CRF1 receptor antagonists in congenital adrenal hyperplasia: A systematic review and meta-analysis of phase 2 open-label and phase 3 clinical trials

Majeed M.W.; Finnegan E.; Gallo Ruelas M.; Quirós M.; da Silva M.B.; Salha I.; Herrán-Fonseca C.; de Oliveira H.M.; Quirós M.C.; Ahmed R.; Humayun Z.; Shah T.H.; Ganie M.A. · Endocrine and Metabolic Science (2025) · DOI: 10.1016/j.endmts.2025.100247

Resumen

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.