<scp>ECM</scp> Biomarkers <scp>PRO</scp>‐<scp>C3</scp> and <scp>PRO</scp>‐<scp>C6</scp> Reveal the Anti‐Fibrotic Effect of the Insulin Sensitizer <scp>MSDC</scp>‐0602 K During <scp>EMMINENCE</scp> 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)