Claims for Patent: 10,151,763

Summary for Patent: 10,151,763

Title:	Treatment and differential diagnosis of Cushing's disease and ectopic Cushing's syndrome
Abstract:	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.
Inventor(s):	Moraitis; Andreas G. (Menlo Park, CA)
Assignee:	Corcept Therapeutics, Inc. (Menlo Park, CA)
Application Number:	15/627,414
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,151,763
Patent Claims:	1. A method of treating a patient suffering from adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome caused by excess ACTH secretion from a tumor or due to pituitary hyperplasia, by concurrently 1) controlling hyperglycemia secondary to hypercortisolemia in the patient suffering from ACTH-dependent Cushing's syndrome and 2) differentially diagnosing Cushing's Disease from Ectopic Cushing's Syndrome in said patient, the method comprising: (i) obtaining a baseline cortisol level and a baseline ACTH level determined from one or more pretreatment samples taken from the patient; (ii) administering a glucocorticoid receptor antagonist (GRA) to the patient; (iii) continuing said administration of said GRA to the patient for a period of not less than 5 weeks, thereby treating ACTH-dependent Cushing's syndrome and controlling hyperglycemia secondary to hypercortisolemia in the ACTH-dependent Cushing's syndrome patient; (iv) obtaining a GRA-exposed ACTH level and a GRA-exposed cortisol level determined from one or more GRA-exposed samples taken from the patient; (v) calculating a baseline ratio of cortisol to ACTH ("baseline C:A ratio") using the baseline levels of cortisol and ACTH, and calculating a GRA-exposed ratio of cortisol to ACTH ("GRA-exposed C:A ratio") using the GRA-exposed cortisol level and the GRA-exposed ACTH level; and, (vi) diagnosing the patient as having Ectopic Cushing's Syndrome if the GRA-exposed C:A ratio is lower than the baseline C:A ratio, or diagnosing the patient as a having Cushing's Disease if the GRA-exposed C:A ratio is higher than the baseline C:A ratio, whereby the ACTH-dependent Cushing's syndrome is treated and differential diagnosis between Cushing's Disease and Ectopic Cushing's Syndrome is made. 2. The method of claim 1, comprising diagnosing the patient as having Ectopic Cushing's Syndrome if the GRA-exposed C:A ratio is lower than the baseline C:A ratio by at least 50% of the baseline C:A ratio, or diagnosing the patient as a having Cushing's Disease if the GRA-exposed C:A ratio is higher than the baseline C:A ratio than the baseline C:A ratio by at least 20% of the baseline C:A ratio. 3. The method of claim 1, wherein the GRA is mifepristone, and the one or more GRA-exposed samples are taken from the patient after mifepristone has been administered for a minimum of 6 weeks and on a daily basis at a dosage that does not exceed 20 mg/kg of the patient. 4. The method of claim 1, wherein the GRA is a non-steroidal GRA, and the GRA-exposed ACTH and GRA-exposed cortisol levels are determined after administration of said GRA for a minimum of 6 weeks. 5. The method of claim 1, where the one or more pretreatment samples and GRA-exposed samples are from saliva, and wherein said GRA-exposed ACTH and cortisol levels are i) determined from a first GRA-exposed saliva sample after administration of said GRA for a period of between 6 and 10 weeks, and ii) are determined from at least one further GRA-exposed saliva sample obtained after administration of the GRA for at least a further 4 weeks after said first GRA-exposed saliva sample was obtained. 6. The method of claim 1 where the one or more pretreatment samples and GRA-exposed samples are from plasma, and wherein said GRA-exposed ACTH and cortisol levels are i) determined from a first GRA-exposed plasma sample after administration of said GRA for a period of between 6 and 10 weeks, and ii) are determined from at least one further GRA-exposed plasma sample obtained after administration of the GRA for at least a further 4 weeks after said first GRA-exposed plasma sample was obtained. 7. The method of claim 1 where the one or more pretreatment samples and GRA-exposed samples are from 24-hour urine collections, and wherein said GRA-exposed ACTH and cortisol levels are i) determined from a first GRA-exposed 24-hour urine collection sample after administration of said GRA for a period of between 6 and 10 weeks, and ii) are determined from at least one further GRA-exposed 24-hour urine collection sample obtained after administration of the GRA for at least a further 4 weeks after said first GRA-exposed 24-hour urine collection sample was obtained. 8. The method of claim 1, comprising diagnosing the patient as having Ectopic Cushing's Syndrome if the GRA-exposed C:A ratio is lower than the baseline C:A ratio by at least about 60% of the baseline C:A ratio, or diagnosing the patient as a having Cushing's Disease if the GRA-exposed C:A ratio is higher than the baseline C:A ratio by at least about 100% of the baseline C:A ratio. 9. The method of claim 8 wherein the GRA is mifepristone, and the one or more GRA-exposed samples are taken from the patient after mifepristone has been administered for a minimum of 10 weeks. 10. The method of claim 1, wherein the GRA is mifepristone. 11. A method of treating a patient suffering from adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome caused by excess ACTH secretion from a tumor or due to pituitary hyperplasia, by concurrently 1) treating symptoms of diabetes associated with hypercortisolemia in the patient suffering from ACTH-dependent Cushing's syndrome and 2) differentially diagnosing Cushing's Disease from Ectopic Cushing's Syndrome in said patient, the method comprising: (i) obtaining a baseline cortisol level and a baseline ACTH level determined from one or more pretreatment samples taken from the patient; (ii) administering a glucocorticoid receptor antagonist (GRA) to the patient; (iii) continuing said administration of said GRA to the patient for a period of not less than 5 weeks, thereby treating ACTH-dependent Cushing's syndrome and controlling hyperglycemia secondary to hypercortisolemia in the ACTH-dependent Cushing's syndrome patient; (iv) obtaining a GRA-exposed cortisol level and a GRA-exposed ACTH level determined from one or more GRA-exposed samples taken from the patient; (v) calculating a baseline ratio of cortisol to ACTH ("baseline C:A ratio") using the baseline levels of cortisol and ACTH, and calculating a GRA-exposed ratio of cortisol to ACTH ("GRA-exposed C:A ratio") using the GRA-exposed cortisol and GRA-exposed ACTH levels; and, (vi) diagnosing the patient as having Ectopic Cushing's Syndrome if the GRA-exposed C:A ratio is lower than the baseline C:A ratio, or diagnosing the patient as having Cushing's Disease if the GRA-exposed C:A ratio is higher than the baseline C:A ratio, whereby the ACTH-dependent Cushing's syndrome is treated and differential diagnosis between Cushing's Disease and Ectopic Cushing's Syndrome is made. 12. The method of claim 11, wherein the GRA is a non-steroidal GRA, and the GRA-exposed ACTH and GRA-exposed cortisol levels are determined after administration of said GRA for a minimum of 6 weeks. 13. The method of claim 11 where the one or more pretreatment samples and GRA-exposed samples are from saliva, and wherein said GRA-exposed ACTH and cortisol levels are i) determined from a first GRA-exposed saliva sample after administration of said GRA for a period of between 6 and 10 weeks, and ii) are determined from at least one further GRA-exposed saliva sample obtained after administration of the GRA for at least a further 4 weeks after said first GRA-exposed saliva sample was obtained. 14. The method of claim 11 where the one or more pretreatment samples and GRA-exposed samples are from plasma, and wherein said GRA-exposed ACTH and cortisol levels are i) determined from a first GRA-exposed plasma sample after administration of said GRA for a period of between 6 and 10 weeks, and ii) are determined from at least one further GRA-exposed plasma sample obtained after administration of the GRA for at least a further 4 weeks after said first GRA-exposed plasma sample was obtained. 15. The method of claim 11 where the one or more pretreatment samples and GRA-exposed samples are from 24-hour urine collections, and wherein said GRA-exposed ACTH and cortisol levels are i) determined from a first GRA-exposed 24-hour urine collection sample after administration of said GRA for a period of between 6 and 10 weeks, and ii) are determined from at least one further GRA-exposed 24-hour urine collection sample obtained after administration of the GRA for at least a further 4 weeks after said first GRA-exposed 24-hour urine collection sample was obtained. 16. A method of treating a patient suffering from adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome caused by excess ACTH secretion from a tumor or due to pituitary hyperplasia, by concurrently 1) controlling hyperglycemia secondary to hypercortisolemia in the patient suffering from ACTH-dependent Cushing's syndrome and 2) differentially diagnosing Cushing's Disease from Ectopic Cushing's Syndrome in said patient, the method comprising: (i) obtaining a baseline cortisol level and a baseline ACTH level determined from one or more pretreatment samples taken from the patient; (ii) administering a glucocorticoid receptor antagonist (GRA) to the patient; (iii) continuing said administration of said GRA to the patient for a period of not less than 5 weeks, thereby treating ACTH-dependent Cushing's syndrome and controlling hyperglycemia secondary to hypercortisolemia in the ACTH-dependent Cushing's syndrome patient; (iv) obtaining a GRA-exposed ACTH level and a GRA-exposed cortisol level determined from one or more GRA-exposed samples taken from the patient; (v) calculating a baseline ratio of cortisol to ACTH ("baseline C:A ratio") using the baseline levels of cortisol and ACTH, and calculating a GRA-exposed ratio of cortisol to ACTH ("GRA-exposed C:A ratio") using the GRA-exposed cortisol level and the GRA-exposed ACTH level; and, (vi) diagnosing the patient as having Ectopic Cushing's Syndrome and thus an extrapituitary tumor if the GRA-exposed C:A ratio is lower than the baseline C:A ratio, or diagnosing the patient as a having Cushing's Disease and thus a) a tumor located in the pituitary, or b) hyperplasia of the pituitary, if the GRA-exposed C:A ratio is higher than the baseline C:A ratio, and treating the patient having Cushing's disease with transsphenoidal surgery to treat the pituitary tumor or pituitary hyperplasia, or treating the patient having Ectopic Cushing's Syndrome with adrenalectomy to treat the extrapituitary tumor, whereby the ACTH-dependent Cushing's syndrome is treated and differential diagnosis between Cushing's Disease and Ectopic Cushing's Syndrome is made. 17. The method of claim 16, comprising diagnosing the patient as having Ectopic Cushing's Syndrome if the GRA-exposed C:A ratio is lower than the baseline C:A ratio by at least 50% of the baseline C:A ratio, or diagnosing the patient as a having Cushing's Disease if the GRA-exposed C:A ratio is higher than the baseline C:A ratio than the baseline C:A ratio by at least 20% of the baseline C:A ratio. 18. The method of claim 16, wherein the GRA is mifepristone, and the one or more GRA-exposed samples are taken from the patient after mifepristone has been administered for a minimum of 6 weeks and on a daily basis at a dosage that does not exceed 20 mg/kg of the patient. 19. The method of claim 16, wherein the GRA is a non-steroidal GRA, and the GRA-exposed ACTH and GRA-exposed cortisol levels are determined after administration of said GRA for a minimum of 6 weeks. 20. The method of claim 16, where the one or more pretreatment samples and GRA-exposed samples are from saliva, and wherein said GRA-exposed ACTH and cortisol levels are i) determined from a first GRA-exposed saliva sample after administration of said GRA for a period of between 6 and 10 weeks, and ii) are determined from at least one further GRA-exposed saliva sample obtained after administration of the GRA for at least a further 4 weeks after said first GRA-exposed saliva sample was obtained. 21. The method of claim 16 where the one or more pretreatment samples and GRA-exposed samples are from plasma, and wherein said GRA-exposed ACTH and cortisol levels are i) determined from a first GRA-exposed plasma sample after administration of said GRA for a period of between 6 and 10 weeks, and ii) are determined from at least one further GRA-exposed plasma sample obtained after administration of the GRA for at least a further 4 weeks after said first GRA-exposed plasma sample was obtained. 22. The method of claim 16 where the one or more pretreatment samples and GRA-exposed samples are from 24-hour urine collections, and wherein said GRA-exposed ACTH and cortisol levels are i) determined from a first GRA-exposed 24-hour urine collection sample after administration of said GRA for a period of between 6 and 10 weeks, and ii) are determined from at least one further GRA-exposed 24-hour urine collection sample obtained after administration of the GRA for at least a further 4 weeks after said first GRA-exposed 24-hour urine collection sample was obtained. 23. The method of claim 16, comprising diagnosing the patient as having Ectopic Cushing's Syndrome if the GRA-exposed C:A ratio is lower than the baseline C:A ratio by at least about 60% of the baseline C:A ratio, or diagnosing the patient as a having Cushing's Disease if the GRA-exposed C:A ratio is higher than the baseline C:A ratio by at least about 100% of the baseline C:A ratio. 24. The method of claim 23 wherein the GRA is mifepristone, and the one or more GRA-exposed samples are taken from the patient after mifepristone has been administered for a minimum of 10 weeks. 25. The method of claim 16, wherein the GRA is mifepristone. 26. A method of treating a patient suffering from adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome caused by excess ACTH secretion from a tumor or due to pituitary hyperplasia, by concurrently 1) treating symptoms of diabetes associated with hypercortisolemia in the patient suffering from ACTH-dependent Cushing's syndrome and 2) differentially diagnosing Cushing's Disease from Ectopic Cushing's Syndrome in said patient, the method comprising: (i) obtaining a baseline cortisol level and a baseline ACTH level determined from one or more pretreatment samples taken from the patient; (ii) administering a glucocorticoid receptor antagonist (GRA) to the patient; (iii) continuing said administration of said GRA to the patient for a period of not less than 5 weeks, thereby treating ACTH-dependent Cushing's syndrome and controlling hyperglycemia secondary to hypercortisolemia in the ACTH-dependent Cushing's syndrome patient; (iv) obtaining a GRA-exposed cortisol level and a GRA-exposed ACTH level determined from one or more GRA-exposed samples taken from the patient; (v) calculating a baseline ratio of cortisol to ACTH ("baseline C:A ratio") using the baseline levels of cortisol and ACTH, and calculating a GRA-exposed ratio of cortisol to ACTH ("GRA-exposed C:A ratio") using the GRA-exposed cortisol and GRA-exposed ACTH levels; and, (vi) diagnosing the patient as having Ectopic Cushing's Syndrome and thus an extrapituitary tumor if the GRA-exposed C:A ratio is lower than the baseline C:A ratio, or diagnosing the patient as having Cushing's Disease and thus a) a tumor located in the pituitary, or b) hyperplasia of the pituitary, if the GRA-exposed C:A ratio is higher than the baseline C:A ratio, and treating the patient having Cushing's disease with transsphenoidal surgery to treat the pituitary tumor or pituitary hyperplasia, or treating the patient having Ectopic Cushing's Syndrome with adrenalectomy to treat the extrapituitary tumor, whereby the ACTH-dependent Cushing's syndrome is treated and differential diagnosis between Cushing's Disease and Ectopic Cushing's Syndrome is made. 27. The method of claim 26, wherein the GRA is a non-steroidal GRA, and the GRA-exposed ACTH and GRA-exposed cortisol levels are determined after administration of said GRA for a minimum of 6 weeks. 28. The method of claim 26 where the one or more pretreatment samples and GRA-exposed samples are from saliva, and wherein said GRA-exposed ACTH and cortisol levels are i) determined from a first GRA-exposed saliva sample after administration of said GRA for a period of between 6 and 10 weeks, and ii) are determined from at least one further GRA-exposed saliva sample obtained after administration of the GRA for at least a further 4 weeks after said first GRA-exposed saliva sample was obtained. 29. The method of claim 26 where the one or more pretreatment samples and GRA-exposed samples are from plasma, and wherein said GRA-exposed ACTH and cortisol levels are i) determined from a first GRA-exposed plasma sample after administration of said GRA for a period of between 6 and 10 weeks, and ii) are determined from at least one further GRA-exposed plasma sample obtained after administration of the GRA for at least a further 4 weeks after said first GRA-exposed plasma sample was obtained. 30. The method of claim 26 where the one or more pretreatment samples and GRA-exposed samples are from 24-hour urine collections, and wherein said GRA-exposed ACTH and cortisol levels are i) determined from a first GRA-exposed 24-hour urine collection sample after administration of said GRA for a period of between 6 and 10 weeks, and ii) are determined from at least one further GRA-exposed 24-hour urine collection sample obtained after administration of the GRA for at least a further 4 weeks after said first GRA-exposed 24-hour urine collection sample was obtained.