Treatment of, and differential diagnosis between, ACTH-dependent Cushing's syndrome and ACTH-independent Cushing's syndrome
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.
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 . 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 . The method of claim 2 , wherein the tumor is a pituitary ACTH secreting tumor.
4 . The method of claim 2 , wherein the tumor is an ectopic ACTH secreting tumor.
5 . The method of claim 1 , wherein the GRA is administered orally.
6 . The method of claim 1 , wherein the glucocorticoid receptor antagonist is mifepristone.
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 . 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 . 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 . 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 . 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 . 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 . The method of claim 9 , wherein the GRA is administered orally.
14 . The method of claim 9 , wherein the glucocorticoid receptor antagonist is mifepristone.
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 . 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: