Nonsteroidal treatment reduces androgen levels in congenital adrenal hyperplasia
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Adults with congenital adrenal hyperplasia who received an oral corticotropin-releasing hormone antagonist for 14 days experienced significant reductions in androgen levels with no serious adverse events, study data show.
The current treatment strategy for congenital adrenal hyperplasia (CAH) involves the administration of glucocorticoids to replace cortisol deficiency and attenuate the loss of negative feedback on the hypothalamus and the pituitary, Richard Auchus, MD, PhD, professor of pharmacology and internal medicine in the division of metabolism, endocrinology and diabetes at the University of Michigan, said during a presentation at ENDO Online. To maintain negative feedback sufficient to lower the production of undesirable androgens, glucocorticoid doses tend to be in excess of physiologic amounts, he said.
“People chronically treated with glucocorticoids for inflammatory conditions over time develop a whole series of complications — low bone density, glucose intolerance, muscle weakness, fragility, and increased cardiovascular mortality,” Auchus told Healio. “The treatment is not benign. Natural history studies from the U.K. and the NIH show that these people have poor quality of life and a lot of comorbidities as a result. There has to be a better way.”
Reducing glucocorticoid exposure
The inhibition of adrenocorticotropic hormone (ACTH) via antagonism of the corticotropin-releasing factor-1 (CRF-1) receptor with crinecerfont (Neurocrine Biosciences) could reduce androgen production and reduce the amount of glucocorticoid needed, Auchus said.
“The concept behind these medications is to reduce the problem to just adrenal insufficiency,” Auchus said in an interview. “You give what they need for cortisol and aldosterone replacement therapy, and then you don’t have to worry about the androgen excess because a different drug takes care of that. if this works chronically, it would be a way to lower the exposure these people get to glucocorticoids to the physiologic range. There is good reason to believe from these other conditions where we have better data that that would mitigate these long-term comorbidities.”
In an open-label, phase 2 study, Auchus and colleagues analyzed data from 23 adults with classic CAH aged 50 years and younger assigned one of four crinecerfont oral dosing regimens in a sequential-cohort design: 50 mg crinecerfont once daily at bedtime (cohort 1; n = 8; mean age, 31 years); 100 mg once daily at bedtime (cohort 2; n = 7; mean age, 33 years); 100 mg once daily (cohort 3; n = 8; mean age, 31 years) and 100 mg once daily with alternative dosing (cohort 4; n = 8; mean age, 29 years). Each regimen was administered for 14 consecutive days. Researchers measured ACTH, the steroid hormone 17-hydroxyprogesterone (17-OHP) and androstenedione serially during a 24-hour period at baseline and 14 days.
At baseline, median plasma ACTH was 151 pg/mL, 232 pg/mL and 470 pg/mL for cohorts 1, 2 and 3, respectively. Median baseline 17-OHP levels across cohorts were 5,352 ng/dL, 12,821 ng/dL and 6,451 ng/dL, respectively, and median baseline androstenedione levels across cohorts were 270 ng/dL, 597 ng/dL and 299 ng/dL, respectively. For participants in cohort 4, median baseline levels were 310 pg/mL for ACTH, 10,783 ng/dL for 17-OHP and 769 ng/dL for androstenedione.
At 14 days, participants in cohort 1 experienced median percent reductions from baseline in plasma ACTH (–54%), serum 17-OHP (–60%), and serum A4 (–21%). Median percent reductions were larger with the 100 mg dose for participants in cohort 2, with median reductions of –67% for ACTH, –75% for 17-OHP and –47% for androstenedione, and for participants in cohort 3, with median reductions of –69% for ACTH, –55% for 17-OHP, and –43% for androstenedione. Median percent reductions for participants in cohort 4 were –66% for ACTH, –64% for 17-OHP and –64% for androstenedione.
‘Viable’ treatment option
“These findings demonstrate that crinecerfont showed consistent and convincing efficacy amongst all the cohorts, particularly the 100 mg or more dose, for several biomarkers of CAH control, so this looks like a viable strategy for treating classic CAH chronically,” Auchus said.
Auchus said any adverse events reported were mild across cohorts, and there were no clinically significant findings from routine laboratory tests, vital signs or ECGs.
"After 14 days of treatment with crinecerfont, clinically meaningful reductions of elevated ACTH, 17-OHP and androstenedione were observed,” Auchus said. “Clinically meaningful reductions in testosterone were also seen in female patients. Further studies with adults and pediatric patients with classic CAH are needed to evaluate the potential of crinecerfont therapy to maintain control of undesirable steroid production over months, to allow reductions of glucocorticoid dosing to physiologic exposure, and to afford clinically meaningful improvements in the known consequences of both disordered steroidogenesis and chronic glucocorticoid treatment.”
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Auchus RJ, et al. Effects of crinecerfont (NBI-74788), a novel CRF1 aeceptor antagonist, on adrenal androgens and precursors in patients with classic congenital adrenal hyperplasia: results. ENDO Online; June 8-19, 2020.
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