Oral therapy cuts androstenedione levels for children with congenital adrenal hyperplasia
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Key takeaways:
- Crinecerfont allowed lower glucocorticoid doses for children with congenital adrenal hyperplasia at 28 weeks.
- Adverse events were similar between the crinecerfont and placebo groups.
BOSTON — Crinecerfont lowered androstenedione levels and allowed for lower glucocorticoid doses for children with classic congenital adrenal hyperplasia, according to findings from the CAHtalyst Pediatric phase 3 trial.
As Healio previously reported, adults with congenital adrenal hyperplasia (CAH) receiving crinecerfont (Neurocrine Biosciences) in the CAHtalyst phase 3 trial had lower daily glucocorticoid doses with maintenance of androgen control than those receiving placebo at 24 weeks. In data presented at ENDO 2024 and simultaneously published in The New England Journal of Medicine, researchers found similar benefits among children with CAH, making the therapy a possible oral, nonglucocorticoid option for treating the condition among people of all ages.
“When treating children with CAH, from the moment they are diagnosed, we are challenged with finding a balance between supraphysiologic glucocorticoid dosing and the need to prevent androgen excess,” Kyriakie Sarafoglou, MD, professor, departments of pediatrics and experimental and clinical pharmacology, divisions of endocrinology and genetics and metabolism at the University of Minnesota, told Healio. “Tipping the scale too far one way or the other can adversely impact growth and pubertal development. Based on the CAHtalyst Pediatric study results, crinecerfont represents a potential nonglucocorticoid therapeutic approach to meet this challenge.”
In the double-blind, placebo-controlled portion of the CAHtalyst pediatric trial, 103 children aged 2 to 17 years with CAH were randomly assigned, 2:1, to oral crinecerfont or placebo twice daily for 28 weeks. Children in the crinecerfont group received 25 mg, 50 mg or 100 mg based on their body weight. The primary efficacy endpoint of the trial was change in androstenedione level from baseline to 4 weeks. Key secondary endpoints included change in serum 17-hydroxyprogesterone level from baseline to 4 weeks and percent change in daily dose of glucocorticoids from baseline to 28 weeks while androstenedione is controlled. Safety assessments included adverse events during the treatment period, 12-lead electrocardiography, clinical laboratory testing, the Brief Psychiatric Rating Scale for Children and the Columbia-Suicide Severity Rating Scale.
Lower androstenedione levels
There were 100 children who remained in the trial at 28 weeks, including 69 in the crinecerfont group and 31 in the placebo group.
The crinecerfont group had a decrease in androstenedione level of 197 ng/dL from baseline to 4 weeks compared with an increase of 71 mg/dL for the placebo group (P < .001). Mean androstenedione values at 4 weeks were 208 ng/dL for children receiving crinecerfont vs. 545 ng/dL for the placebo group. The crinecerfont group had a 5,865 ng/dL decrease in 17-hydroxyprogesterone from baseline to 4 weeks compared with a 556 ng/dL increase for the placebo group.
At 28 weeks, children receiving crinecerfont had an 18% decrease in glucocorticoid dose vs. a 5.6% increase for those receiving placebo (P < .001). The observed mean glucocorticoid dose at 28 weeks was 12.8 mg/m2 per day for the crinecerfont group and 17 mg/m2 for the placebo group. Of the crinecerfont group, 30% achieved a physiologic glucocorticoid dose of less than 11 mg/m2 per day with maintenance of androstenedione control at 28 weeks compared with no participants in the placebo group.
“In addition to meeting primary and key secondary endpoints related to reducing elevated androstenedione and supraphysiologic glucocorticoid dosing during the 28-week study, treatment with crinecerfont also showed favorable trends in ameliorating the consequences of the current treatment regimen, with reductions in body weight, improved insulin resistance and reduced hirsutism in females,” Sarafoglou said.
Safety outcomes
The percentage of children who experienced an adverse event was similar between the two groups and most adverse events were mild to moderate in severity. Two children receiving crinecerfont had an adverse event that led to trial discontinuation. One participant had body aches, upper abdominal pain and nausea that was considered unrelated to the study treatment, whereas the other had nausea, dizziness, retching and motion sickness that was possibly related to treatment. Serious adverse events occurred among four children in the placebo group and one in the crinecerfont group, none of which were related to the trial regimen.
Sarafoglou said most participants from the study chose to continue treatment during a 24-week open-label extension study that is ongoing.
“It will be interesting to analyze the open-label data from both the pediatric and the adult studies to learn more about the potential long-term impact of crinecerfont,” Sarafoglou said.
Reference:
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Sarafoglou K, et al. SUN-441. Presented at: ENDO annual meeting; June 1-4, 2024; Boston.
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