1 Hepatology, Radcliffe Department of Medicine, University of Oxford, UK. Electronic address: email@example.com.
2 Texas Liver Institute, San Antonio, TX, USA.
3 Momentum Research, Inc., Durham, NC, USA.
4 Virginia Commonwealth University School of Medicine, Richmond, VR, USA.
5 Cirius Therapeutics, Inc., San Diego, CA, USA.
6 NAFLD Research Center, University of California at San Diego, La Jolla, CA, USA.
7 University of Florida, Gainesville, FL, USA.
8 Pendulum Therapeutics, San Francisco, CA, USA.
BACKGROUND & AIMS:
MSDC-0602K is a novel insulin sensitizer designed to preferentially target the mitochondrial pyruvate carrier while minimizing direct binding to the transcriptional factor PPARγ. Herein, we aimed to assess the efficacy and safety of MSDC-0602K in patients with non-alcoholic steatohepatitis.
Patients with biopsy-confirmed NASH and fibrosis (F1-F3) were randomized to daily oral placebo, or 1 of 3 MSDC-0602K doses in a 52-week double-blind study. The primary efficacy endpoint was hepatic histological improvement of ≥2 points in non-alcoholic fatty liver disease activity score (NAS) with a ≥1-point reduction in either ballooning or lobular inflammation and no increase in fibrosis stage at 12?months. Secondary endpoints included NAS improvement without worsening fibrosis, NASH resolution, and fibrosis reduction. Exploratory endpoints included changes in insulin sensitivity, liver injury and liver fibrosis markers.
Patients were randomly assigned to placebo (n?=?94), or 62.5?mg (n?=?99), 125?mg (n?=?98), or 250?mg (n?=?101) of MSDC-0602K. At baseline, glycated hemoglobin was 6.4?±?1.0%, 61.5% of patients had fibrosis F2/F3 and the average NAS was 5.3. The primary endpoint was reached in 29.7%, 29.8%, 32.9% and 39.5% of patients in the placebo, 62.5?mg, 125?mg and 250?mg dose arms, respectively, with adjusted odds ratios relative to placebo of 0.89 (95% CI 0.44-1.81), 1.22 (95% CI 0.60-2.48), and 1.64 (95% CI 0.83-3.27). The 2 highest doses of MSDC-0602K led to significant reductions in glucose, glycated hemoglobin, insulin, liver enzymes and NAS compared to placebo. The incidence of hypoglycemia and PPARγ-agonist-associated events such as edema and fractures were similar in the placebo and MSDC-0602K groups.
MSDC-0602K did not demonstrate statistically significant effects on primary and secondary liver histology endpoints. However, effects on non-invasive liver cell injury and measures of glucose metabolism support further exploration of MSDC-0602K's safety and potential efficacy in patients with type 2 diabetes and liver injury. [ClinicalTrials.gov Identifier: NCT02784444].
First-generation insulin sensitizers are used to treat type 2 diabetes, but are associated with side effects including edema, bone fractures, and hypoglycemia. MSDC-0602K is a second-generation insulin sensitizer designed to reduce these side effects. We hypothesized that insulin sensitization could improve non-alcoholic steatohepatitis. In the current study of patients with non-alcoholic steatohepatitis, MSDC-0602K did not demonstrate significant effects on liver histology with the biopsy techniques used. However, useful information was gained for the design of future studies and MSDC-0602K significantly decreased fasting glucose, insulin, glycated hemoglobin, and markers of liver injury without dose-limiting side effects.