A Phase 1/2a Study of the 2S,4R Enantiomer of Ketoconazole in Subjects With Type 2 Diabetes Mellitus

DiObex is developing a modified form of ketoconazole (enantiomer) (DIO-902) as an investigational new drug for the treatment of the elevated blood sugar associated with type 2 diabetes. Other benefits may include reduced total and LDL cholesterol, and reduced blood pressure. With chronic treatment, reduced visceral fat may also be seen. Ketoconazole (racemic) is an approved drug for the treatment of a variety of fungal infections. The approved racemic ketoconazole inhibits cortisol synthesis. In patients with Cushings Disease racemic ketoconazole reduces glucose, cholesterol and blood pressure. Elevated cortisol may be a contributing causal factor in the development of type 2 diabetes; clinical trials with racemic ketoconazole have been carried out in these patients. The results of these clinical trials support the concept of treating type 2 diabetes through a lowering of plasma cortisol and provide evidence of the safety and tolerability of racemic ketoconazole. Racemic ketoconazole has, however, been associated with liver toxicity which is generally mild in nature. However, in rare cases (1:10,000 to 15,000 patients) severe liver toxicity may occur, and in extremely rare cases this adverse event may be irreversible and life-threatening. Preclinical results suggest that DIO-902 may be both safer and more efficacious than the racemic mixture.