Crinecerfont therapy tied to reduced adrenal androgen production and lower glucocorticoid administration in CAH patients: NEJM

In patients with congenital adrenal hyperplasia, crinecerfont treatment led to a more substantial reduction from baseline in the mean daily glucocorticoid dose, including a decrease to the physiological range, compared to placebo, following the assessment of adrenal androgen levels, the researchers wrote in the New England Journal of Medicine.

In patients with classic 21-hydroxylase deficiency CAH, adrenal insufficiency is managed with glucocorticoid replacement therapy. To control excess adrenal-derived androgens, patients often require supraphysiologic glucocorticoid doses, which can lead to complications related to glucocorticoid use. In Phase 2 trials, crinecerfont, an oral antagonist of the corticotropin-releasing factor type 1 receptor, demonstrated efficacy by lowering androstenedione levels in individuals with CAH.

Against the above background, Richard J. Auchus, University of Michigan Medical School, Ann Arbor, Michigan, and colleagues randomly assigned adults with CAH in a 2:1 ratio to receive crinecerfont or placebo for 24 weeks. Glucocorticoid treatment was held at a constant level for four weeks to assess androstenedione levels. Following this period, the glucocorticoid dose was gradually reduced and optimized over 20 weeks to find the lowest effective dose that kept androstenedione levels under control (≤120% of baseline or within the reference range).

The primary efficacy endpoint was the percentage change in the daily glucocorticoid dose from baseline to week 24 while maintaining control of androstenedione levels.

The following were the key findings of the study:

• In the 24-week analysis, all 182 patients who underwent randomization (122 to the crinecerfont group and 60 to the placebo group) were included, with the imputation of missing values; 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.
• A physiologic glucocorticoid dose (with androstenedione control) was reported in 63% of the patients in the crinecerfont group and 18% in the placebo group.
• At week 4, androstenedione levels decreased with crinecerfont (−299 ng per deciliter) but increased with placebo (45.5 ng per deciliter).
• Fatigue and headache were the most common adverse events in the two trial groups.

The findings of the study offer hope for a new therapeutic approach for CAH patients, who have traditionally relied on high doses of glucocorticoids with significant potential for adverse effects.

The researchers concluded that crinecerfont’s potential to reduce these doses while effectively managing the disease marks a significant advancement in the field.

Reference:

Auchus RJ, Hamidi O, Pivonello R, Bancos I, Russo G, Witchel SF, Isidori AM, Rodien P, Srirangalingam U, Kiefer FW, Falhammar H, Merke DP, Reisch N, Sarafoglou K, Cutler GB Jr, Sturgeon J, Roberts E, Lin VH, Chan JL, Farber RH; CAHtalyst Adult Trial Investigators. Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia. N Engl J Med. 2024 Jun 1. doi: 10.1056/NEJMoa2404656. Epub ahead of print. PMID: 38828955.