Cirius Therapeutics announced positive results from an interim analysis of exploratory endpoints from its ongoing, fully enrolled Phase 2b clinical trial (the EMMINENCE trial) evaluating MSDC-0602K in 402 patients diagnosed with non-alcoholic steatohepatitis (NASH) with fibrosis. The interim analysis, which was conducted in the first 328 patients to reach their six-month follow-up visit, showed that patients treated with MSDC-0602K had significant improvements from baseline in measures of liver function and insulin resistance at six months. MSDC-0602K, a second-generation insulin sensitizer, is designed to selectively modulate the mitochondrial pyruvate carrier (MPC), which at the cellular level mediates the effects of overnutrition, a major cause of NASH and other metabolic disorders.
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The subjects included in this interim analysis had significant liver disease, as established by liver biopsy, with an average non-alcoholic fatty liver disease (NAFLD) activity score at baseline of 5.3. Almost sixty percent of these subjects had a baseline fibrosis score of 2 or 3 and approximately fifty percent also had a diagnosis of Type 2 diabetes at baseline. Overall, baseline characteristics were well-balanced across treatment groups.
Key findings from the interim analysis include improvements in liver enzymes, with placebo-corrected reductions at 6 months of 14.3 U/L (p<0.001) and 7.9 U/L (p=0.012) in ALT and AST, respectively, in the 125mg cohort, and 10.6 U/L (p=0.004) and 4.0 (NS) in ALT and AST, respectively, in the 250mg cohort. Placebo-corrected reductions, relative to baseline, were 25% and 18% in ALT and AST, respectively, in the 125mg cohort, and 19% and 9% in ALT and AST, respectively, in the 250mg cohort. Importantly, normalization of hepatic enzymes was observed across all three dose levels of MSDC-0602K.
"We believe these interim results around improved measures of liver function and glycemic control, together with the preliminary adverse event profile, support MSDC-0602K's potential to be used in the treatment of NASH with fibrosis, including for those patients with Type 2 diabetes, a group which represents approximately 50% of patients with NASH," said Cirius' chief medical officer Howard Dittrich, M.D. "These results support the view that therapies directed toward the MPC have the potential to achieve insulin sensitizing pharmacology with an improved profile over first generation insulin sensitizers. We look forward to presenting full data to the scientific community."
In addition to the improvement in ALT and AST, observations included significant improvement at six months in fasting glucose, HbA1c, insulin levels and HOMA-IR at the 125mg and 250mg dose levels. Significant improvement in HbA1c was also observed in subjects with a diagnosis of Type 2 diabetes in the 125mg and 250mg cohorts.
In this interim analysis, the overall rate of treatment emergent adverse events was similar across placebo and all MSDC-0602K cohorts. There was a higher rate of treatment emergent adverse events reported in the 250mg dose compared to placebo in the musculoskeletal and connective tissue disorders category. Within this category, arthralgia and back pain were the most frequently reported individual adverse events across the pooled 328 subjects. A modest dose-dependent increase in body weight was seen in MSDC-0602K treated subjects, a finding seen with insulin and with other therapies that seek to improve insulin resistance. The rate of peripheral edema observed at six months was similar to that observed at baseline and was comparable across placebo and all MSDC-0602K cohorts.