Single-dose study of a corticotropin-releasing factor receptor-1 antagonist in women with 21-hydroxylase deficiency
Open accessAbstract
Context: Treatment of 21-hydroxylase deficiency (21OHD) is difficult to optimize. Normalization of excessive ACTH and adrenal steroid production commonly requires supraphysiologic doses of glucocorticoids. Objectives: We evaluated the safety and tolerability of the selective corticotropin releasing factor type 1 (CRF1) receptor antagonist NBI-77860 in women with classic 21OHD and tested the hypothesis that CRF1 receptor blockade decreases early-morning ACTH and 17α-hydroxyprogesterone (17OHP) in these patients. Participants: The study enrolled eight classic 21OHD females, ages 18–58 years, seen at a single tertiary referral university setting. Design: This was a phase Ib, single-blind, placebo-controlled, fixed-sequence, single-dose trial. During three treatment periods separated by 3-week washout intervals, patients sequentially received placebo, NBI-77860 300 mg, and NBI-77860 600 mg at 10 pm; glucocorticoid therapy was withheld for 20 hours. We evaluated ACTH, 17OHP, androstenedione, and testosterone as well as NBI-77860 pharmacokinetics over 24 hours. Results: Dose-dependent reductions of ACTH and/or 17OHP were observed in six of eight subjects. Relative to placebo, NBI-77860 led to an ACTH and 17OHP reduction by a mean of 43% and 0.7% for the 300 mg dose, respectively, and by 41% and 27% for the 600 mg dose, respectively. Both NBI-77860 doses were well tolerated. Conclusion: The meaningful reductions in ACTH and 17OHP following NBI-77860 dosing in 21OHD patients demonstrate target engagement and proof of principle in this disorder. These promising data provide a rationale for additional investigations of CRF1 receptor antagonists added to physiologic doses of hydrocortisone and fludrocortisone acetate for the treatment of classic 21OHD.
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When added to HC 20 mg/d, 6 days of treatment with 100-250 mg/d of abiraterone acetate normalized androstenedione in 6 adult women with parallel reductions in testosterone, androgen metabolites, and 11-oxoandrogens.
“When added to HC 20 mg/d, 6 days of treatment with 100-250 mg/d of abiraterone acetate normalized androstenedione in 6 adult women (496) with parallel reductions in testosterone, androgen metabolites, and 11-oxoandrogens (497).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [496]
A phase I proof-of-principle study with a corticotropin-releasing factor type 1 receptor antagonist lowered morning ACTH or 17OHP in 6 of 8 females with classic 21-OH deficiency after a single dose.
“A phase I, proof-of-principle study with a corticotropin-releasing factor type 1 receptor antagonist, lowered morning ACTH or 17OHP in 6 of 8 females with classic 21-OH deficiency after a single dose.143”
From Congenital adrenal hyperplasia (2017) · cites this paper as [143]
The first proof-of-concept study of an oral small-molecule CRF1 antagonist was a phase Ib single-blind placebo-controlled fixed-sequence single-dose trial in eight women with classic CAH, which showed dose-dependent reduction of serum ACTH and/or 17-OHP.
“The first proof-of-concept study of an oral small-molecule (Neurocrine Biosciences, USA) CRF1 antagonist was a phase Ib, single-blind, placebo-controlled, fixed-sequence (placebo, NBI-77860 300 mg and 600 mg), single-dose trial in eight women (aged 18–58 years) with classic CAH, which showed a dose-dependent reduction of serum levels of ACTH and/or 17-OHP126.”
From Management challenges and therapeutic advances in congenital adrenal hyperplasia (2022) · cites this paper as [126]
A single-dose trial in eight women with classic CAH found that adding NBI-77860 to usual treatment lowered the mean morning ACTH rise by more than 40% and 17OHP by as much as 27%, while androstenedione and testosterone fell variably.
“The study drug reduced the mean morning increase in ACTH by .40% and that of 17OHP by up to 27% with variable reductions of androstenedione and testosterone.”
From Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society* Clinical Practice Guideline (2018) · cites this paper as [325]
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References 18 · Cited by 61
- Authors
- Turcu, A. F., Spencer-Segal, J. L., Farber, R. H., Luo, R., Grigoriadis, D. E., Ramm, C. A., Madrigal, D., Muth, T., O'Brien, C. F., & Auchus, R. J.
- Affiliations
- University of Michigan (US)
- Neurocrine Biosciences (United States) (US)
- Neurocrine Biosciences (R.H.F., R.L., D.E.G., C.F.O.), San Diego, California 92130
- Corresponding author
- Auchus, Richard J.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2016-03-01
- Volume
- 101
- Issue
- 3
- Pages
- 1174-1180
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC4803170
- OpenAlex
- W2237847983
- Cited by
- 61
- References
- 18
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 8 · 2020: 5 · 2019: 4 · 2018: 8 · 2017: 7 · 2016: 1
- FWCI
- 6.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR000433)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007313, T32DK007245)
- National Center for Research Resources (UL1RR024986)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- 21-hydroxylase deficiency, classic congenital adrenal hyperplasia, CRF1 receptor antagonist, ACTH, 17-hydroxyprogesterone, steroid-sparing therapy, cortisol, fludrocortisone acetate, pharmacokinetics, safety and tolerability, women
- MeSH terms
- CRF Receptor, Type 1, Adrenal Hyperplasia, Congenital, Adrenocorticotropic Hormone, Adult, Dose-Response Relationship, Drug, Female, Humans, Middle Aged, Oxadiazoles, Time Factors, Receptors, Corticotropin-Releasing Hormone, 17-alpha-Hydroxyprogesterone, Azabicyclo Compounds, Young Adult
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