METHODS OF TREATING CONGENITAL ADRENAL HYPERPLASIA
Patients with congenital adrenal hyperplasia (CAH) need adequate care and treatment in order to lead normal lives. Hence, there is a need for new methods of treating CAH. This disclosure provides new compounds, salts, compositions and uses thereof in the treatment of CAH.
1 . A method of treating Congenital Adrenal Hyperplasia (CAH), comprising administering a glucocorticoid or a pharmaceutically acceptable salt thereof, and a corticotropin-releasing factor type-1 (CRF 1 ) antagonist to a subject in need thereof, wherein the CRF 1 antagonist is SSR125543 or (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine, or a pharmaceutically acceptable salt thereof,
wherein when said subject has a level of androstenedione (A4) that is less than two times an upper limit of a reference range of A4 and a level of adrenocorticotropic hormone (ACTH) that is less than two times an upper limit of a reference range of ACTH, a dose of said glucocorticoid or a pharmaceutically acceptable salt thereof is reduced compared to a dose of said glucocorticoid or a pharmaceutically acceptable salt thereof administered to a CAH patient that does not receive said CRF 1 antagonist or a pharmaceutically acceptable salt thereof, and
wherein the subject is in a fed state.
2 . The method of claim 1 , wherein the CRF 1 antagonist is SSR125543, or a pharmaceutically acceptable salt thereof.
3 . The method of claim 1 , wherein the CRF 1 antagonist is (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine, or a pharmaceutically acceptable salt thereof.
4 . The method of claim 1 , wherein the glucocorticoid is beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, or triamcinolone.
5 . The method of claim 1 , wherein the subject is an adult.
6 . The method of claim 1 , wherein the CRF 1 antagonist is orally administered twice daily.
7 . The method of claim 6 , wherein the CRF 1 antagonist is administered at a dose of about 10 mg to about 200 mg total daily dose to the subject.
8 . The method of claim 7 , wherein the CRF 1 antagonist is administered at a dose of about 200 mg total daily dose to the subject.
9 . The method of claim 7 , wherein the CRF 1 antagonist is administered at a dose of about 100 mg total daily dose to the subject.
10 . The method of claim 7 , wherein the CRF 1 antagonist is administered at a dose of about 50 mg total daily dose to the subject.
11 . The method of claim 1 , wherein the CRF 1 antagonist is administered in the evening.
12 . The method of claim 11 , wherein the CRF 1 antagonist is administered less than about 3 hours before sleep.
13 . The method of claim 12 , wherein the CRF 1 antagonist is administered less than about 1 hour before sleep.
14 . The method of claim 6 , wherein the CRF 1 antagonist is formulated as a capsule.
15 . The method of claim 1 , wherein administering the CRF 1 antagonist reduces a plasma concentration of one or more biomarkers comprising 17-hydroxyprogesterone (17-OHP), adrenocorticotropic hormone (ACTH), androstenedione (A4), or a combination thereof.
16 . The method of claim 15 , wherein the one or more biomarkers is ACTH, A4, or both.
17 . The method of claim 1 , wherein prior to the administering the subject has a plasma concentration of 17-OHP that is at least twice the upper normal limit of 17-OHP.
18 . The method of claim 17 , wherein prior to the administering the subject has a plasma concentration of 17-OHP that is at least four times the upper normal limit of 17-OHP.