ESPE Yearbook of Paediatric Endocrinology

J Clin Endocrinol Metab. 2021; 106(11): e4666-e4679. PMID: 34146101https://pubmed.ncbi.nlm.nih.gov/34146101/

Brief Summary: These clinical trials evaluated the safety and efficacy of tildacerfront, a CRF1R antagonist, in suppressing adrenal androgen secretion in adult patients with classical Congenital adrenal hyperplasia (CAH) during a treatment period of 12 weeks.

CAH due to 21-hydroxylase deficiency (21OHD) is typically treated with lifelong supraphysiologic doses of glucocorticoids (GCs) (1). Tildacerfont, a corticotropin-releasing factor type-1 receptor (CRF1R) antagonist, may reduce excess adrenal androgen production, thus allowing the use of lower GC doses (2-4). In these two Phase 2 open-label studies, the authors evaluated the efficacy and safety of tildacerfont. In study 1, doses of 200 mg to 1000 mg once daily (escalating doses) or 100 mg or 200 mg twice daily were administered orally for 14 days to adults with CAH. In study 2, the participants received 400 mg once daily for 12 weeks. In total, 36 participants were enrolled (age range 19-67 yrs; mean age 45 yrs) provided their morning concentrations of serum 17OHP concentrations prior to GC medication were >= 24 nmol/L. No severe adverse events were noted. Eleven participants were on dexamethasone and were excluded from the efficacy analysis since the concentrations of dexamethasone in blood were doubled during the tildacerfont treatment period. In the group of the remaining 25 participants, 11/16 in study 1 and 5/8 in study 2 were considered to have poor disease control at baseline. After receiving tildacerfont for 14 days, the morning concentrations of ACTH, 17OHP and A4 were reduced in the poor disease control group. No dose-response relationship was observed across the evaluated dose range. For participants with good disease control (ACTH and A4 below the upper normal reference range) there were no additive effects of tildacerfont on ACTH or A4 concentrations, and only a modest decrease in 17OHP concentrations was noted. In the 12-week study group (study 2, 400 mg/day) a similar result was observed for the biomarker reduction in the poor disease-control group, while the good disease-control group showed no benefit of tildacerfont. Whether tildacerfont has the power to reduce GC doses further in the good disease-control group remains to be tested.

In conclusion, these open label studies demonstrate proof of concept the achievement of receptor engagement (reductions in ACTH) and suppression of adrenal steroids (17-OHP and A4) in 21OHD CAH. In Study 1, the mean levels of ACTH, 17-OHP, and A4 were reduced relative to baseline across all doses tested. Study 2 showed that continued reductions could be achieved across each of the key biomarkers with longer term therapy, including normalization of ACTH and A4 levels in patients with poor baseline control. Tildacerfont was generally well-tolerated and safe. The findings from these studies support the ongoing late-stage studies of tildacerfont in participants with 21OHD.

References: 1 Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018; 103(11): 4043–4088. 2. Chen C. Recent advances in small molecule antagonists of the corticotropin-releasing factor type-1 receptor-focus on pharmacology and pharmacokinetics. Curr Med Chem. 2006; 13(11): 1261–1282. 3. Kehne J, De Lombaert S. Non-peptidic CRF1 receptor antagonists for the treatment of anxiety, depression and stress disorders. Curr Drug Targets CNS Neurol Disord. 2002; 1(5):467–493. 4. Sarafoglou K, Newfield R, Vogiatzi M, et al. SUN-LB064 a phase 2, dose-escalation, safety and efficacy study of tildacerfont (TILDACERFONT) for the treatment of patients with classic congenital adrenal hyperplasia. J Endocr Soc. 2019; 3(Suppl 1): A494–A495.