Treatment of congenital adrenal hyperplasia
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Publication Number
US-11311544-B2
Publication Date
2022-04-26
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 relates to a method of treating Congenital Adrenal Hyperplasia (CAH) in a subject in need thereof already being treated with a glucocortocoid. The method administers an effective amount of a CRF1 receptor antagonist, including SSR-125543 or a pharmaceutically acceptable salt thereof, to inhibit CRF1-mediated signaling associated with ACTH release.
The disclosure further relates to isotopically labeled CRF1 receptor antagonist compounds, including deuterated CRF1 antagonists and other stable or radioactive isotopes substituted into the compounds. Isotopic substitution, particularly deuterium (2H), may improve metabolic stability and half-life of CRF1 antagonist compounds, and isotopes including 3H and 14C are referenced.
Embodiments describe dosing aligned with circadian release of ACTH, including bedtime or pre-circadian administration prior to expected ACTH release. The document also characterizes CRF1 antagonists using dissociation half-life values and discusses pharmacodynamic effects in adrenalectomized rats and human studies, including reductions in ACTH, 17-OHP, and corticosterone.
Claims Coverage
The consolidated claim coverage identifies two independent claim themes. One centers on treating CAH in a subject already being treated with a glucocortocoid by administering a CRF1 receptor antagonist, specifically SSR-125543 or a pharmaceutically acceptable salt. The other centers on isotopically labeled CRF1 receptor antagonist compounds, with dependent refinements addressing dosing timing and CAH subgroups.
Treating ca h already on glucocorticoid with crf1 receptor antagonist
A method of treating Congenital Adrenal Hyperplasia (CAH) in a subject in need thereof already being treated with a glucocortocoid, comprising administering an effective amount of a CRF1 receptor antagonist, including SSR-125543 or a pharmaceutically acceptable salt thereof.
Isotopically labeled crf1 receptor antagonist compounds
CRF1 receptor antagonist compounds comprising isotopic substitution, including deuterated compounds and other stable or radioactive isotopes, with isotopes including 3H and 14C referenced.
Reducing glucocorticoid dose after crf1 receptor antagonist administration
The method wherein the dose of a glucocorticoid is reduced by at least 20% after administering a CRF1 receptor antagonist.
Classical ca h patient selection
The method wherein the CAH is classical CAH.
CYP21A2 mutation at chromosome 6p21
The method wherein the subject has a mutation in the CYP21A2 gene located on chromosome 6p21.
Excluding 11β2-hydroxylase mutation
The method wherein the subject does not have a mutation in the 11β2-hydroxylase gene CYP11B1 (11β2-OH CAH).
Bedtime administration
The method wherein the CRF1 receptor antagonist is administered at bedtime.
Overall, the claim coverage centers on CAH treatment in subjects already receiving a glucocortocoid by administering a CRF1 receptor antagonist, specifically SSR-125543, with dependent refinements for glucocorticoid dose reduction, CAH classification, genetic inclusion or exclusion criteria, bedtime administration, and isotopically labeled CRF1 receptor antagonist compounds.
Stated Advantages
Isotopic substitution, especially deuterium, may improve metabolic stability and half-life of CRF1 antagonist compounds.
CRF1 antagonism reduces ACTH and related biomarkers such as 17-OHP and corticosterone, supporting CAH treatment.
Normalization of androgen production via inhibition of ACTH release.
In some cases, permitting reduction of glucocortocoid dosing to reduce side effects.
Documented Applications
Treatment of Congenital Adrenal Hyperplasia (CAH), including use in the setting of patients already being treated with a glucocorticoid and with circadian-targeted dosing prior to ACTH release.
Pharmacodynamic evaluation of CRF1 antagonism in adrenalectomized rats by measuring reductions in ACTH and biomarkers such as 17-OHP.
Human study contexts in which reductions in ACTH and related biomarkers support CRF1 antagonist use for CAH.
Monitoring ACTH and 17-OHP as outcomes during treatment.
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