CRF1 receptor antagonists in congenital adrenal hyperplasia: a systematic review and meta-analysis of phase 2 open-label and phase 3 clinical trials
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Introduction
Classical Congenital Adrenal Hyperplasia (CAH) due to 21 hydroxylase deficiency is a rare autosomal recessive disorder. Recent clinical trials indicate that type 1 Corticotropin-releasing hormone receptor OR CRFR1 receptor OR CRF1 antagonists could provide a new treatment option for CAH. Hence, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of these drugs in patients with CAH.
Methods
Medline, Embase, and Cochrane Library were searched for eligible studies. Analysis of Phase 2b and Phase 3 clinical trials was carried out. Mean percent changes and event numbers were pooled to perform a single-arm meta-analysis. Binary data was pooled from Phase 3 clinical trials. Statistical analysis was performed using RStudio version 4.1.2 (R Foundation for Statistical Computing), under a random-effects model. Heterogeneity was assessed using I2 statistics.
Results
From Phase 2 clinical trials, pooled efficacy data from studies with CRF1 antagonists resulted in a mean decrease from baseline levels in adrenocorticotropic hormone (ACTH) -57.86 %; 95 % CI -71.15 to −44.58 %; I2 = 0 %), 17-OHP (17-hydroxyprogesterone) (Mean − 40.01 %;95 % CI -66.31 to −13.71 %; I2 = 66 %) and androstenedione (−39.24 %; 95 % CI -62.77 to −15.70 %; I2 = 78 %). Overall, 71 % (95 % CI 53.91 % to 85.39 %) of the included patients experienced adverse events of any grade, with no significant difference between drug-type subgroups (P = 0.83). In Phase 3 trials, compared to placebo, CRF1 receptor antagonists resulted in a significant reduction of 17-OHP (MD: −6049.40 ng/dL; 95 % CI: −6665.23 to −5433.58 ng/dL; p < 0.01; I2 = 0 %), androstenedione levels (MD: −313.58 ng/dL; 95 % CI: −400.14 to −227.02 ng/dL; p < 0.01; I2 = 0 %) and need for glucocorticoid dose reduction (MD: −20.37 %; 95 % CI: −26.73 % to −14.00 %; p < 0.01; I2 = 47 %) No statistically significant difference was found between the two groups with respect to treatment emergent adverse effects 1.02 (95 % CI: 0.91 to 1.15; p = 0.72; I2 = 0 %) or treatment discontinuation 3.28 (95 % CI: 0.41 to 26.51; p = 0.27; I2 = 0 %).
Conclusion
CRF1 antagonists, especially Crinecerfont, are promising in the treatment of CAH. Phase 2b and Phase 3 clinical trials of CRF1 antagonists involving Crinecerfont demonstrated consistent results supporting its efficacy and safety. These studies showed significant reductions in ACTH, 17-OHP and androstenedione levels, as well as a decreased need for glucocorticoid doses, with no notable difference in adverse effects compared to placebo.
Classical Congenital Adrenal Hyperplasia (CAH) due to 21 hydroxylase deficiency is a rare autosomal recessive disorder. Recent clinical trials indicate that type 1 Corticotropin-releasing hormone receptor OR CRFR1 receptor OR CRF1 antagonists could provide a new treatment option for CAH. Hence, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of these drugs in patients with CAH.
Methods
Medline, Embase, and Cochrane Library were searched for eligible studies. Analysis of Phase 2b and Phase 3 clinical trials was carried out. Mean percent changes and event numbers were pooled to perform a single-arm meta-analysis. Binary data was pooled from Phase 3 clinical trials. Statistical analysis was performed using RStudio version 4.1.2 (R Foundation for Statistical Computing), under a random-effects model. Heterogeneity was assessed using I2 statistics.
Results
From Phase 2 clinical trials, pooled efficacy data from studies with CRF1 antagonists resulted in a mean decrease from baseline levels in adrenocorticotropic hormone (ACTH) -57.86 %; 95 % CI -71.15 to −44.58 %; I2 = 0 %), 17-OHP (17-hydroxyprogesterone) (Mean − 40.01 %;95 % CI -66.31 to −13.71 %; I2 = 66 %) and androstenedione (−39.24 %; 95 % CI -62.77 to −15.70 %; I2 = 78 %). Overall, 71 % (95 % CI 53.91 % to 85.39 %) of the included patients experienced adverse events of any grade, with no significant difference between drug-type subgroups (P = 0.83). In Phase 3 trials, compared to placebo, CRF1 receptor antagonists resulted in a significant reduction of 17-OHP (MD: −6049.40 ng/dL; 95 % CI: −6665.23 to −5433.58 ng/dL; p < 0.01; I2 = 0 %), androstenedione levels (MD: −313.58 ng/dL; 95 % CI: −400.14 to −227.02 ng/dL; p < 0.01; I2 = 0 %) and need for glucocorticoid dose reduction (MD: −20.37 %; 95 % CI: −26.73 % to −14.00 %; p < 0.01; I2 = 47 %) No statistically significant difference was found between the two groups with respect to treatment emergent adverse effects 1.02 (95 % CI: 0.91 to 1.15; p = 0.72; I2 = 0 %) or treatment discontinuation 3.28 (95 % CI: 0.41 to 26.51; p = 0.27; I2 = 0 %).
Conclusion
CRF1 antagonists, especially Crinecerfont, are promising in the treatment of CAH. Phase 2b and Phase 3 clinical trials of CRF1 antagonists involving Crinecerfont demonstrated consistent results supporting its efficacy and safety. These studies showed significant reductions in ACTH, 17-OHP and androstenedione levels, as well as a decreased need for glucocorticoid doses, with no notable difference in adverse effects compared to placebo.
Date Issued
2025-06-01
Date Acceptance
2025-05-17
Citation
Endocrine and Metabolic Science, 2025, 18
ISSN
2666-3961
Publisher
Elsevier
Journal / Book Title
Endocrine and Metabolic Science
Volume
18
Copyright Statement
© 2025 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
10.1016/j.endmts.2025.100247
Subjects
CAH CRF-1 receptor antagonists ACTH ACTH, adrenocorticotropic hormone
CAH, Congenital adrenal hyperplasia
CI, confidence intervals
CRF, corticotropin-releasing factor
CRF1, Type 1 corticotropin-releasing hormone receptor
HPA, hypothalamic-pituitary-adrenal
PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analysis
PROSPERO, International Prospective Register of Systematic Reviews
17-OHP-17, hydroxyprogesterone
Publication Status
Published
Article Number
100247
Date Publish Online
2025-05-19