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MSDC-0602K shows glycemic control, reduces aminotransferases in NASH
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VIENNA — Interim results from a phase 2b study of MSDC-0602K for nonalcoholic steatohepatitis demonstrated significant positive effects on liver enzymes and glycemic control, according to data presented at the International Liver Congress 2019.
MSDC-0602K is a second-generation thiazolidinedione designed to selectively modulate the mitochondrial pyruvate carrier relative to PPAR-gamma, which reduces PPAR-gamma-induced adverse effects therefore mitigating the deleterious effect of nutrient excess in NASH.
“Overnutrition is a major driver of downstream metabolic signaling and so when you look at the setting of overnutrition, excess pyruvate is transported via the mitochondrial pyruvate carrier into mitochondria and this leads to metabolic disfunction,” Stephen A. Harrison, MD, from the University of Oxford in the United Kingdom, said during his presentation. “MSDC-0602K was developed to modulate [mitochondrial pyruvate carrier] and minimize direct PPAR-gamma agonism.”
Harrison and colleagues enrolled 402 patients with a nonalcoholic fatty liver disease activity score of 4 or higher and fibrosis scores between stage 1 and stage 3 in the 12-month randomized control EMMINENCE study.
Study arms included three dose groups (62.5 mg, 125 mg, and 250 mg) and a placebo cohort. The interim analysis included data from 328 patients at 6 months.
Compared with placebo, patients in the 125 mg group (27%; P < .001) and those in the 250 mg group (20.1%; P = .004) had significant reductions in alanine aminotransferase.
Patients in the 125 mg group had significant reductions in aspartate aminotransferase (21.3%; P = .012), bilirubin, alkaline phosphatase, and gamma-glutamyl transferase. This group also showed improvements in markers of fibrosis based on AST-to-platelet ratio index, cytokeratin-18 level, the Enhanced Liver fibrosis Score, Fibrosis-4 index, and FibroTest.
In a subgroup of patients with type 2 diabetes, HbA1c decreased by 0.03% in the 62.5 mg group (P = .022), 0.49% in the 125 mg group (P = .001), and 0.55% in the 250 mg group (P = .006) compared with placebo.
MSDC-0602K was well-tolerated with similar adverse event rates compared with placebo.
Harrison noted that the modest placebo corrected weight gain was expected with a potent insulin sensitizer, “but importantly, no signal for peripheral edema was seen at 6 months.”
“Trends of improved markers of fibrosis were seen at the 6-month timepoint in advance of the paired biopsy results schedule for mid-2019,” he said. “The interim data from [this] study demonstrate a significant dose dependent effect on serum aminotransferases and glycemic control of MSDC-0602K in NASH subjects with and without type 2 diabetes.” – by Talitha Bennett
Reference:
Harrison SA. Abstract PS-111. Presented at: International Liver Congress; April 10-14, 2019; Vienna, Austria.
Disclosures: Harrison reports being on the speakers bureau for AbbVie and Alexion; acting as a consultant and participating on advisory boards for Allergan, Axcella, Capulus, Echosens, CiVi Biopharma, Bristol-Myers Squibb, Chronic Liver Disease Foundation, Cirius, Corcept, Cymabay, Galmed, Genfit, Gilead, HistoIndex, Intercept, IQVIA, Madrigal, MedPace, NGM Bio, Novartis, Novo Nordisk, Perspectum, Pfizer, Pharmaceutical Product Development, Prometheus, Second Genome; and he received grant or research support from Allergan, Cirius, Conatus, Galectin, Galmed, Genfit, Gilead, Immuron, Intercept, Madrigal and NGM Bio.