Pemvidutide, a glucagon-like peptide 1/glucagon dual receptor agonist, improves metabolic dysfunction-associated steatohepatitis activity and fibrosis in a clinical quantitative systems pharmacology model

Authors: Harrison S, Suschak J, McDaniel MC, Kenz Z, Tomah S, Roberts MS, Siler SQ, Harris MS, Browne S
Conference: EASL Congress
Keywords: fibrosis, MASH, MASLD, NAFLDsym, Pemvidutide, peptide, QSP (quantitative systems pharmacology), QSP (quantitative systems pharmacology) modeling program, steatohepatitis
Software: NAFLDsym®
Division: Quantitative Systems Pharmacology (QSP)

Introduction

Elevated liver fat content (LFC) is the primary pathophysiologic driver of metabolic dysfunction-associated steatohepatitis (MASH). In prior clinical trials, pemvidutide, a balanced (1:1) dual glucagon-like peptide 1 (GLP-1)/glucagon receptor (GCGR) agonist, achieved significant reductions in LFC and improvements in two non-invasive markers of MASH inflammation: alanine aminotransferase (ALT) levels and corrected T1 magnetic resonance imaging.

Aim

Employ NAFLDsym, a mechanistic quantitative systems pharmacology (QSP) model, to predict the effects of pemvidutide and the relative contributions of GLP-1 and GCGR receptor agonism on LFC, nonalcoholic fatty liver disease activity score (NAS), fibrosis, and weight loss in a simulated cohort of MASH subjects.

Methods

The QSP modeling of pemvidutide was coupled to simulated pemvidutide pharmacokinetic profiles using a 1-compartment model. Clinical trial data of pemvidutide from subjects with metabolic dysfunction-associated steatotic liver disease (MASLD) and/or overweight/obesity were used to calibrate the quantitative effects of pemvidutide 1.2 mg and 1.8 mg once weekly dosing over 24 weeks.

Results

  • A strong correlation was observed between clinically reported and QSP predicted effects of pemvidutide on weight loss and LFC at 24 and 12 weeks, respectively.
  • At 24 weeks, the QSP model predicted pemvidutide 1.8 mg to result in complete resolution of NAS and a 1-point median improvement in MASH fibrosis.
  • Adding GCGR agonism to GLP-1R agonism lead to further reductions in LFC from 21% to 62% and resulted in a 4-point greater decrease in median NAS.
  • GLP-1 receptor agonism alone was predicted to have no effect on fibrosis within the 24-week timeframe.

Conclusions

The QSP model predicted the additive effects of GLP-1 and GCGR agonism in pemvidutide would have additive effects on reducing MASH LFC, NAS, and fibrosis and suggested that pemvidutide will have successful outcomes on MASH resolution and fibrosis improvement endpoints in an ongoing 24-week MASH clinical trial.

By Stephen Harrison, John Suschak, Matt McDaniel, Zackary Kenz, Shaheen Tomah, Jonathan Kasper, M. Scot Roberts, Scott Q. Siler, M. Scott Harris, Sarah K. Browne

The European Association for the Study of the Liver (EASL) Congress 2024, June 5-8, 2024, Milan, Italy