Effectiveness of The PPAR Agonist Saroglitazar in Nonalcoholic Steatohepatitis: Positive Data from Preclinical & Clinical Studies

Abstract

Background & Aims: Saroglitazar, a novel peroxisome proliferator-activated receptor (PPAR) α/γ agonist, was evaluated in preclinical and clinical studies to evaluate its effectiveness in NASH. Methods: Preclinical studies included: (a) choline deficient L-amino acid-defined high fat diet (CDAHFD) murine NASH model; (b) Long Evans and Wistar rats model for hepatotropic activity; (c) DIAMOND™ NASH mice model. Clinical studies included: Phase 2 and Phase 3 studies in patients with biopsy proven NASH in India.Results: In CDAHFD murine NASH model, Saroglitazar improved aspartate aminotransferase (AST), alanine aminotransferase (ALT) and prevented hepatocellular steatosis, hepatocyte ballooning and lobular inflammation. In Long Evans and Wistar rats model, Saroglitazar was found to be hepatotropic. In the DIAMOND™ NASH mice model, Saroglitazar showed a systemic effect with resolution of steatohepatitis and improvement in all the key histological features of NASH, dyslipidemia and insulin sensitivity. In the phase 2 study, Saroglitazar 4 mg significantly reduced ALT levels (U/L) from baseline (95.86±37.65) to week 12 (44.37±35.43). In the phase 3 study, there was a significantly higher proportion of patients with decrease in NAS ≥2 spread across at least 2 of the NAS components without worsening of fibrosis at week 52 in Saroglitazar 4 mg group (52.3%) compared to placebo group (23.5%) (p value – 0.0427), achieving the primary efficacy endpoint. In the phase 3 study, there were no concerns with the safety profile of Saroglitazar.Conclusions: Positive results from the preclinical and clinical studies provide evidence for the effectiveness of Saroglitazar in the treatment of NASH.Trial registration numbers:Phase 2 Study – CTRI (www.ctri.nic.in) identifier: CTRI/2010/091/000108Phase 3 Study – CTRI (www.ctri.nic.in) identifier: CTRI/2015/10/006236