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VITAE PHARMACEUTICALS, INC filed this Form S-1 on 08/12/2014
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tissues. We believe inhibition of cortisol activation should increase glucose uptake in muscle and adipose tissue, decrease hepatic glucose production and offer a new therapeutic option in type 2 diabetes with metabolic syndrome.

        Using Contour, we have discovered potent, selective 11b HSD1 inhibitors in collaboration with BI. We optimized these compounds for inhibiting the isolated enzyme and inhibiting the conversion of cortisone to cortisol in biopsies of human adipose tissue and selected VTP-34072 for further development. In Phase 1 clinical trials involving 142 individuals conducted by BI, VTP-34072 was found to be safe and well tolerated in a single ascending dose trial and an ascending two week daily dosing trial. In these clinical trials, VTP-34072 inhibited 11b HSD1 enzyme activity in adipose tissue by greater than 90% at multiple dose levels at 24 hours after the last dose, and demonstrated a long half-life in plasma, which we believe is consistent with once-a-day dosing in humans. A Phase 2 clinical trial in obese patients with type 2 diabetes is expected to commence in July 2014, with data expected in the first half of 2015.

    Cortisol in Metabolic Disease

        Two diseases, Cushing's syndrome and Addison's disease, support the role of cortisol in metabolic syndrome. In Cushing's syndrome, patients have high levels of cortisol which causes many of the same morbidities that afflict metabolic syndrome patients, including visceral obesity, abdominal obesity, high TGs, low HDL-C, elevated blood pressure and elevated glucose levels, with Cushing's Syndrome patients being predisposed to having overt diabetes. Conversely, in Addison's disease, which is caused by a deficiency in cortisol, patients have decreased hepatic glucose production and hypoglycemia, or low blood glucose. Rodent models of metabolic syndrome also provide support for the role of elevated cortisol levels in metabolic syndrome. Rodents with elevated levels of corticosteroids have impaired glucose uptake in muscle and adipose tissue, and enhanced liver glucose production.

    11b HSD1 as a Target in Type 2 Diabetes and Metabolic Syndrome

        As shown in the Figure 1 below, 11b HSD1 catalyzes the conversion of inactive cortisone to the active steroid hormone, cortisol. 11b HSD1 is highly expressed in most tissues, including liver, adipose and brain tissue and is the only enzyme known to generate cortisol from cortisone in peripheral tissues. Another enzyme, 11b HSD2, catalyzes the reverse reaction, inactivating cortisol and converting it to cortisone. 11b HSD2 is expressed in the kidney, sweat and salivary glands. Its main biological role is to protect the kidney from excess cortisol.


Figure 1: The interconversion between inactive cortisone and active cortisol is mediated by two distinct enzymes, 11b HSD1 and 11b HSD2.

        We believe that 11b HSD1 inhibition in metabolic syndrome patients will protect them from progression to type 2 diabetes and the associated atherosclerotic vascular disease, also known as hardening of the arteries, by lowering their liver and adipose tissue cortisol levels, without lowering cortisol levels in the blood. This tissue specific lowering of cortisol levels, without lowering blood levels, is important to prevent treated patients from developing symptoms of Addison's disease. The beneficial effects of