Arrowhead Grants Madrigal Global Rights to ARO-PNPLA3 with $25M Upfront, $975M Milestones
Arrowhead granted Madrigal exclusive global rights to develop and commercialise RNAi therapy ARO-PNPLA3, earning a $25m upfront payment and up to $975m in milestones plus tiered royalties. Phase I results showed 46% liver fat reduction at 12 weeks in homozygous PNPLA3 I148M patients with no significant adverse events.
1. Deal Structure
Under the agreement, Madrigal will pay Arrowhead $25 million upfront for exclusive global rights to ARO-PNPLA3, with Arrowhead eligible for up to $975 million in development, regulatory and commercial milestones, plus tiered royalties on net sales.
2. Clinical Data
A Phase I trial in 55 MAFLD patients with PNPLA3 I148M variants demonstrated up to 46% liver fat reduction at 12 weeks after a single high dose in homozygous subjects, with effects sustained to 24 weeks and no notable safety concerns; heterozygous patients showed no significant response.
3. Mechanism and Rationale
ARO-PNPLA3 targets the PNPLA3 protein, addressing the I148M gene variant linked to hepatic steatosis, elevated liver enzymes and fibrosis risk, and leverages Arrowhead’s TRiM platform for targeted RNAi therapeutics.
4. Strategic Implications
Partnering with Madrigal, a leader in MASH, accelerates ARO-PNPLA3 development and commercialisation beyond Arrowhead’s cardiometabolic focus and exemplifies the company’s business development strategy for clinically validated pipeline assets.