Diurnal (United Kingdom)

Abstract Disclosure: R.J. Ross: Employee; Self; Diurnal, A Neurocrine Biosciences Company. D.P. Merke: None. A. Mallappa: None. W. Arlt: None. A. Brac de la Perriere: None. A.L. Hirschberg: None. A. Juul: None. J.D. Newell-Price: None. C.G. Perry: None. A. Prete: None. A. Rees: None. N. Reisch: None. M. Stikkelbroeck: None. P.A. Touraine: None. N. Aslam: Employee; Self; Diurnal Ltd, a Neurocrine Biosciences company. H. Coope: Employee; Self; Diurnal Ltd, a Neurocrine Biosciences company. J. Porter: Employee; Self; Diurnal Ltd, a Neurocrine Biosciences Company. Background: Management of congenital adrenal hyperplasia (CAH) involves replacing cortisol deficiency and controlling raised adrenal androgens. Guidelines recommend a target daily hydrocortisone dose of ≤25mg to replace adrenal insufficiency; however, cohort studies show doses >25mg are used to control androgens in CAH patients. Modified-release hydrocortisone (MRHC) capsules, (Efmody, UK), replicate the cortisol diurnal rhythm and improve the control of CAH compared to standard glucocorticoid therapy1. This post-hoc analysis examines total glucocorticoid daily dose and 9am 17-hydroxyprogesterone (17-OHP) levels in MRHC treated patients after 24 months in an ongoing MRHC single-arm extension study. Methods: All patients (n=71) that completed 24 months in the extension study at the time of the interim data cut were reviewed. Patients were recruited predominantly from the 6-month randomised phase III study comparing MRHC to standard glucocorticoid with blind titration of MRHC doses. In this extension phase the dose was titrated by the investigator on the 17-OHP and androstenedione levels at 4, 12, 24 weeks and 6 monthly. Androgen control was defined as 17-OHP <36 nmol/L (<1190 ng/dL). After 24 months, 64 of the patients had 9am 17-OHP data. A Wilcoxon-signed ranks test was performed to assess the change in total MRHC daily dose from baseline to 24 months. A Fisher’s exact test was performed to determine if the number of patients that achieved androgen control on a hydrocortisone (HC) dose ≤25 mg showed a statistically significant increase. Results: The median daily HC dose at baseline was 30mg (Inter-quartile range (IQR) 25-40) and at 24 months had reduced to 20mg (IQR 15-25), p<0.0001.Quadrant analysis revealed the following data: Baseline: &gt 36nmol/L 17-OHP & &lt 25mg/day 9/71 (13%). &gt 36nmol/L 17-OHP & &gt 25mg/day18/71 (25%). &lt 36nmol/L 17-OHP & &lt 25mg/day 22/71 (31%). &lt 36nmol/L 17-OHP & &gt 25mg/day 22/71 (31%). 24 months: &gt 36nmol/L 17-OHP & &lt 25mg/day 16/64 (25%). &gt 36nmol/L 17-OHP & &gt 25mg/day 2/64 (3%). &lt 36nmol/L 17-OHP & &lt 25mg/day 31/64 (48%). &lt 36nmol/L 17-OHP & &gt 25mg/day 15/64 (23%). 48% of subjects achieved androgen control based on 9am 17-OHP level at a HC dose ≤ 25 mg following 24 months of MRHC treatment compared with 31% at baseline (31% vs 48%, p= 0.03 by Fisher’s exact test). Conclusions: After 24 months of MRHC treatment the median daily HC dose was reduced from a median of 30mg to 20mg and the number of patients achieving androgen control based on 9am 17-OHP while receiving HC ≤25mg/day increased significantly.

International audience

Treatment of congenital adrenal hyperplasia (CAH) is suboptimal. Inadequate suppression of androgens and glucocorticoid excess are common and current glucocorticoid formulations cannot replace the cortisol circadian rhythm. The primary objective was to characterize the pharmacokinetic profile of Chronocort, a modified-release hydrocortisone formulation, in adults with CAH. Secondary objectives included examining disease control following 6 months of Chronocort with dose titration. Sixteen adults (eight females) with classic CAH participated in an open-label, nonrandomized, Phase 2 study at the National Institutes of Health Clinical Center. Twenty-four-hour blood sampling was performed on conventional glucocorticoids and following 6 months of Chronocort. Chronocort was initiated at 10 mg (0700 h) and 20 mg (2300 h). Dose titration was performed based on androstenedione and 17-hydroxyprogresterone (17-OHP) levels and clinical symptomatology. The primary outcome was cortisol pharmacokinetics of Chronocort and secondary outcomes included biomarkers of CAH control (androstenedione and 17-OHP). In patients with CAH, Chronocort cortisol profiles were similar to physiologic cortisol secretion. Compared with conventional therapy, 6 months of Chronocort resulted in a decrease in hydrocortisone dose equivalent (28 ± 11.8 vs 25.9 ± 7.1 mg/d), with lower 24-hour (P = .004), morning (0700-1500 h; P = .002), and afternoon (1500-2300 h; P = .011) androstenedione area under the curve (AUC) and lower 24-hour (P = .023) and morning (0700-1500 h; P = .02) 17-OHP AUC. Twice-daily Chronocort approximates physiologic cortisol secretion, and was well tolerated and effective in controlling androgen excess in adults with CAH. This novel hydrocortisone formulation represents a new treatment approach for patients with CAH.