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US-12625150-B2 - Treatment of, and differential diagnosis between, ACTH-dependent Cushing's syndrome and ACTH-independent Cushing's syndrome

US12625150B2US 12625150 B2US12625150 B2US 12625150B2US-12625150-B2

Abstract

Methods for treating and differential diagnosis between ACTH-Dependent and ACTH-Independent Cushing's syndrome are disclosed, in which a glucocorticoid receptor antagonist (GRA) is administered to a Cushing's syndrome patient with a basal ACTH level less than about 25 pg/mL. If i) the patients blood ACTH and ii) the patients blood cortisol, or adrenal hormone, or adrenal pre-hormone levels rise, or if the ACTH:cortisol ratio increases, then ACTH-Dependent Cushing's syndrome is diagnosed. If those levels do not rise, or if the ACTH:cortisol ratio decreases, then ACTH-Independent Cushing's syndrome is diagnosed. In some instances, the patient is recovering from surgery to remove an ACTH secreting tumor, and the method described herein is used to determine if the tumor resection was successful or complete. The GRA may be mifepristone, or a non-steroidal GRA having a heteroaryl-ketone fused azadecalin backbone, an octahydro fused azadecalin backbone, a cyclohexyl pyrimidine backbone, or a fused azadecalin backbone.

Inventors

  • Andreas G. Moraitis
  • Joseph Belanoff

Assignees

  • CORCEPT THERAPEUTICS INCORPORATED

Dates

Publication Date
20260512
Application Date
20201218

Claims (16)

  1. 1 . A method of treating Cushing's syndrome in a patient and differentially diagnosing between adrenocorticotropin hormone (ACTH)-Dependent Cushing's syndrome and ACTH-Independent Cushing's syndrome during the treatment, the method comprising: (a) selecting a patient having Cushing's syndrome, having a basal level of plasma or serum cortisol, and having a basal level of plasma or serum ACTH that is between about 5 picograms per milliliter (pg/mL) and about 25 μg/mL; (b) administering to the patient for at least 6 weeks a daily dose of a glucocorticoid receptor antagonist (GRA) selected from: a dose of mifepristone of between about 300 milligrams (mg) and about 1200 mg, and a dose of between about 25 mg and about 550 mg of a GRA compound selected from the group of GRA compounds having a non-steroidal backbone consisting of a GRA compound having a cyclohexyl pyrimidine backbone, a GRA compound having a fused azadecalin backbone, a GRA compound having a heteroaryl-ketone fused azadecalin backbone, and a GRA compound having an octahydro fused azadecalin backbone, wherein said GRA administration comprises a treatment of said Cushing's syndrome; (c) measuring a level of ACTH or of cortisol in an after-GRA plasma or serum sample obtained from the patient after said at least six weeks of daily GRA administration, wherein said after-GRA sample is a plasma or serum sample corresponding to the type of sample from which the basal level was determined; and (d) determining that the patient has ACTH-Dependent Cushing's syndrome if, after said at least six weeks of daily GRA administration, one or both of the patient's ACTH levels or the patient's cortisol levels, as measured in said plasma or serum sample, are increased by at least 10% in the plasma or serum sample as compared to their respective basal levels; or (e) determining that the patient has ACTH-Independent Cushing's syndrome if, after said at least six weeks of daily GRA administration, neither the patient's ACTH level nor the patient's cortisol level are increased as compared to their respective basal levels, whereby Cushing's syndrome is further treated with said GRA administration or with surgical treatment to remove a tumor depending on the differential diagnosis between a) ACTH-Dependent Cushing's syndrome and between b) ACTH-Independent Cushing's syndrome in the patient.
  2. 2 . The method of claim 1 , wherein the patient is identified as having ACTH-Dependent Cushing's syndrome and then undergoes surgery to remove an adrenocorticotrophic hormone (ACTH) secreting tumor.
  3. 3 . The method of claim 2 , wherein the tumor is a pituitary ACTH secreting tumor.
  4. 4 . The method of claim 2 , wherein the tumor is an ectopic ACTH secreting tumor.
  5. 5 . The method of claim 1 , wherein the GRA is administered orally.
  6. 6 . The method of claim 1 , wherein the glucocorticoid receptor antagonist is mifepristone.
  7. 7 . The method of claim 1 , wherein the glucocorticoid receptor antagonist (GRA) comprises a GRA compound having a non-steroidal backbone selected from a cyclohexyl pyrimidine backbone, a fused azadecalin backbone, a heteroaryl-ketone fused azadecalin backbone, and an octahydro fused azadecalin backbone.
  8. 8 . The method of claim 7 , wherein the glucocorticoid receptor antagonist is selected from the cyclohexyl pyrimidine compound (E)-6-(4-Phenylcyclohexyl)-5-(3-trifluoromethylbenzyl)-1H-pyrimidine-2,4-dione, which has the structure: the fused azadecalin compound (R)-4-a-ethoxymethyl-1-(4-fluoro-phenyl)-6-(4-trifluoromethyl-benzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1H,1,2,6-triaza-cyclopenta[b]naphthalene, which has the structure: the heteroaryl-ketone fused azadecalin compound (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, which has the following structure: the heteroaryl-ketone fused azadecalin compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,-7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl) (thiazol-2-yl)methanone, which has the following structure: the heteroaryl-ketone fused azadecalin compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl) sulfonyl)-4, 4a, 5,6,7,8-hexahydro-1-H-pyrazolo P,4-g]isoquinolin-4a-yl) (pyridin-2-yl)methanone, which has the following structure: and the octahydro fused azadecalin compound ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl) sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl) (4-(trifluoromethyl)pyridin-2-yl)methanone, which has the structure:
  9. 9 . A method of treating Cushing's syndrome in a patient and differentially diagnosing between adrenocorticotropin hormone (ACTH)-Dependent Cushing's syndrome and ACTH-Independent Cushing's syndrome during the treatment, the method comprising: (a) selecting a patient having Cushing's syndrome, having a basal level of plasma or serum cortisol, and having a basal level of plasma or a basal level of serum ACTH having a numerical value that is between about 5 picograms per milliliter (pg/mL) and about 25 μg/mL; (b) determining a basal ACTH:cortisol ratio by dividing the numerical value of the plasma or serum basal ACTH level by a numerical value of the corresponding plasma or serum basal cortisol level to provide said basal ACTH:cortisol ratio; (c) administering to the patient for at least 6 weeks a daily dose of a glucocorticoid receptor antagonist (GRA) selected from: a dose of mifepristone of between about 300 milligrams (mg) and about 1200 mg, and a dose of between about 25 mg and about 550 mg of a GRA compound selected from the group of GRA compounds having a non-steroidal backbone consisting of a GRA compound having a cyclohexyl pyrimidine backbone, a GRA compound having a fused azadecalin backbone, a GRA compound having a heteroaryl-ketone fused azadecalin backbone, and a GRA compound having an octahydro fused azadecalin backbone, wherein said GRA administration comprises a treatment of said Cushing's syndrome; (d) measuring a level of ACTH to determine a numerical value of the ACTH level and a level of cortisol to determine a numerical value of the cortisol level in an after-GRA plasma sample or a serum sample obtained from the patient after said 6 weeks of daily GRA administration, wherein said after-GRA sample is a plasma or serum sample corresponding to the type of sample from which the basal level was determined; (e) determining an after-GRA ACTH:cortisol ratio by dividing the numerical value of the plasma or serum ACTH level measured after GRA administration by the numerical value of the corresponding plasma or serum cortisol level measured after said at least six weeks of daily GRA administration to provide said after-GRA ACTH:cortisol ratio; and differentially diagnosing between adrenocorticotropin hormone (ACTH)-Dependent Cushing's syndrome and ACTH-Independent Cushing's syndrome by comparing said basal ACTH:cortisol ratio to said after-GRA ACTH:cortisol ratio, wherein if the basal ACTH:cortisol ratio is greater than the after-GRA ACTH:cortisol ratio by at least about 10% of the basal ACTH:cortisol ratio, then the patient is diagnosed with ACTH-independent Cushing's syndrome; and if the basal ACTH:cortisol ratio is smaller than the after-GRA ACTH:cortisol ratio by at least about 10% of the basal ACTH:cortisol ratio, then the patient is diagnosed with ACTH-dependent Cushing's syndrome, whereby Cushing's syndrome is further treated with said GRA administration or with surgical treatment to remove a tumor depending on the differential diagnosis between a) ACTH-Dependent Cushing's syndrome and between b) ACTH-Independent Cushing's syndrome in the patient.
  10. 10 . The method of claim 9 , further comprising comparing the basal ACTH:cortisol ratio determined before GRA treatment with the after-GRA ACTH:cortisol ratio determined after GRA treatment to determine a change in ACTH:cortisol ratio, wherein the change in ACTH:cortisol ratio from before GRA treatment to after GRA treatment is at least about 15% of the basal ACTH:cortisol ratio.
  11. 11 . The method of claim 9 , further comprising comparing the basal ACTH:cortisol ratio determined before GRA treatment with the after-GRA ACTH:cortisol ratio determined after GRA treatment to determine a change in ACTH:cortisol ratio, wherein the change in ACTH:cortisol ratio from before GRA treatment to after GRA treatment is at least about 20% of the basal ACTH:cortisol ratio.
  12. 12 . The method of claim 9 , further comprising comparing the basal ACTH:cortisol ratio determined before GRA treatment with the after-GRA ACTH:cortisol ratio determined after GRA treatment to determine a change in ACTH:cortisol ratio, wherein the change in ACTH:cortisol ratio from before GRA treatment to after GRA treatment is greater than about 25% of the basal ACTH:cortisol ratio.
  13. 13 . The method of claim 9 , wherein the GRA is administered orally.
  14. 14 . The method of claim 9 , wherein the glucocorticoid receptor antagonist is mifepristone.
  15. 15 . The method of claim 9 , wherein the glucocorticoid receptor antagonist (GRA) comprises a GRA compound having a non-steroidal backbone selected from a GRA compound having a cyclohexyl pyrimidine backbone, a GRA compound having a fused azadecalin backbone, a GRA compound having a heteroaryl-ketone fused azadecalin backbone, and a GRA compound having an octahydro fused azadecalin backbone.
  16. 16 . The method of claim 15 , wherein the glucocorticoid receptor antagonist is selected from the cyclohexyl pyrimidine compound (E)-6-(4-Phenylcyclohexyl)-5-(3-trifluoromethylbenzyl)-1H-pyrimidine-2,4-dione, which has the structure: the fused azadecalin compound (R)-4-a-ethoxymethyl-1-(4-fluoro-phenyl)-6-(4-trifluoromethyl-benzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1H,1,2,6-triaza-cyclopenta[b]naphthalene, which has the structure: the heteroaryl-ketone fused azadecalin compound (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, which has the following structure: the heteroaryl-ketone fused azadecalin compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,-7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl) (thiazol-2-yl)methanone, which has the following structure: the heteroaryl-ketone fused azadecalin compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4, 4a, 5,6,7,8-hexahydro-1-H-pyrazolo P,4-g]isoquinolin-4a-yl) (pyridin-2-yl)methanone, which has the following structure: and the octahydro fused azadecalin compound ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl) sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl) (4-(trifluoromethyl)pyridin-2-yl)methanone, which has the structure:

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a 371 U.S. National Phase of PCT International Patent Application No. PCT/US2020/065916, filed Dec. 18, 2020, which claims priority to, and the benefit of, U.S. Provisional Patent Application Ser. No. 62/952,242, filed Dec. 21, 2019, the entire contents of which are hereby incorporated by reference in their entirety. BACKGROUND Cortisol is a steroid produced by the adrenal glands. Cortisol is used in the body to respond to physical and emotional stress, and maintain adequate energy supply and blood sugar levels. Cortisol production is highly regulated by the hypothalamic-pituitary-adrenal axis (HPA) through a complex set of direct influences and negative feedback interactions. In healthy individuals, insufficient cortisol in the bloodstream triggers the hypothalamus to release corticotropin-releasing hormone (CRH) which signals to the pituitary gland to release adrenocorticotropic hormone (ACTH), which in turn stimulates the adrenal glands to produce more cortisol. ACTH also stimulates the production and secretion of adrenal pre-hormones and other adrenal hormones (e.g., 17α-hydroxy pregnenolone, 17α-hydroxy progesterone, 11-deoxycortisol, pregnenolone, progesterone, 11-deoxycorticosterone, corticosterone, 18-hydroxycorticosterone, aldosterone, dehydroepiandrosterone (androstenolone, DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione). Excessive cortisol inhibits the hypothalamus from producing CRH, thus inhibiting the pituitary gland from releasing ACTH, which in turn suppresses cortisol production (and also reduces production of other adrenal pre-hormones and adrenal hormones). The HPA regulation also results in a diurnal rhythm of cortisol levels, reaching peaks in the morning and nadirs around midnight. Pathological conditions associated with the HPA can affect the diurnal rhythm of the cortisol and ACTH production and cause serious health problems. Impairment of the hypothalamic-pituitary-adrenal (HPA) axis due to a pituitary dysfunction disorder or an adrenal dysfunction disorder, such as adrenal insufficiency can cause deficient production or secretion of cortisol, or disorders which result in excess cortisol such as Cushing's syndrome (which may result, e.g., from hormone-secreting tumors, or administration of drugs which mimic cortisol). The biological effects of cortisol, including those caused by hypercortisolemia, can be modulated at the GR level using receptor modulators, such as agonists, partial agonists and antagonists. Several different classes of agents are able to block the physiologic effects of GR-agonist binding. These antagonists include compositions which, by binding to GR, block the ability of an agonist to effectively bind to and/or activate the GR. One such known GR antagonist, mifepristone, has been found to be an effective anti-glucocorticoid agent in humans (Bertagna (1984) J. Clin. Endocrinol. Metab. 59:25). Mifepristone binds to the GR with high affinity, with a dissociation constant (Kd) of 10-9 M (Cadepond (1997) Annu. Rev. Med. 48:129). Hypercortisolism, often referred to as Cushing's syndrome, is caused by excessive activity of the stress hormone cortisol. Endogenous Cushing's syndrome is an orphan disease that most often affects adults aged 20-50. In the United States, an estimated 20,000 patients have Cushing's syndrome, with about 3,000 new patients being diagnosed each year. Symptoms vary, but most people experience one or more of the following manifestations: high blood sugar (hyperglycemia), diabetes, high blood pressure, upper-body obesity, rounded face, increased fat around the neck, thinning arms and legs, easy bruising, facial plethora, acne, red purple stripes across the body, severe fatigue and weak muscles. Irritability, anxiety, cognitive disturbances and depression are also common. Cushing's syndrome can affect every organ system in the body and can be lethal if not treated effectively. Cushing's syndrome includes ACTH-independent Cushing's syndrome, characterized by an overproduction of cortisol in the absence of elevation of ACTH secretion; and ACTH-dependent Cushing's syndrome, characterized by excessive ACTH secretion. ACTH-Dependent Cushing's syndrome includes roughly 70% of patients having endogenous Cushing's syndrome and consists of two major forms: Cushing Disease and ectopic ACTH syndrome. The former is caused by a pituitary tumor and the latter is caused by a tumor outside the pituitary. Correct differential diagnosis between ACTH-Dependent Cushing's syndrome on the one hand, and ACTH-Independent Cushing's syndrome on the other hand, is important for endocrinologists to recommend transsphenoidal surgery (for a pituitary tumor), adrenal surgery, or appropriate imaging to localize and identify the source of the ectopic ACTH secretion. Cushing's syndrome patients may be treated by glucocorticoid receptor modulators, such as mifepristone, to reduce or block the effects of ex