SAT626 The Use Of Salivary Cortisol Measurement By Mass Spectrometry To Identify Low Serum Cortisol Values In Healthy Volunteers Receiving CRN04894, A Melanocortin 2 Receptor (MC2R) Antagonist
Authors: Ayala Alejandro , LaCerte Carl , Luo Rosa , Davidson Christopher , Wang Jian , Trainer Peter , Krasner Alan 
Published: October 2023

Disclosure: A. Ayala: Employee; Self; Crinetics Pharmaceuticals Inc. C. LaCerte: Employee; Self; Crinetics Pharmaceuticals Inc. R. Luo: Employee; Self; Crinetics Pharmaceuticals Inc. C. Davidson: Employee; Self; Crinetics Pharmaceuticals Inc. J. Wang: Employee; Self; Crinetics Pharmaceuticals Inc. P. Trainer: Employee; Self; Crinetics Pharmaceuticals Inc. A. Krasner: Employee; Self; Crinetics Pharmaceuticals Inc.

Clinical trials of cortisol-lowering drug candidates would benefit from user-friendly methods to measure cortisol in an outpatient setting. CRN04894 is a potent, orally bioavailable, MC2R antagonist in development for the treatment of ACTH-dependent Cushing’s syndrome and congenital adrenal hyperplasia. We have previously reported results from a randomized, double-blinded, placebo-controlled (6 active:3 placebo/cohort), multiple (10-day) ascending dose (40 to 80 mg/day) study in healthy volunteers. Declines in basal and ACTH-stimulated serum cortisol levels and a median reduction of 75% in 24-hr urinary-free cortisol (UFC) were seen in the 80 mg cohort. Asymptomatic glucocorticoid deficiency (defined as 08:00 serum cortisol of &lt;5 µg/dL) was the most commonly observed adverse event. Here we report the comparison of salivary cortisol measurements with serum cortisol day curves and 24-hr UFC observed in this study. We evaluated cortisol and ACTH data from the three cohorts dosed once daily (QD) at 22:00 with either 40, 60, or 80 mg. Cortisol (salivary & serum) and ACTH day curves (results reported as the mean of 4 or 5 available samples collected at 22:00, 08:00, 12:00, 16:00 & 20:00) studies were undertaken on days -1, 1, 4, and 9. Mean serum cortisol was moderately correlated with 24-hr UFC:creatinine ratio (ug/g) (r = 0.495) and strongly correlated (r = 0.734) with mean salivary cortisol. There was across all three doses of CRN04894 a consistent magnitude ranking change in measured cortisol analytes: serum (free plus bound) &lt; saliva &lt; urine, with substantial changes being seen within 24 hours of initiation of CRN04894 and no loss of cortisol suppression over 9 days despite median ACTH changes of &gt;1000% from baseline (60 & 80 mg doses). Time-matched individual saliva and serum cortisol values were used (without timepoint or visit restrictions) to explore the relationship between low serum cortisol and salivary levels. A saliva cutoff for cortisol deficiency was optimized for diagnostic accuracy (92.2%) using a serum cortisol value of &lt;5 µg/dL as the reference. Four subjects had 08:00 serum cortisol &lt;5 µg/dL and saliva cortisol data. All four cases were correctly identified as cortisol-deficient using a simultaneous saliva cortisol cutoff of &lt;0.0491 µg/dL. In conclusion, CRN04894 effectively lowered cortisol measured in serum, saliva, and urine in healthy volunteers. Salivary cortisol measured by tandem mass spectrometry correlated well with serum cortisol day curves and may be useful in the diagnosis of biochemical cortisol deficiency in outpatient studies. Future studies will explore the use of salivary glucocorticoid measurement in patients with Cushing’s disease receiving CRN04894.

Presentation: Saturday, June 17, 2023