been deterred, though, touting ARO-PNPLA3’s precision approach to treating patients at risk of MASH.
“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.
The asset will further bolster Madrigal’s MASH pipeline, which has already been swollen by a run of similar deals so far this year. Despite having made history with the blockbuster Rezdiffra, the first FDA-approved therapy to treat MASH, the company has been on the hunt for further bets in the fatty liver disease space.
In February, Madrigal inked a heavily backloaded $4.4 billion deal with Ribo Life Science and its Swedish subsidiary Ribocure Pharmaceuticals to source six preclinical siRNA programs, with the aim of developing MASH therapies that can be combined with Rezdiffra. A few weeks before the Ribo deal, Madrigal paid Pfizer $50 million for the rights to a DGAT2 inhibitor that it also plans to pair with Rezdiffra.
Meanwhile, Arrowhead’s ability to silence genes and reduce fat is not limited to liver disease and is expanding further into the metabolic market. Last August, Sanofi paid $140 million upfront for the China rights to Arrowhead’s RNAi rare metabolic disease treatment, which aced a phase 3 trial that significantly reduced triglycerides in patients with familial chylomicronemia syndrome.
In January 2026, Arrowhead reported early-phase data on a pair of gene-silencing drug candidates in obesity. When dosed with Eli Lilly’s Zepbound, ARO-INHBE resulted in 9.4% body weight loss by Week 16 in patients with obesity and Type 2 diabetes.
