Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia

Abstract

Background: Adrenal insufficiency in patients with classic 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) is treated with glucocorticoid replacement therapy. Control of adrenal-derived androgen excess usually requires supraphysiologic glucocorticoid dosing, which predisposes patients to glucocorticoid-related complications. Crinecerfont, an oral corticotropin-releasing factor type 1 receptor antagonist, lowered androstenedione levels in phase 2 trials involving patients with CAH.

Methods: In this phase 3 trial, we randomly assigned adults with CAH in a 2:1 ratio to receive crinecerfont or placebo for 24 weeks. Glucocorticoid treatment was maintained at a stable level for 4 weeks to evaluate androstenedione values, followed by glucocorticoid dose reduction and optimization over 20 weeks to achieve the lowest glucocorticoid dose that maintained androstenedione control (≤120% of the baseline value or within the reference range). The primary efficacy end point was the percent change in the daily glucocorticoid dose from baseline to week 24 with maintenance of androstenedione control.

Results: All 182 patients who underwent randomization (122 to the crinecerfont group and 60 to the placebo group) were included in the 24-week analysis, with imputation of missing values; 176 patients (97%) remained in the trial at week 24. The mean glucocorticoid dose at baseline was 17.6 mg per square meter of body-surface area per day of hydrocortisone equivalents; the mean androstenedione level was elevated at 620 ng per deciliter. At week 24, the change in the glucocorticoid dose (with androstenedione control) was -27.3% in the crinecerfont group and -10.3% in the placebo group (least-squares mean difference, -17.0 percentage points; P<0.001). A physiologic glucocorticoid dose (with androstenedione control) was reported in 63% of the patients in the crinecerfont group and in 18% in the placebo group (P<0.001). At week 4, androstenedione levels decreased with crinecerfont (-299 ng per deciliter) but increased with placebo (45.5 ng per deciliter) (least-squares mean difference, -345 ng per deciliter; P<0.001). Fatigue and headache were the most common adverse events in the two trial groups.

Conclusions: Among patients with CAH, the use of crinecerfont resulted in a greater decrease from baseline in the mean daily glucocorticoid dose, including a reduction to the physiologic range, than placebo following evaluation of adrenal androgen levels. (Funded by Neurocrine Biosciences; CAHtalyst ClinicalTrials.gov number, NCT04490915.).

Figure 1.. Efficacy Endpoints

Differences between crinecerfont and placebo are shown for the following: percent reduction in glucocorticoid (GC) dose while maintaining androstenedione (adrenal androgen) control (Panel A) and percentage of participants achieving reduction to a physiological GC range (≤11 mg/m²/day in hydrocortisone equivalents) while maintaining androstenedione control (Panel B); changes from baseline to week 4 in serum androstenedione (Panel C) and 17-hydroxyprogesterone (17OHP) (Panel D). Change in GC dose was set to zero in participants who had a reduction in GC dose but did not achieve androgen control. Androstenedione and 17OHP values for the two 4-week end points (Panels C and D) are based on samples collected before participants received their morning GC doses. Androstenedione control was defined as equal to or less than either 120% of baseline or the upper limit of normal, based on samples collected after participants received their morning GC doses. Error bars represent 95% confidence intervals (CI) for mean changes. The widths of these CIs have not been adjusted for multiplicity, and the intervals may not be used in place of hypothesis testing. Least-squares mean differences (LSMDs) with 95% CIs and P-values are presented for the primary end point (Panel A) and first key secondary end point (Panel C); P-value for the second key secondary end point is also presented (Panel B, LSMD not applicable). Analyses for the primary and key secondary end points included all randomized participants, as missing values were imputed (Methods).