New Oral Insulin Sensitizer Azemiglitazone May Preserve Lean Muscle With Weight-Loss GLP1s

Cirius Therapeutics, a clinical-stage biopharmaceutical company based in Kalamazoo, Michigan, has unveiled new promising data concerning its second-generation insulin sensitizer, azemiglitazone (MSDC-0602K). This drug, which functions through a newly identified mitochondrial target, may offer enhanced cardiometabolic benefits when paired with GLP-1 receptor agonists (GLP-1s). These findings, recently highlighted in Hepatology and presented at the European Association for the Study of Liver Disease (EASL) annual meeting in Milan, suggest significant potential for this combination therapy.

Azemiglitazone, tailored to exploit the mitochondrial pyruvate carrier (MPC) without directly activating the transcription factor PPAR-γ, provides a safer alternative to first-generation insulin sensitizers. This innovative mechanism is designed to mitigate some of the limitations associated with GLP-1 receptor agonists, such as their finite usage period and the simultaneous loss of adipose and lean mass.

At the EASL annual meeting, Cirius Therapeutics, in collaboration with Dr. Kyle McCommis’ lab at St. Louis University, shared a late-breaking poster. This presentation detailed both a post-hoc analysis of 23 patients from the Phase 2B EMMINENCE trial who had type 2 diabetes and were on a stable GLP-1 regimen, and preclinical studies involving diabetic db/db mice treated with the GLP-1 liraglutide.

Key findings from these studies include:
1. Enhanced Circulating Parameters: The addition of azemiglitazone to GLP-1 therapies improved crucial metabolic indicators, notably HbA1c and liver histology.
2. Preservation of Lean Muscle Mass: In preclinical trials, mice receiving both azemiglitazone and liraglutide exhibited significant preservation of lean body mass compared to those treated with liraglutide alone.
3. Synergistic Improvement in Glucose Tolerance: The combination therapy enhanced glucose tolerance with less increase in circulating insulin levels and improved pancreatic insulin content.
4. Increased Brown Adipose Tissue (BAT): Azemiglitazone administration, alone or with liraglutide, increased BAT levels, which are crucial for calorie burning and energy storage.

These results suggest that the combination of azemiglitazone and GLP-1 receptor agonists could optimize metabolic control, promoting healthier weight loss and maintenance. Dr. Jerry Colca, Chief Scientific Officer of Cirius Therapeutics, emphasized the unique mechanism of azemiglitazone, noting its potential to help patients lose fat without sacrificing muscle mass.

Dr. Kyle McCommis highlighted the importance of MPC in regulating metabolism across various cell types, expressing excitement for further studies on this novel mechanism. These findings could pave the way for more effective treatments of chronic metabolic diseases, including Type 2 Diabetes and MASH (Metabolic dysfunction-associated steatohepatitis).

Looking forward, Cirius Therapeutics plans to continue advancing azemiglitazone through Phase 3 clinical trials. These trials will explore its full potential as a partner to GLP-1 therapies, aiming to address the underlying pathophysiology of metabolic diseases.

Cirius Therapeutics remains committed to developing and commercializing innovative therapies targeting metabolic diseases. Their lead product, azemiglitazone, stands as a promising candidate designed to mitigate the adverse effects of overnutrition, a major contributor to various metabolic disorders. This drug's ability to modulate the mitochondrial target MPC positions it as a potential best-in-class therapy for these conditions.

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