medwireNews: Phase 3 trial findings support the use of an oral corticotropin-releasing factor type 1 receptor antagonist for the treatment of classic congenital adrenal hyperplasia (CAH) in children with 21-hydroxylase deficiency.
“The results of this trial showed that crinecerfont therapy reduced production of excess adrenal androgens, which allowed substantial and clinically meaningful reduction of glucocorticoid doses to more physiologic levels in pediatric participants with CAH”, report the CAHtalyst Pediatric Trial investigators in The New England Journal of Medicine.
The study included 103 children (51% boys) aged 2–17 years (average 12.1 years) who required a stable glucocorticoid dose of at least 12.0 mg/m2 per day and had both an androstenedione level above the reference range midpoint and a 17-hydroxyprogesterone (17-OHP) level at least twice the upper limit of normal. None of the participants required long-term glucocorticoid therapy for any indication other than CAH.
The children were randomly assigned, after stratification for Tanner stage and sex, to receive oral crinecerfont twice daily at a weight-guided dose of 25 mg (10 to <20 kg), 50 mg (20 to <55 kg) or 100 mg (≥55 kg) for 28 weeks, or placebo.
The primary efficacy endpoint was the change in androstenedione between baseline and week 4 of treatment; the 69 children given crinecerfont experienced a “substantial” least squares mean decrease of 6.9 nmol/L, report Kyriakie Sarafoglou (University of Minnesota Medical School, Minneapolis, USA) and co-workers.
By contrast, the 31 children given placebo had a least squares mean increase in androstenedione of 2.5 nmol/L over the same time point, giving a significant least squares mean difference of –9.3 nmol/L between the treatment groups. At week 4, the average androstenedione levels before morning glucocorticoid dosing were 7.3 nmol/L in the crinecerfont arm and 19.0 nmol/L in the placebo arm.
Crinecerfont therapy also achieved a decrease in 17-OHP by week 4, whereas there was an increase with placebo, giving a significant least squares mean difference of 195 nmol/L. At week 4, the average 17-OHP level was 84.0 nmol/L with crinecerfont versus 285 nmol/L with placebo.
Glucocorticoid dosing was maintained at baseline levels for the first 4 weeks of the trial and decreased to a daily dose target of 8.0–10.0 mg/m2 providing that the androstenedione level was maintained at no more than 120% of baseline level or within the correct reference range for sex and either age or puberty status.
Sarafoglou et al say that the crinecerfont-treated patients achieved an 18.0% least squares mean decrease in their glucocorticoid dose between baseline and week 28, while the placebo-treated controls required a 5.6% increase, with a significant –23.5 percentage point difference between the groups. At week 28, the average daily glucocorticoid dose was 12.8 and 17.0 mg/m2, respectively.
Overall, 30% of 67 crinecerfont-treated patients who completed follow-up achieved a physiological glucocorticoid daily dose of 11.0 mg/m2 or below at week 28 versus none of the controls. And 57% of the crinecerfront group achieved either physiological dosing or a greater than 2.5 mg/m2 reduction in daily glucocorticoid dosing by week 28 versus just 3% of controls.
The researchers note that there were also “discernible” changes to other markers associated with excess glucocorticoids among children given crinecerfont who reduced their glucocorticoid dose, such as improvements in BMI and insulin resistance. These were accompanied by changes in markers of excess androgens, such as reduced hirsutism in girls and an improved androstenedione-to-testosterone ratio in boys.
The rate of adverse events in the trial was “similar” between the crinecerfont and placebo groups, the researchers say, at 84% and 82%, respectively, and most events were mild or moderate. Two patients discontinued crinecerfont due to adverse events, with symptoms of nausea, dizziness and motion sickness in one patient thought possibly related to treatment. There were no serious adverse events attributed to treatment or reports of adrenal crises.
Sarafoglou and co-authors therefore conclude: “Crinecerfont appears to be a potential new therapeutic option for patients with CAH, who face substantial disease burden and adverse health outcomes throughout their lives.
“Secondary and exploratory end points related to consequences of long-term supraphysiologic glucocorticoid therapy showed favorable trends, but longer treatment periods are needed to determine the extent of these effects”, they add.
Wiebke Arlt (Imperial College London, UK) notes in an accompanying editorial that the CAHtalyst Pediatric Trial only measured mixed adrenal and gonadal levels and that “it would be reassuring to see whether crinecerfont can effectively control the exclusively adrenal-derived 11-oxygenated androgens”.
She concludes that the current findings are “highly promising, but further studies will be needed to show that these changes translate into favorable long-term health outcomes.”
By Lynda Williams
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