Tildacerfont in Adults with Classic Congenital Adrenal Hyperplasia: Results from Two Phase 2 Studies

Kyriakie Sarafoglou, Chris N. Barnes, Michael Huang, Erik A. Imel, Ivy Joan Madu, Deborah P. Merke, David Moriarty, Samer Nakhle, Ron S. Newfield, Maria G. Vogiatzi, Richard J. Auchus

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Context: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is typically treated with lifelong supraphysiologic doses of glucocorticoids (GCs). Tildacerfont, a corticotropin-releasing factor type-1 receptor antagonist, may reduce excess androgen production, allowing for GC dose reduction. Objective: Assess tildacerfont safety and efficacy. Design and Setting: Two Phase 2 open-label studies. Patients: Adults with 21OHD. Intervention: Oral tildacerfont 200 to 1000 mg once daily (QD) (n = 10) or 100 to 200 mg twice daily (n = 9 and 7) for 2 weeks (Study 1), and 400 mg QD (n = 11) for 12 weeks (Study 2). Main Outcome Measure: Efficacy was evaluated by changes from baseline at 8 am in adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), and androstenedione (A4) according to baseline A4 ≤ 2× upper limit of normal (ULN) or A4 > 2× ULN. Safety was evaluated using adverse events (AEs) and laboratory assessments. Results: In Study 1, evaluable participants with baseline A4 > 2× ULN (n = 11; 19-67 years, 55% female) had reductions from baseline in ACTH (-59.4% to -28.4%), 17-OHP (-38.3% to 0.3%), and A4 (-24.2% to -18.1%), with no clear dose response. In Study 2, participants with baseline A4 > 2× ULN (n = 5; 26-63 years, 40% female) had ∼80% maximum mean reductions in biomarker levels. ACTH and A4 were normalized for 60% and 40%, respectively. In both studies, participants with baseline A4 ≤ 2× ULN maintained biomarker levels. AEs (in 53.6% of patients overall) included headache (7.1%) and upper respiratory tract infection (7.1%). Conclusions: For patients with 21OHD, up to 12 weeks of oral tildacerfont reduced or maintained key hormone biomarkers toward normal.

Original languageEnglish (US)
Pages (from-to)E4666-E4679
JournalJournal of Clinical Endocrinology and Metabolism
Issue number11
StatePublished - Nov 1 2021

Bibliographical note

Funding Information:
Spruce Biosciences, Inc. provided funding for this clinical trial and the manuscript produced by Simcoe Consultants, Inc. This research was supported in part by the Intramural Research Program of the NIH.

Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press on behalf of the Endocrine Society.


  • 17-hydroxyprogesterone
  • CRF-receptor antagonist
  • adrenocorticotropic hormone
  • androstenedione
  • congenital adrenal hyperplasia
  • tildacerfont


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