MSDC-0602K improves liver enzymes, glycemic control in NASH with diabetes
BOSTON — Treatment with MSDC-0602K safely produced positive effects on glycemic control along with consistent improvement in liver enzymes and noninvasive hepatic markers in patients with nonalcoholic steatohepatitis and type 2 diabetes, according to data presented at The Liver Meeting 2019.
“When we talk about NASH, we talk about a disease that’s in the setting of overnutrition. Overnutrition can result in insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease and NASH, which frequently coexist,” Stephen A. Harrison, MD, medical director of Pinnacle Clinical Research in San Antonio, said during his presentation. “MSDC-0602K ... may represent a potential option to treat these disorders.”
MSDC-0602K (Cirius Therapeutics) is a second-generation thiazolidinedione designed to avoid peroxisome proliferator-activated receptor gamma (PPAR-gamma) related side effects.
Harrison said that the site of action for MSDC-0602K is the mitochondrial pyruvate center (MPC).
“In the setting of overnutrition, excessive pyruvate enters the mitochondria via this carrier. MSDK-0602K slows pyruvate entry into the citric acid cycle, and by doing so it normalizes the rest of metabolism, ultimately improving de novo lipogenesis and increased fatty live oxidation and improving insulin sensitivity,” he said.
The 12-month EMMINENCE study comprised 392 patients with NASH and fibrosis randomly assigned to 62.5 mg, 125 mg or 250 mg of daily oral MSDC-0602K or placebo. At least 50% of patients had fibrosis stage 2 or stage 3.
Post-hoc analysis showed that patients in the 250 mg group achieved the primary endpoint of histologic improvement in NAFLD Activity Score (NAS) of 2 points with no worsening of fibrosis compared with placebo (42.6 vs. 27.7; P = .029). Additionally, the 250 mg group met the exploratory endpoint of NASH resolution including 2-point reduction in NAS with no worsening of fibrosis compared with placebo (26.7% vs. 13.8%; P = .026).
Regarding liver enzymes, 20.8% of those in the 150 mg group (P = .019) and 33.3% of those in the 250 mg group (P < .001) achieved alanine aminotransferase normalization compared with baseline.
Both groups also showed improvements in aspartate aminotransferase and alkaline phosphatase (both, P < .0001), gamma-glutamyl transferase (150 mg, P < .0003; 250 mg, P < .0001), HbA1c (both, P < .001), fasting insulin (both, P < .001), and fasting glucose (150 mg, P < .01; 250 mg, P < .05).
MSDC-0602K was well-tolerated with numerically higher discontinuation rates among controls compared with treatment groups. The number of adverse and serious adverse events were similar across all groups including edema, bone fractures and hypoglycemia, which are known PPAR-gamma related side effects.
“Twelve-month results demonstrate that the mitochondrial pyruvate center modulator MSDC-0602K is a potent and well tolerated insulin sensitizer with effects on glycemic control, liver injury, and histology,” Harrison concluded. – by Talitha Bennett
Reference: Harrison SA, et al. Abstract LO1. Presented at: The Liver Meeting; Nov. 7-12, 2019; Boston.
Disclosure: Harrison reports he is a consultant for 3VBio, Akero, Albereo, Axcella, Blade Therapeutics, Bristol-Myers Squibb, Cirius, Civi, CLDF, ConSynance, ContraVir, Corcept, CymaBay, Echosens, Galectin, Galmed, Gilead, HighTide, HistoIndex, Innovate, Intercept, IQVIA, Lipocine, Madrigal, Medpace, Metacrine, NGM, Novartis, Novo Nordisk, Perspectum, Pfizer, Poxel, PPD, Prometheus, Prometic and Terns; is on the speakers bureau with Alexion; and has received research support from Allergan, Axcella, Cirius, Conatus, CymaBay, Galectin, Galmed, Genfit, Gilead, HighTide, Immuron, Intercept, Madrigal, NGM, Novartis, Novo Nordisk, Pfizer, Second Genome and Tobira.