CONSHOHOCKEN, PA — Madrigal Pharmaceuticals (NASDAQ: MDGL) licensed a clinical-stage gene-silencing therapy from Arrowhead Pharmaceuticals to expand its pipeline of treatments for metabolic dysfunction-associated steatohepatitis, or MASH, including patients with a genetic mutation linked to more severe liver disease progression.
The agreement gives Madrigal exclusive global rights to develop, manufacture, and commercialize ARO-PNPLA3, a small interfering RNA, or siRNA, therapy targeting the PNPLA3 gene mutation associated with increased liver fat, fibrosis, cirrhosis, and liver cancer risk.
Arrowhead will receive a $25 million upfront payment and could receive as much as $975 million in milestone payments, along with royalties on future net sales.
Madrigal plans to study the therapy in combination with Rezdiffra, its approved treatment for MASH patients with moderate to advanced liver fibrosis.
The PNPLA3 I148M mutation is particularly prevalent among Hispanic patients with MASH. Madrigal cited clinical data indicating about 30% of patients with moderate-to-advanced fibrosis carry two copies of the variant.
Phase 1 clinical data published in The New England Journal of Medicine showed liver fat reductions of as much as 46% after a single dose in patients carrying two copies of the mutation.
The placebo-controlled trial enrolled 55 patients in the United States, about 93% of whom identified as Hispanic or Latino. The company reported liver fat reductions within six weeks that were sustained for at least 24 weeks, with no clinically meaningful adverse events observed.
A separate Phase 1 study conducted in Japan produced similar findings, according to Madrigal.
“The addition of an siRNA program targeting PNPLA3 to our pipeline reflects Madrigal’s commitment to shaping the future of MASH patient care,” Bill Sibold said.
Chief Medical Officer David Soergel stated that the company intends to consult with the FDA on the design of a Phase 2 combination study involving Rezdiffra and ARO-PNPLA3.
MASH, formerly known as nonalcoholic steatohepatitis, is a progressive liver disease that can lead to cirrhosis, liver failure, liver cancer, and transplantation. Madrigal noted that patients with moderate-to-advanced fibrosis face sharply higher liver-related mortality risks as the disease progresses.
Rezdiffra received approval for adults with MASH and moderate-to-advanced fibrosis but not cirrhosis. The drug’s approval was based on improvements in liver scarring and disease markers, with confirmatory clinical studies ongoing.
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