Arrowhead Pharmaceuticals licenses ARO-PNPLA3 to Madrigal Pharmaceuticals, advancing a Phase 1 RNAi therapy targeting PNPLA3-driven MASH with up to 46% liver fat reduction at 12 weeks.
Written By: Chikkula Pavan Kumar, PharmD
Reviewed By: Pharmacally Editorial Team
Arrowhead Pharmaceuticals has announced an exclusive worldwide licensing agreement with Madrigal Pharmaceuticals for its clinical-stage RNA interference (RNAi) therapeutic, ARO-PNPLA3, for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). The collaboration highlights a growing shift toward genetically targeted approaches in liver disease.
ARO-PNPLA3 is an investigational RNAi-based therapy designed to silence the PNPLA3 gene, a key contributor to liver fat accumulation and disease progression in MASH. The therapy specifically targets patients who are homozygous for the PNPLA3 I148M mutation, one of the strongest genetic risk factors linked to disease severity. This represents a genotype-driven treatment strategy, an area that remains relatively underexplored in MASH.
Phase 1 clinical data from small patient cohorts showed up to a 46% reduction in liver fat (MRI-PDFF) at 12 weeks following a single subcutaneous dose, with favorable tolerability and no dose-limiting toxicities. These surrogate endpoints suggest potential disease-modifying effects, although larger studies are required to confirm impact on MASH resolution, fibrosis regression, and clinical outcomes. The results of the phase 1 trial are published in New England Journal of Medicine.
MASH is the inflammatory and fibrotic subtype of metabolic dysfunction-associated steatotic liver disease (MASLD) and can progress to cirrhosis and liver failure. It represents a significant global health burden, with limited treatment options, particularly for patients with genetically driven disease.
Under the agreement, Madrigal will receive exclusive global rights to develop and commercialize ARO-PNPLA3. Arrowhead will receive $25 million upfront and is eligible for up to $975 million in development, regulatory, and commercial milestones, along with tiered royalties on future sales.
RNA interference therapeutics work through sequence-specific degradation of messenger RNA (mRNA), particularly in hepatocytes, preventing the production of disease-associated proteins. ARO-PNPLA3 uses Arrowhead’s TRiM™ platform to enable targeted delivery to the liver, aiming to influence disease biology rather than only manage symptoms.
The deal further strengthens Madrigal’s position in the MASH landscape by expanding its pipeline beyond metabolic therapies, including its approved treatment Resmetirom, into genetically targeted RNAi approaches. ARO-PNPLA3 remains investigational and has not received regulatory approval.
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About the Writer
Chikkula Pavan Kumar, PharmD is a Doctor of Pharmacy with a keen interest in clinical pharmacy, pharmacovigilance, and evidence-based practice. In his words, he is passionate about patient safety and translating complex medical information into clear, research-driven communication.