Investigational drug for paediatric congenital adrenal hyperplasia succeeds in phase III trial

The novel oral corticotropin-releasing factor type 1 receptor antagonist crinecerfont helps supress androstenedione levels in children with congenital adrenal hyperplasia (CAH) and reduce the need for glucocorticoids, as shown in the phase III CAHtalyst Pediatric trial.

The primary endpoint of androstenedione level from baseline to week 4 decreased among children receiving crinecerfont but increased among those receiving placebo (−197 ng/dL [−6.9 nmol/L] vs 71 ng/dL [2.5 nmol/L]; least-squares mean difference, −268 ng/dL [−9.3 nmol/L]; p<0.001). Observed mean androstenedione values, which were obtained before the morning glucocorticoid dose, was 208 ng/dL (7.3 nmol/L) in the crinecerfont group as compared with 545 ng/dL (19.0 nmol/L) in the placebo group.  [N Engl J Med 2024;391:493-503]

Additionally, crinecerfont yielded substantial reductions in 17-hydroxyprogesterone, whereas placebo induced a slight increase (least-squares mean difference, −6,421 ng/dL [−195 nmol/L]; p<0.001). Observed mean 17-hydroxyprogesterone values at week 4 were 2,772 ng per decilitre (84.0 nmol per litre) in the crinecerfont group and 9,418 ng per decilitre (285 nmol per litre) in the placebo group.

“The crinecerfont group had marked reductions in androstenedione and 17-hydroxyprogesterone levels by week 4 (while the glucocorticoid dose was stable), after which the glucocorticoid dose was reduced by 18.0 percent by week 28 while androstenedione control was maintained,” the investigators noted.

“By contrast, the androstenedione level increased from baseline to weeks 4 and 28 in the placebo group despite a 5.6-percent increase in the mean glucocorticoid dose by week 28,” they added.

The least-squares mean difference in the mean glucocorticoid dose at week 28 was −23.5 percentage points (p<0.001). Notably, glucocorticoid dose dropped to a physiologic range (≤11.0 mg per square meter per day) with androstenedione control in 30 percent of children in the crinecerfont group as opposed to none in the placebo group.

“This trial showed that in paediatric participants with CAH, reduction in the glucocorticoid doses to the target physiologic range could be accomplished with apparent safety. No adrenal crises were observed during the double-blind period, and the incidence of adverse events (AEs) leading to glucocorticoid stress dosing was similar in the two groups,” the investigators said.

The rate of treatment-emergent AEs was similar between the crinecerfont and the placebo groups (84 percent vs 82 percent). Most AEs were mild to moderate in severity, with headache, pyrexia, and vomiting being the most common.

The incidence of serious AEs was higher in the placebo group than in the crinecerfont group (12 percent vs 1 percent). Two children (3 percent) in the crinecerfont group had AEs that led to treatment discontinuation—the first had body aches, upper abdominal pain, and nausea while the second had nausea, dizziness, retching, and motion sickness (which were deemed possibly related to the treatment). No deaths were recorded.

“No safety signals or major risks were identified during the 28-week treatment period, which, in conjunction with the efficacy results, supports a favourable risk–benefit profile for crinecerfont,” the investigators said.

Current treatment limitations

“Children with classic CAH due to 21-hydroxylase deficiency require treatment with glucocorticoids, usually at supraphysiologic doses, to address cortisol insufficiency and reduce excess adrenal androgens. Hydrocortisone, the recommended glucocorticoid for children, is usually administered in three daily doses because of its short elimination half-life, which is even shorter in children with CAH,” the investigators said. [Br J Clin Pharmacol 2021;87:1098-1110; J Clin Endocrinol Metab 2001;86:2701-2708]

“Consequently, most of the hydrocortisone dose is eliminated from the body within 4 to 5 hours, which results in a rebound of adrenal androgens between doses, especially in the early morning hours when corticotropin-driven adrenal androgen production increases. Thus, children are exposed to alternating periods of androgen excess and supraphysiologic glucocorticoid doses throughout the day,” they continued.

Children who participated in CAHtalyst Pediatric had suboptimal androgen control with substantially elevated mean androstenedione and 17-hydroxyprogesterone levels at baseline despite supraphysiologic glucocorticoid doses. This, according to the investigators, underscores the failure of conventional treatment to consistently control androgen excess.

“Finding a balance between androgen excess and exposure to supraphysiologic glucocorticoids, both of which can adversely affect growth and pubertal development, is an ongoing challenge,” they said.

The results of CAHtalyst Pediatric highlight crinecerfont as a potential new therapeutic option for patients with CAH, “who face substantial disease burden and adverse health outcomes throughout their lives,” they added.

CAHtalyst Pediatric included 103 children (mean age 12.1 years, 51 percent boys, 63 percent White, 58 percent had BMI ≥85th percentile) with CAH who were randomly assigned to treatment with crinecerfont (n=69) or placebo (n=34) for 28 weeks. A stable glucocorticoid dose was maintained for the first 4 weeks of treatment, after which the dose was adjusted to a target of 8.0–10.0 mg/m² of body-surface area per day (hydrocortisone dose equivalents), provided that the androstenedione level was controlled (≤120 percent of the baseline level or within the reference range).

At baseline, the mean glucocorticoid dose was 16.4 mg/m² per day, and the mean androstenedione level was 431 ng/dL (15.0 nmol/L).