CRN04894: an oral, nonpeptide ACTH (MC2) receptor antagonist decreaseds basal and stimulated cortisol secretion in healthy volunteers
P. Trainer*a (Prof), C. Ferrara-Cooka (Dr), A. Ayalaa (Dr), R. Luob (Ms), S. Millera (Ms), Y. Wanga (Mr), M. Hernandez-Illasc (Dr), S. Sturthersd (Dr), S. Betzd (Dr), A. Krasnerd (Dr)
a Crinetics Pharmaceuticals, San Diego, UNITED STATES ; b Crinetics Pharmaceuticals, San Deigo, UNITED STATES ; c QPS, Miami, UNITED STATES ; d Crinetics, San Diego, UNITED STATES
CRN04894 is a potent, orally bioavailable, nonpeptide Melanocortin type 2 Receptor (MC2R) antagonist that is >1000-fold selective for MC2R (exclusively expressed in the adrenal cortex) over other MCR subtypes.
We report results from a randomized, double-blinded, placebo-controlled (6 active:3 placebo/cohort), multiple ascending dose (40, 60 & 80 mg) study in health volunteers evaluating the safety, pharmacokinetics, and pharmacodynamics of oral, once-daily CRN04894 administered at 22:00 for 10 days. Serum cortisol was measured daily at 08:00 and circadian rhythm studies were undertaken at baseline and on days 1-2, 4-5, 9-10. An IV 1 mcg ACTH (1-24) test was undertaken on day 11, 8 hours after the last dose of CRN04894. The protocol defined glucocorticoid deficiency as an 08:00 cortisol of <5 mcg/dl and triggered the addition of hydrocortisone (10 mg 08:00, 5 mg 14:00) 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. In addition, median 24-hour UFC decreased by 75%, while 24-hour mean AUC for plasma ACTH increased ~5-fold compared to baseline. In the 80 mg cohort the median peak cortisol in response to the day 11 ACTH stimulation test was 12 mcg/dl and in all subjects was <18 mcg/dl (500 nmol/l), the cut-off used to diagnose adrenal insufficiency. These analyses include data from 2 out of 6 subjects who received hydrocortisone replacement per protocol while treated with CRN04894 in the 80 mg cohort.
CRN04894 was well tolerated, and all adverse events (AEs) were considered mild or moderate and there were no serious AEs. Biochemical glucocorticoid deficiency, as defined above, was the most common treatment-related adverse event, although no symptoms of clinical adrenal insufficiency were reported.
In summary, treatment with CRN04894 was well tolerated and resulted in meaningful suppression of cortisol and androstendione secretion despite exposure to persistent endogenous and acute exogenous ACTH challenges in healthy volunteers. Studies are planned in patients with Cushing’s disease and CAH.
The author has declared no conflict of interest.