Because excessive cortisol actively plays a role in weight gain and has other adverse metabolic effects we believe that our pipeline of selective cortisol (GR-II) receptor antagonists may have utility in addressing weight gain and other metabolic disorders.

For example, we believe that if GR-II antagonists can prevent weight gain commonly associated with the use of certain antipsychotic drugs they could provide a significant health and quality-of-life benefit for patients taking these medications. The group of medications known as atypical antipsychotics, including Zyprexa® (olanzapine), Risperdal® (risperidone), Clozaril® (clozapine) and Seroquel® (quetiapine), are widely used to treat schizophrenia and bipolar disorder. All medications in this group are associated with treatment-emergent weight gain of varying degrees and carry a warning in their labels relating to treatment-emergent hyperglycemia and diabetes mellitus. Because of the profound metabolic effects associated with use of these antipsychotics over a relatively short duration of use, there may be an opportunity to demonstrate prevention or treatment of these side effects with an efficient development program which will also provide proof of concept for the mechanism in a broader range of other metabolic diseases.

To test this hypothesis, we conducted clinical and preclinical studies of mifepristone to investigate whether the regulation of cortisol activity through the blockade of the cortisol receptor may have utility in the mitigation of weight gain caused by atypical antipsychotics.

• In a rat study, mifepristone both reduced the weight gain associated with the ongoing use of olanzapine (the active ingredient in Zyprexa®) and mitigated the weight gain associated with the initiation of treatment with olanzapine
• Corcept has conducted two preliminary, short-term, proof of concept studies to evaluate the use of mifepristone to prevent weight gain associated with antipsychotic medications. In lean, healthy human male volunteers, the studies demonstrated a beneficial impact on weight gain and other metabolic measures.

To further test our hypothesis, we conducted clinical and pre-clinical studies with several of our new compounds. The animal studies we have completed so far have demonstrated that these compounds have the potential both to reduce weight gain caused by olanzapine and to prevent weight-gain caused by initiation of treatment with olanzapine. The two studies were conducted in the rat model of olanzapine-induced weight gain described above, in which mifepristone was tested with olanzapine. In addition, one compound has produced statistically significant results in the prevention of weight gain and insulin insensitivity in mice fed a high fat, high sucrose diet.

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