Madrigal Secures ARO-PNPLA3 siRNA License with $25M Upfront, 46% Fat Reduction Data
Madrigal Pharmaceuticals has secured an exclusive global license for ARO-PNPLA3, a clinical-stage siRNA asset targeting the PNPLA3 gene, with an upfront payment of $25 million, up to $975 million in milestones and royalties. Phase 1 data showed a 46% liver fat reduction in homozygous patients and no safety concerns.
1. License Agreement Terms
Madrigal obtained an exclusive global license for ARO-PNPLA3, a GalNAc-conjugated siRNA targeting the PNPLA3 I148M variant, from Arrowhead. The deal includes a $25 million upfront payment, up to $975 million in development and commercial milestones, plus tiered royalties on net sales.
2. Phase 1 Clinical Data
In a first-in-human Phase 1 trial of 55 MAFLD patients, of whom 93% were Hispanic, ARO-PNPLA3 delivered up to 46% liver fat reduction in homozygous PNPLA3 I148M carriers at the highest dose, with rapid onset at six weeks, sustained through 24 weeks, and no clinically meaningful adverse events.
3. Precision Medicine Strategy
This addition complements Madrigal’s portfolio of over ten MASH programs anchored by Rezdiffra, aiming for personalized strategies that address key genetic risk factors. The PNPLA3 I148M homozygous variant, present in about 30% of moderate-to-advanced fibrosis patients, drives liver fat accumulation, inflammation and progression to cirrhosis.
4. Next Steps and Pipeline Integration
Madrigal will engage the FDA to design a Phase 2 trial combining ARO-PNPLA3 with Rezdiffra and plans to explore broader patient cohorts. The asset expands the company’s R&D strategy to include precision-medicine approaches targeting validated disease drivers in MASH.