Madrigal Pharmaceuticals expands MASH pipeline with genetic treatment
Experimental treatment ARO-PNPLA3 shows promise for Hispanic patients
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Madrigal Pharmaceuticals has secured worldwide rights to develop ARO-PNPLA3, an experimental treatment created by Arrowhead Pharmaceuticals for people with metabolic dysfunction-associated steatohepatitis (MASH), a severe form of steatotic liver disease.
The therapy is specifically designed for MASH patients who carry a mutation that is known to contribute to MASH and is more frequent in Hispanic populations.
Madrigal is the developer of Rezdiffra (resmetirom), which in 2024 became the first treatment approved for MASH in the U.S. Earlier this year, the company also secured rights to several experimental MASH treatments in a deal with Pfizer.
“We are pleased to add ARO-PNPLA3 to our pipeline as we continue to expand Madrigal’s leadership in MASH,” David Soergel, MD, chief medical officer of Madrigal, said in a company press release. “This licensing agreement advances our R&D strategy of developing therapies that target validated disease mechanisms and may complement Rezdiffra’s broad therapeutic effects, especially in patient populations with specific needs. Encouraging Phase 1 data support continued development of this targeted approach for patients with a well-defined genetic driver of disease, and we will begin planning for combination studies with Rezdiffra.”
Under the agreement, Madrigal will pay Arrowhead $25 million upfront, with the potential for an additional $975 million in payments if the therapy successfully hits various development, regulatory, and sales milestones. Arrowhead will also receive royalties on sales of ARO-PNPLA3 if the therapy is ultimately approved for commercial use.
“Madrigal’s leadership in the MASH space [makes] them a natural and attractive partner to advance ARO-PNPLA3,” Christopher Anzalone, PhD, president and CEO of Arrowhead, said in a company press release.
Treatment targets messenger RNA of key gene
MASH is a severe form of steatotic liver disease in which the buildup of liver fat leads to inflammation and scarring (fibrosis), which can interfere with liver function and set the stage for life-threatening complications.
ARO-PNPLA3 (also known as JNJ-75220795) is a therapy based on small interfering RNAs (siRNAs), which are molecules that specifically target a gene’s messenger RNA, or the intermediate molecule derived from DNA that guides protein production. By doing so, siRNAs are potent gene silencers.
Madrigal’s newly acquired therapy targets the messenger RNA of the PNPLA3 gene, which encodes a protein of the same name, specifically in the livers of people carrying the PNPLA3 mutation I148M.
This variant results in higher-than-normal PNPLA3 protein levels and is the most common genetic risk factor for liver fat accumulation and MASH. This mutation is especially common in Hispanics.
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.
ARO-PNPLA3 has already been tested in MASH patients carrying the I148M variant in two small Phase 1 clinical trials, one in the U.S. (NCT04844450) and one in Japan (NCT05039710).
In the U.S.-based trial, 55 MASH patients (93% Hispanic or Latino) were randomly assigned to receive a single under-the-skin injection of either the therapy at various doses or a placebo. Most participants carried the mutation in both copies of the PNPLA3 gene (homozygous), while the rest carried it in only one copy (heterozygous).
Results showed that the therapy was well-tolerated overall. In homozygous participants, low doses of ARO-PNPLA3 did not affect liver fat, but higher doses led to a marked reduction in liver fat content.
Patients given high doses had evidence of reduced liver fat within two months of receiving the injection, and by 12 weeks (about three months) after treatment, liver fat was reduced by up to 46%.
In heterozygous participants, ARO-PNPLA3 had no effect on liver fat at any tested dose. The researchers therefore concluded that ARO-PNPLA3 shows promise as a potential treatment for MASH patients who are homozygous.
Results of the Japan-based trial, in which a single high dose of the therapy was tested against a placebo in homozygous patients, also supported ARO-PNPLA3’s therapeutic potential in this population.
“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,” said Bill Sibold, CEO of Madrigal. “We’re particularly excited about the potential to advance research for members of the Hispanic community, who are disproportionately affected by MASH.”
