ECM Biomarkers PRO-C3 and PRO-C6 Reveal the Anti-Fibrotic Effect of the Insulin Sensitizer MSDC-0602 K During EMMINENCE Randomised Clinical Trial

Abstract

MSDC-0602 K is a second-generation insulin sensitizer that inhibits the mitochondrial pyruvate carrier without activating the transcription factor PPARγ. The EMMINENCE phase IIb trial evaluated MSDC-0602 K in patients with metabolic dysfunction-associated steatohepatitis (MASH). MSDC-0602 K missed statistical significance on endpoints based on liver histology while producing significant reductions in metabolic biomarkers. Here, we assessed the extracellular matrix-based biomarkers PRO-C3 and PRO-C6, surrogates of collagen type III synthesis and the profibrotic, pro-inflammatory fragment endotrophin. 392 MASH patients were randomised to placebo (PL), 62.5 mg, 125 mg or a 250 mg daily dose of MSDC-0602 K for 12 months. 334 completed the study. The primary efficacy endpoint was defined as an improvement of ≥ 2 points in NAS score, with ≥ 1 decrease in either ballooning or inflammation and no increase in fibrosis stage. Blood samples were collected at baseline, 6 months, and 12 months to assess biochemical markers PRO-C3 and PRO-C6. The 125 mg and 250 mg doses of MSDC-0602 K reduced PRO-C3 at 6 months (p = 0.0103 and p = 0.026 respectively) and 12 months (p = 0.0274 and p = 0.0311) compared to placebo. Furthermore, the 62.5 mg and 250 mg doses reduced PRO-C6 at 12mo (p = 0.0467 and p = 0.0266) compared to placebo. Treated patients who reached the primary endpoint had lower baseline PRO-C3 (p = 0.026), and PRO-C3 levels discriminated between regressing, stable or progressing fibrosis (p = 0.0076). MSDC-0602 K significantly reduced PRO-C3 and PRO-C6, suggesting anti-fibrotic and pro-metabolic effects. Lower baseline fibroblast activity (PRO-C3) at baseline was associated with improvement in fibrosis, while higher baseline PRO-C3 was associated with fibrosis progression. Our findings suggest that MSDC-0602 K has anti-fibrogenesis and pro-metabolic effects not detected by liver histology.

Trial Registration: EMMINENCE clinical trial number (ClinicalTrials.gov NCT02784444)