SFEBES2022 Poster Presentations Neuroendocrinology and Pituitary (72 abstracts)
CRN04894: an oral, nonpeptide adrenocorticotropic hormone (ACTH) receptor antagonist decreases basal and stimulated cortisol secretion in healthy volunteers
Peter Trainer 1 , Christine Ferrara-Cook 1 , Alejandro Ayala 1 , Rosa Luo 1 , Stephanie Miller 1 , Yang Wang 1 , Martha Hernandez-Illas 2 , R. Scott Struthers 1 , Stephen Betz 1 & Alan Krasner 1
1Crinetics Pharmaceuticals, San Diego, USA; 2QPS Miami, Miami, USA
CRN04894 is a potent, orally bioavailable nonpeptide that is a highly selective antagonist for melanocortin type 2 receptor (MC2R). This receptor is found exclusively in the adrenal cortex and is the primary mediator of adrenal activation. We report results from a randomized, double-blinded, placebo-controlled (6 active:3 placebo/cohort), multiple ascending dose (40, 60, and 80 mg) study in health volunteers evaluating safety, pharmacokinetics, and pharmacodynamics of oral, once-daily CRN04894 administered at 22:00 for 10 days. Serum cortisol was measured daily at 08:00; circadian rhythm studies were undertaken at baseline and days 1-2, 4-5, 9-10. A 1 mg ACTH (1-24) test was undertaken on day 11, 8 hours post CRN04894 last dose. The protocol defined glucocorticoid deficiency as 08:00 cortisol of <138 nmol/l which triggered the addition of oral replacement hydrocortisone to ongoing CRN04894 dosing. CRN04894 was rapidly, orally absorbed (Tmax 0.5-1.5 hour), and demonstrated a dose dependent increase in systemic exposure, with a T1/2 of ~24 hours. In the 80 mg cohort: mean 24-hour AUC for serum cortisol and androstenedione fell by 51% and 40%, respectively, at day 10 compared to baseline; median 24-hour urinary-free cortisol (UFC) decreased by 75%, while 24-hour mean ACTH AUC increased ~5-fold compared to baseline; peak cortisol in response to the day 11 ACTH stimulation test was <500 nmol/l in all subjects. These analyses include data from 2 subjects receiving replacement hydrocortisone. All adverse events (AEs) were considered mild or moderate with no serious AEs. Glucocorticoid deficiency was the most common treatment-related AE (n=11), although no patients had symptoms of adrenal insufficiency. In summary, CRN04894 in healthy volunteers was well tolerated and resulted in meaningful suppression of cortisol and androstenedione secretion despite exposure to persistent elevated endogenous ACTH levels. Studies are planned in patients with ACTH-dependent Cushing’s syndrome and congenital adrenal hyperplasia.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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