MSDC-0602K (azemiglitazone) is a second-generation insulin sensitizer that was designed based on the knowledge of the activity of active metabolites of the first-generation insulin sensitizer pioglitazone. This molecule was purposely designed not to bind to PPAR transcription factors but to maintain the interaction with the mitochondrial target of pioglitazone and its metabolites, namely the mitochondrial pyruvate carrier. A one-year dose-escalating phase 2b clinical trial in subjects with biopsy-proven NASH with and without diabetes was conducted from 2016-2019. This study demonstrated similar insulin sensitizing pharmacology as pioglitazone, but without dose-liming issues at up to two times the exposures that occur with the highest approved dose of pioglitazone (45 mg). Here we have looked specifically at the 23 subjects with NASH (MASH) and type 2 diabetes who had been enrolled in the trial while on a stable dose of a GLP1 agonist (11 liraglutide, 8 dulaglutide, and 4 exenatide). A further analysis of this subset showed that any dose of azemiglitazone was able to further lower fasting glucose, insulin and liver enzymes. On average there was a further decrease in HbA1 by 0.5% (from an average baseline of 7.2%) with several subjects showing more than a 2% decrease. Of particular interest with respect to the hepatic pathology, 5 of the 19 subjects who had been on both azemiglitazone and a GLP1 agonist had a reduction in the liver fibrosis scores in the post-treatment liver biopsies. GLP1 agonists are particularly useful in producing weight loss. Some subjects who had been on a GLP1 continued to lose weight while others did not. Given the major effects of his pharmacology to improve insulin sensitivity Iin skeletal muscle and based on some existing precedent with high dose pioglitazone, maintenance of lean mass could be a component of the overall pharmacology achieved with oral metabolic modulators.
J.R. Colca: Stock/Shareholder; Cirius Therapeutics, Inc.
