A Breakthrough in Treatment for Congenital Adrenal Hyperplasia

Source: Sarafoglou K , Kim MS , Lodish M , et al . Phase 3 trial of crinecerfont in pediatric congenital adrenal hyperplasia [published online ahead of print June 2, 2024]. N Engl J Med. doi: 10.1056/NEJMoa2404655.Investigators from multiple institutions conducted a randomized controlled trial to assess the efficacy and safety of crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, for treatment of children with congenital adrenal hyperplasia (CAH). Participants were patients 2–17 years old with CAH who were receiving glucocorticoid doses >12 mg/m2/day (hydrocortisone dose equivalent) and had 17-hydroxyprogesterone levels >2 times higher than the upper limit of normal. Study children were enrolled at 37 centers in the US, Canada, and Europe and were randomized 2:1 to receive crinecerfont, 25 to 100 mg twice daily, or placebo for 28 weeks. Androstenedione and 17-hydroxyprogesterone levels were monitored throughout the trial. During the first 4 weeks of treatment, glucocorticoid doses remained stable in participants. Following this, glucocorticoid doses were adjusted in a stepwise fashion to a target of 8–10 mg/m2/day, provided that the androstenedione level was not >120% of baseline level or no higher than the upper limit of normal. The primary study outcome was change in androstenedione level from baseline to week 4. Secondary outcomes included percent change in glucocorticoid dose from baseline to week 28 and change in 17-hydroxyprogesterone level from baseline to week 4. Differences between children in the 2 treatment groups were assessed using analysis of covariance models. In addition, adverse events were assessed throughout the trail.A total of 103 children were enrolled in the study, and 100 continued in the trial through week 28, including 69 who received crinecerfont and 31 randomized to placebo. The mean age of study participants was 12.1 ±1.5 years, and mean glucocorticoid dose was 16.4 ±3.9 mg/m2/day. From baseline to week 4, the mean androstenedione level decreased by 197 ±39 ng/dL for children randomized to crinecerfont and increased by 71 ±56 ng/dL for those randomized to placebo (P <0.001). Similarly, the mean changes in 17-hydroxyprogesterone levels during this period were -5,865 ±572 ng/dL and 556 ±818 ng/dL, respectively, for participants assigned to crinecerfont or placebo treatment (P <0.001). At week 28, the mean glucocorticoid dose was 12.8 mg/m2/day for patients randomized to crinecerfort and 17.0 mg/m2/ day for those receiving placebo. The mean changes in glucocortoid dose from baseline to week 28 were -18% and 5.6%, respectively, for children receiving crinecerfont or placebo (P <0.001). At least 1 adverse event was reported in 84% of patients randomized to crinecerfont and 82% of those receiving placebo. Two patients in the crinecerfont group were withdrawn from the study because of symptoms including nausea, upper abdominal pain, and retching.The authors conclude that crinecerfont treatment for children with CAH was associated with a decrease in the glucocorticoid dose required to maintain control of androstenedione.Dr Goyal has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.CAH is estimated to affect about 1 per 15,000 newborns.1 Over 90% of CAH cases are caused by a defect in the 21-OH gene (CYP21), resulting in a deficiency in 21-hydroxylase, which leads to impaired synthesis of cortisol and often aldosterone. Newborn screening for CAH is mandatory in all US states and is effective for early identification to prevent infant mortality and morbidity associated with salt-wasting.2,3 The current mainstay of treatment is hydrocortisone, typically three times daily due to its short half-life, often at supraphysiologic doses that increase the risk of side effects including growth suppression, weight gain, and insulin resistance.3 As a result, clinical management is challenging, and even with frequent monitoring for both over-and under-treatment, children with CAH often face lifelong impaired metabolic and reproductive health.The current study investigated crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, for treatment of children with CAH. Interestingly, findings from this study revealed the inadequacy of current treatment paradigms for CAH, as children in the study had high baseline rates of both obesity and androgen excess. Treatment with crinecerfont was associated with significant reductions in androstenedione and 17-hydroxyprogesterone levels. Children in the crinecerfort treatment arm were able to receive lower doses of glucocorticoid, with a commensurate decrease in glucocorticoid side effects including insulin resistance.These results support crinecerfont as a safe and effective option that likely will soon receive FDA approval as the first non-glucocorticoid treatment of children with CAH. Further research will be needed to demonstrate the impact for younger children and to measure longer-term outcomes, including bone age and linear growth. Still, results from this rigorously designed study warrant initial enthusiasm for a breakthrough for this rare, but serious, condition.Crinecerfont is a new non-glucocorticoid treatment that may improve care of children with CAH.Gene therapy for CAH, a monogenic disease exemplar, using an adenoviral vector to deliver functional copies of the CYP21A2 gene, is currently being explored in US adult patients (see ClinicalTrials.gov, NCT04783181).4

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