INSULIN RESISTANCE AND METABOLIC DISEASES

Insulin resistance is a core driver behind the chronic metabolic diseases that impact hundreds of millions of people across the globe. We believe restoring insulin response is key to truly resolving these diseases. 

With our next generation oral insulin sensitizer, azemiglitazone (MSDC-0602K), we are tackling metabolic dysfunction at its root – by re-balancing mitochondrial metabolism. Reversing insulin resistance in this way not only markedly improves glycemic control in patients with Type 2 Diabetes (T2D), it also increases lean muscle mass and shifts visceral adipose tissue and organ fat (together, “bad fat”) to metabolically beneficial subcutaneous and brown adipose tissue (together, “good fat”) in patients with a variety of metabolic diseases. 

0602K targets the mitochondrial pyruvate carrier (MPC), a recently discovered protein complex in the inner mitochondrial membrane that mediates the rate of entry of pyruvate into the mitochondria. 

MPC controls insulin response and the flow of nutrients into mitochondria, and inhibiting it can shift mitochondrial metabolism from glucose to using fatty acids and amino acids. This not only increases insulin sensitivity, but also increases mitochondrial biogenesis and function, preserves/restores lean muscle mass, and shifts “bad fat” to “good fat”. MPC inhibition has also been shown to beneficially modulate the immune system, reducing inflammation and fibrosis, even in disorders not historically considered metabolic diseases.

Optimizing for MPC-inhibition efficacy and minimizing PPARg-activation toxicity, 0602K safely builds on 1st gen former blockbuster Actos®. 0602K has demonstrated equal/better benefit as the older drug – without the edema and heart failure risks. This delivers the safer insulin sensitizer endocrinologists describe as the missing piece for patients with T2D, and a potential key to solving metabolic diseases.

In a 52-week placebo-controlled Phase 2b (N=392), 0602K markedly improved glycemic control, insulin response, fatty liver and a variety of key metabolic biomarkers, and was well tolerated. Importantly, there was no increase in edema versus placebo – even followed as a specific endpoint – or of other adverse events associated with the PPARg activation that burdened 1st generation insulin sensitizers. Having completed multiple clinical, chronic toxicity and carcinogenicity studies, and EOP2 meetings with the FDA, 0602K is poised to begin Phase 3.

GLP-1 receptor agonists (GLP-1s) and 0602K offer an ideal combination, reducing caloric intake while increasing insulin secretion (GLP-1) and insulin sensitivity (0602K). The combination not only further lowers HbA1c, particularly in patients not yet achieving their HbA1c target, but also increases lean muscle mass and shifts “bad fat” to “good fat”. These improvements in body composition may offer higher quality and more durable weight loss in patients suffering from obesity.

With complementary mechanisms, GLP-1s and 0602K in combination may further offer better options for patients with other metabolic diseases as well, such as metabolic disorder-associated steatohepatitis (MASH) or chronic kidney disease (CKD).