Corcept Therapeutics Incorporated

Corcept Therapeutics Incorpoarted

Andreas G Moraitis

Joseph K Belanoff

Pejman Cohan

Hazel Joan Hunt

John Francis Unitt

Stacie Shepherd

Andrew Greenstein

Pituitary tumors may be reduced in size by administration of relacorilant. Pituitary tumors include, without limitation, non-secreting tumors, hormone-secreting tumors, adenomas, and carcinomas. Relacorilant administration may be effective to reduce hormone secretion from a hormone-secreting pituitary tumor, e.g., to reduce adrenocorticotrophic hormone (ACTH) secretion. A pituitary tumor may be imaged before and/or after relacorilant administration. Relacorilant may be administered independent of surgery, and before, during, or after surgery to treat a pituitary tumor. Relacorilant may aid or improve surgical outcomes, and may reduce the size or growth of pituitary tumor tissue before surgery, and any tumor tissue remaining following surgical treatment. Relacorilant may be orally administered for the treatment of pituitary tumors. Relacorilant may be orally administered to a fasted patient, or to a fed patient. Relacorilant may be administered in conjunction with other pituitary tumor targeting treatments, including surgical treatments, radiation treatments, chemotherapy for carcinomas, and other pharmaceutical treatments.

Methods for shrinking pituitary tumors

Methods for treating, identifying and localizing tumors expressing somatostatin receptors (SRs), including methods of enhancing the efficacy of imaging techniques by administration of a heteroaryl-ketone fused azadecalin glucocorticoid receptor modulator (HKGRM) effective to increase SR expression in tumors. HKGRM administration for enhancing SR-based tumor imaging and treating neuroendocrine tumors. HKGRM and somatostatin or somatostatin analog combination therapy for treating and enhancing SR-based tumor imaging.

Methods for imaging and treatment of somatostatin-receptor positive tumors

Applicant discloses methods for treating a glucocorticoid receptor positive (GR) neuroepithelial tumor in a subject, comprising administering a selective glucocorticoid receptor modulator (SGRM) in an amount effective to reduce the tumor load in a subject. The GRneuroepithelial tumor may be a neurofibromatosis type 2 (NF 2) tumor; the GRneuroepithelial tumor may be a schwannoma, meningioma, or ependymoma. In embodiments, the GRneuroepithelial tumor is not an adrenocorticotropic hormone (ACTH)-secreting tumor. In embodiments, the SGRM comprises a steroidal backbone. In embodiments, the SGRM is mifepristone. In embodiments, the SGRM comprises a non-steroidal backbone, such as, e.g., a cyclohexyl pyrimidine, a fused azadecalin, a heteroaryl ketone fused azadecalin, or an octahydro fused azadecalin backbone. The SGRM may be administered orally. The SGRM may be administered alone. In embodiments, the SGRM is administered with at least one non-SGRM therapy, e.g., a chemotherapy, a radiation therapy, or other therapeutic agents.

Methods of treating neuroepithelial tumors using selective glucocorticoid receptor modulators

Novel methods for preventing, reducing the risk of development of, and for treating hypercoagulopathy in Cushing's syndrome patients with elevated risk of developing hypercoagulopathy are disclosed. The methods are further useful to prevent, to reduce the risk of developing, and to treat deep vein thrombosis (DVT), pulmonary embolism (PE), and venous thromboembolism (VTE); and to treat inflammatory states. The methods include: administering heteroaryl-ketone fused azadecalin glucocorticoid receptor modulator (HKGRM) to a Cushing's syndrome patient at risk of developing hypercoagulopathy, thereby treating hypercoagulopathy. Methods of preventing, reducing risk of developing, and of treating DVT, PR, or VTE in a Cushing's syndrome patient comprise administering a HKGRM to the patient. Methods of unmasking and subsequently reducing an inflammatory state comprise administering an effective amount of a HKGRM to a Cushing's syndrome patient, effective first to increase inflammatory symptoms and then to subsequently decrease said inflammatory symptoms in the patient.

Treatment of hypercoagulopathy in Cushing's syndrome by administration of glucocorticoid receptor modulators

Methods and compositions are disclosed for diagnosing a patient suspected of suffering from, and for treating a patient suffering from, a disorder such as hypercortisolemia, metabolic syndrome, pre-diabetes, diabetes, Cushing's syndrome, Cushing's Disease, hyperglycemia secondary to hypercortisolemia, a liver disease, a cardiac disorder, high blood pressure, a blood clotting disorder, a cancer, a psychological disorder, weight gain, a disorder of glucose control, a bone disorder (e.g., osteoporosis), hypogonadism, pseudoacromegaly, pituitary tumors, functional hypercortisolism, ACTH secreting tumors, peripheral neuropathy, dyslipidemia and other disorders. The methods and compositions include administration of a heteroaryl-ketone fused azadecalin glucocorticoid receptor modulator (GRM). The preferred heteroaryl-ketone fused azadecalin GRM is relacorilant ((R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone). In some cases, the GRM (e.g., relacorilant) is orally administered. In some cases, the GRM (e.g., relacorilant) is orally administered without food.

Therapeutic uses of relacorilant, a heteroaryl-ketone fused azadecalin glucocorticoid receptor modulator

This invention provides for a method of treating secondary adrenal insufficiency by co-administrating therapeutically effective amounts of a glucocorticoid and a glucocorticoid receptor antagonist to the patient in need thereof. In some embodiments, the method includes the proviso that the patient not be otherwise in need of treatment with a glucocorticoid and a glucocorticoid receptor antagonist. The treatment method can increase the patient's morning or basal cortisol level to at least about 12 μg/dL or a standard control level, and in turn, expedite significantly the recovery of the HPA axis. The method provided herein can improve health outcomes and life-threatening complications associated with secondary adrenal insufficiency.

Use of glucocorticoid receptor antagonists in combination with glucocorticoids to treat adrenal insufficiency

Applicant discloses methods for treating a glucocorticoid receptor positive (GR) neuroepithelial tumor in a subject, comprising administering a selective glucocorticoid receptor modulator (SGRM) in an amount effective to reduce the tumor load in subject. The GRneuroepithelial tumor may be a neurofibromatosis type 2 (NF 2) tumor; the GRneuroepithelial tumor may be a schwannoma, meningioma, or ependymoma. In embodiments, the GRneuroepithelial tumor is not an adrenocorticotropic hormone (ACTH)-secreting tumor. In embodiments, the SGRM comprises a steroidal backbone. In embodiments, the SGRM is mifepristone. In embodiments, the SGRM comprises a non-steroidal backbone, such as, e.g., a cyclohexyl pyrimidine, a fused azadecalin, a heteroaryl ketone fused azadecalin, or an octahydro fused azadecalin backbone. The SGRM may be administered orally. The SGRM may be administered alone. In embodiments, the SGRM is administered with at least one non-SGRM therapy, e.g., a chemotherapy, a radiation therapy, or other therapeutic agents.

This invention provides new methods for a) identifying Cushing's Syndrome patients at high risk of developing hypokalemia during glucocorticoid receptor modulator (GRM) treatment, and b) for prophylactically treating such patients to prevent, or reduce the severity of, hypokalemia. Patients at such high risk may be identified prior to their developing hypokalemia. Such a patient may be an adult patient with endogenous Cushing's Syndrome having type 2 diabetes mellitus or glucose intolerance to control hyperglycemia secondary to hypercortisolism. Patients may be identified by an above-threshold level of ACTH or cortisol in a patient sample taken post-GRM administration or pre-GRM administration, respectively. Upon identifying such a patient prior to the development of low potassium, the present methods provide for prophylactically treating the patient by administration of one or more hypokalemia treatments concurrently with an increased dose of GRM or with an initial dose of GRM to prevent hypokalemia.

Use of cortisol in assessment and prophylactic treatment of hypokalemia associated with glucocorticoid receptor modulator treatment of Cushing's syndrome patients

Novel methods for treating cancer include: administering a glucocorticoid receptor modulator (GRM) to a patient, and determining whether or not the expression level of a gene is decreased in comparison with baseline levels of the gene measured in the patient prior to the GRM administration, thereby identifying a patient as being likely to benefit from cancer chemotherapy in conjunction with GRM administration where the expression level of a gene following GRM administration is decreased in comparison with corresponding gene baseline levels; and administering to said identified patient a combination of a GRM and cancer chemotherapy, whereby the cancer is treated in the patient. The GRM may be selected from relacorilant, CORT125281, CORT122928, and CORT113176. The cancer chemotherapy agent may be a taxane. The gene expression level measured may be selected from 50 identified genes, and may be selected from COX2, DUSP1, GSK3b, MCL-1, PIK3CG, RGS-2, SGK1, and STAT3.

Methods of treating cancer comprising administration of a glucocorticoid receptor modulator and a cancer chemotherapy agent

Improved methods and systems for diagnosing and for treating Cushing's syndrome and Cushing's Disease are provided herein, including methods and systems for concurrently treating Cushing's syndrome and differentially diagnosing Cushing's Disease from Ectopic Cushing's Syndrome in a patient with an established diagnosis of ACTH-dependent Cushing's syndrome. Treatment methods can use glucocorticoid receptor antagonists (GRAs), which differentially affect the ratio of cortisol to ACTH levels in patients having Cushing's Disease versus patients having Ectopic Cushing's Syndrome. Methods for concurrently treating and differentially diagnosing Cushing's Disease from Ectopic Cushing's Syndrome include obtaining baseline cortisol and ACTH levels of a patient, treating the patient with a GRA according to a protocol that would typically substantially elevate cortisol levels, obtaining post-treatment cortisol and ACTH levels of the patient, determining a differential relationship between baseline cortisol and ACTH levels and post-treatment cortisol and ACTH levels and providing a positive diagnosis based on the differential relationship.

Treatment and differential diagnosis of Cushing's disease and ectopic Cushing's syndrome

Methods are provided for assessing a clinical response to a glucocorticoid receptor antagonist (GRA) in a human subject and for diagnosing Cushing's syndrome.

Growing community of inventors

Menlo Park, CA, United States of America

Andreas G Moraitis