(T1430-11-61) SNP-630, a Novel Compound with Multiple Mechanisms, Reverses Non-alcoholic Steatohepatitis-Derived Liver Injury and Fibrosis

Purpose: Therapeutic strategies against non-alcoholic steatohepatitis (NASH) target different pathways. Discovering a drug candidate that impinges on multiple NASH targets is reasonable. This study aims to determine whether SNP-630, the novel synthetic molecule with multiple mechanisms of action (i.e., inhibiting CYP2E1 to stop the formation of reactive oxygen species, reducing hepatic triglyceride accumulation, and reducing chemokine levels), could mitigate NASH-derived liver injury in both a mouse model and NASH patients.

Methods: SNP-630 and a mixture of two of its active metabolites (SNP-612) were administered respectively to NASH mouse model. Furthermore, SNP-612 tolerability, safety, and efficacy in 35 NASH patients was also evaluated. The primary and secondary end points were the change in serum alanine aminotransferase (ALT), liver inflammation, steatosis and fibrosis at week 12 of administration.

Results: Inflammation, liver steatosis and fibrosis were significantly improved in mice treated with SNP-630 compared to the NASH control. Likewise, ALT levels, fibrosis-related biomarkers (ie, a-SMA, Col1a1, Col3a1 and Timp-1). and hepatic triglyceride content were reduced in both SNP-630- and SNP-612-treated mice. In the clinical trial, patients treated with SNP-612, demonstrated a significant change in ALT at week 12 compared to baseline values, with no sever adverse events observed. In addition, SNP-612 demonstrated antifibrotic potential, including a significant decrease in fibrogenesis-related biomarkers (ie, CCL4 and CCL5). Moreover, FibroScan measurements indicated the efficacy of SNP-612 to ameliorate liver fibrosis in subgroup analysis.

Conclusion: These preclinical and phase 2 clinical data demonstrate that SNP-612 and SNP-630 can suppress NASH inflammation and fibrosis through novel and multiple mechanisms.