Melanocortin subtype-2 receptor (MC2R) antagonist for the treatment of disease

Inventors

FERRARA-COOK, Christine • KRASNER, Alan S.

Assignees

Crinetics Pharmaceuticals Inc

Abstract

Provided herein are methods and compositions for the treatment of diseases of ACTH excess, such as Cushing's disease, ectopic ACTH syndrome, and congenital adrenal hyperplasia.

Core Innovation

The invention provides MC2R antagonists comprising a compound having the structure of Compound 1, or a pharmaceutically acceptable salt thereof. The disclosed compound is a potent oral small molecule with Ki <10 nM at MC2R and about 2900-fold selectivity over other human melanocortin receptors including MC1R, MC3R, MC4R, and MC5R. The approach targets the ACTH-driven pathway involved in adrenal cortisol synthesis through ACTH→MC2R/MRAP→cAMP signaling.

The background problem addressed is disorders associated with excess ACTH and elevated adrenal steroid hormones, including Cushing’s disease, ectopic ACTH syndrome (EAS), and congenital adrenal hyperplasia (CAH). The disclosed treatment is directed to reducing endogenous and ACTH-stimulated adrenal steroid hormones, especially cortisol, and also includes reductions involving A4, 17-OHP, aldosterone, and DHEAS/DHEA. The rationale is that blocking MC2R prevents ACTH-stimulated signaling that drives adrenal cortisol production.

The document further describes selecting patients based on elevated cortisol/ACTH and biomarker thresholds, and assessing pharmacodynamics using ACTH-stimulated cortisol measurements and related cortisol biomarkers. The treatment regimen is described as oral dosing once or twice daily with dosing in the range of about 5 to 300 mg, with titration based on urine free cortisol (UFC)/cortisol response. The preclinical and clinical evaluation includes suppression of corticosterone in ACTH challenge assays and suppression in repeated ACTH dosing and in an ACTH-secreting AtT-20 tumor model, and a first-in-human Phase 1 SAD/MAD trial assessing pharmacokinetics (PK) and pharmacodynamics (PD) including ACTH-stimulated serum cortisol and cortisol in saliva and urine.

Claims Coverage

The partial content identifies 2 independent claims, both centered on administering a therapeutically effective amount of a compound having the structure of Compound 1 (or a pharmaceutically acceptable salt) to reduce ACTH-stimulated cortisol levels in humans with Cushing’s disease or ectopic ACTH syndrome (EAS). Across the independent claims, the core inventive feature set is limited to MC2R antagonist administration with an efficacy criterion requiring at least about 35% reduction of ACTH-stimulated cortisol, with dependent claims tightening the reduction threshold and specifying oral dosing quantities and symptom/cortisol-measurement scopes.

Both independent claims require administering Compound 1 (or a pharmaceutically acceptable salt) to humans with Cushing’s disease or ectopic ACTH syndrome (EAS), with the treatment/endpoint defined by reducing ACTH-stimulated cortisol levels by at least about 35%. The partial dependent-claim coverage further refines the efficacy threshold (e.g., at least about 40% and at least about 45%), and expands scope to symptom reduction and cortisol assessment in specified specimen types.

Stated Advantages

Documented Applications