medwireNews: The CRF1 receptor antagonist crinecerfont achieves “substantial reductions” in adrenal androgens and androgen precursors in adolescents with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), US researchers say.
The three boys and five girls aged 14–16 years who participated in the phase 2, open-label trial achieved “substantial and clinically meaningful decreases” in adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17OHP) and androstenedione, say Ron Newfield (University of California San Diego) and co-workers.
These reductions are “consistent” with those previously reported for crinecerfont use in a study of adults with 21OHD CAH, they report in The Journal of Clinical Endocrinology & Metabolism.
The participants had experienced no more than one (median=0) adrenal crisis in the previous 2 years and were on a stable regimen of hydrocortisone or prednisone, with or without fludrocortisone, for at least 30 days before entering the study. Four of the five girls were postmenarcheal and had a median menstrual cycle of 28 days.
The participants received oral crinecerfont 50 mg twice daily with a meal for 14 days, giving a median crinecerfont exposure of 25.5 µg/hour per mL, and continued on glucocorticoid (GC) therapy throughout the study at a median hydrocortisone equivalent of 16.2 mg/m2 per day.
Levels of ACTH, 17OHP, androstenedione and testosterone were measured 1 week before beginning treatment, and again on days 1–2 and 14–15 of treatment, with samples taken 15 minutes before the evening dose and 1, 4, 6, 8, 12, 15, 20 and 24 hours after.
The 24-hour profile for patients exhibited the “expectedly high” circulating levels of ACTH, 17OHP and androstenedione at baseline, peaking around 10 am, at which point morning GC was administered. After 14 days of crinecerfont treatment, concentrations were “substantially lower” across the day, particularly in the period prior to the morning GC dose, report Newfield et al.
During the 24-hour monitoring, ACTH fell from a median 59 pg/mL at baseline to 34 pg/mL on day 14, while the morning window values decreased from a median 226 to 74 pg/mL. The corresponding differences in median 24-hour and morning values for 17OHP over the study were 2740 versus 668 ng/dL and 7704 versus 1789 ng/dL, respectively, while for androstenedione the values were a median 216 versus 80 ng/dL and 368 versus 134 ng/dL.
The girls also had decreases in median testosterone levels over both the 24-hour monitoring (26 to 25 ng/dL) and the morning window (64 to 40 ng/dL). No such difference was detected among the boys but the reduction in androstenedione meant their androstenedione/testosterone ratio decreased by a median percentage of 67% during the morning window.
Overall, 50% or greater reductions in baseline morning window values were achieved for ACTH, 17OHP and androstenedione in 63%, 75% and 50% of the eight patients, and among 60% of the five girls for testosterone and 67% of the three boys for their androstenedione/testosterone ratio.
This included a return to normal values of androstenedione in three of the six patients who had baseline values above the upper limit of normal (ULN) for their age and sex, one of the two girls with testosterone above the ULN and two of the three boys with an androstenedione/testosterone ratio above the ULN.
There were “no clinically meaningful” differences in cortisol exposure for the participants over the study, the researchers add.
Six patients experienced 12 treatment-emergent adverse events, all of which were mild and did not require treatment discontinuation. These included transient headache and dizziness, which were considered “possibly” related to crinecerfont.
While acknowledging the small size and duration of the study, Newfield and co-workers write that “the magnitude of reduction in participants’ hormone concentrations is beyond what would be expected with stable GC dosing, including the variations that normally occur even when patients consistently adhere to their treatment regimens.”
They add: “Long-term studies of crinecerfont in pediatric and adult patients (NCT04806451 and NCT04490915, respectively) with this disorder are underway to assess whether the improvements in androgen control can translate to more physiologic GC dosing and improvement in clinical endpoints such as weight, growth, and development.”
By Lynda Williams
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