Arrowhead Pharmaceuticals Licenses Clinical MASH Program Targeting PNPLA3 to Madrigal Pharmaceuticals
- Precision approach targets patients who have a mutation in the PNPLA3 gene, which is highly prevalent among Hispanic patients with MASH
- Phase 1 data published in
“The early clinical data for ARO-PNPLA3 have been quite compelling and demonstrate reductions in liver fat up to 46% following a single dose in patients homozygous for the PNPLA3 I148M mutation, a well-established genetic contributor to MASH progression,” said
PNPLA3 has strong genetic and preclinical validation as a driver of fat accumulation and damage in the livers of patients who carry the I148M mutation. The I148M genetic variant is involved with the underlying pathophysiology and is a known risk factor for hepatic steatosis, steatohepatitis, elevated plasma liver enzyme levels, hepatic fibrosis, and cirrhosis.
Phase 1 Trials of ARO-PNPLA3 Provide Potential Proof of Concept
A Phase 1, first-in-human, double-blind, placebo-controlled trial of ARO-PNPLA3 was conducted in
- Reductions in liver fat up to 46% (as measured by MRI-PDFF) at 12 weeks following a single dose at the highest dose level tested in PNPLA3 I148M homozygous patients
- Rapid onset of effect, with reductions observed at six weeks and sustained through at least 24 weeks
- No clinically meaningful adverse events were observed
- No effect on liver fat content was observed in heterozygous participants at any of the doses studied
-
Results from a second Phase 1 trial conducted in
Japan (n=9) support these findings
Summary of License Agreement
Under the terms of the agreement, Madrigal will receive an exclusive global license to develop, manufacture, and commercialize ARO-PNPLA3, a clinical stage program that utilizes Arrowhead’s TRiMTM platform designed to silence hepatocyte expression of PNPLA3 as a potential treatment for patients with MASH.
Summary Financial Terms
Upon closing, Madrigal will make a
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1 Fabbrini, E., Rady, B., Koshkina, A., et al. (2024). Phase 1 Trials of PNPLA3 siRNA in I148M Homozygous Patients with MAFLD.
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