Treatment of congenital adrenal hyperplasia
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Publication Number
US-11730739-B2
Publication Date
2023-08-22
Expiration Date
Abstract
CRF1 receptor antagonists have the potential to directly inhibit ACTH release in patients with CAH and thereby allow normalization of androgen production while using lower, more physiologic doses of hydrocortisone, and thus reducing treatment-associated side effects.
Core Innovation
The invention provides a method of treating classical Congenital Adrenal Hyperplasia (CAH) by administering an effective amount of a CRF1 receptor antagonist to a subject in need thereof. The CRF1 receptor antagonist is SSR-125543, or a pharmaceutically acceptable salt thereof.
The disclosure relates CRF1 receptor antagonist activity to modulation of the HPA axis, including lowering plasma ACTH, inhibiting ACTH release, and reducing excessive androgen production in classical CAH. It presents this approach as supporting normalization of androgen production and reduced, more physiologic hydrocortisone/glucocorticoid dosing while maintaining endocrine control.
Embodiments emphasize pharmacokinetic/pharmacodynamic timing and biomarker effects, including bedtime dosing or administration 3–4 hours before expected circadian ACTH release. Reported pharmacodynamic endpoints include reduced ACTH and biomarker levels such as 17-hydroxyprogesterone (17-OHP), androstenedione, testosterone, and cortisol.
Claims Coverage
The document includes one independent claim directed to treating classical CAH by administering a CRF1 receptor antagonist, specifically SSR-125543. Dependent claims further specify subject selection by elevated pre-administration 17-OHP, reduced ACTH relative to pre-administration level, timing relative to expected circadian ACTH release, and monitoring for glucocorticoid overtreatment.
Crf1 receptor antagonist for treating classical CAH
A method of treating classical Congenital Adrenal Hyperplasia (CAH) comprising administering an effective amount of a CRF1 receptor antagonist to a subject in need thereof.
SsR-125543 as the CRF1 antagonist
The CRF1 receptor antagonist is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-(2-propyn-1-yl)-2-thiazolamine (SSR-125543), or a pharmaceutically acceptable salt thereof.
Subject selection with elevated 17-OHP
The subject has an elevated pre-administration 17-hydroxyprogesterone (17-OHP) level.
Reduced ACTH relative to pre-administration level
After administration, the subject shows a reduced ACTH level compared with the subject’s pre-administration ACTH level.
Timing relative to expected circadian ACTH release
Administering the CRF1 receptor antagonist 3–4 hours before the expected circadian release of ACTH.
Monitoring for iatrogenic Cushing's syndrome
Monitoring the subject for development of iatrogenic Cushing's syndrome caused by glucocorticoid overtreatment.
The claim coverage centers on treating classical CAH with SSR-125543 as a CRF1 receptor antagonist, with additional inventive features directed to elevated pre-treatment 17-OHP, reduced ACTH, timing relative to circadian ACTH release, and monitoring for glucocorticoid overtreatment-related iatrogenic Cushing's syndrome.
Stated Advantages
Enables inhibition of ACTH release to reduce excessive androgen production in classical CAH.
Supports normalization of androgen production.
Enables reduced, more physiologic hydrocortisone/glucocorticoid dosing.
Fewer side effects are described in the patent summary.
Clinically meaningful reductions in HPA-axis biomarkers after bedtime dosing in adult females with classical CAH.
Sustained ACTH lowering associated with longer residence time and integrated exposure.
Documented Applications
Treating classical congenital adrenal hyperplasia (CAH) by administering a CRF1 receptor antagonist, including SSR-125543.
Managing circadian ACTH dynamics by administering CRF1 receptor antagonist in relation to expected circadian ACTH release.
Treatment of classical Congenital Adrenal Hyperplasia (CAH) in a subject, supported by pharmacodynamic effects on HPA-axis biomarkers after bedtime dosing in adult females.
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