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

Abstract

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.

• Authors: 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
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 106 Issue 11 Pg. e4666-e4679 (10 21 2021) ISSN: 1945-7197 [Electronic] United States
• PMID: 34146101 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

Chemical References

• Biomarkers
• Receptors, Corticotropin-Releasing Hormone
• Androstenedione
• CRF receptor type 1
• 17-alpha-Hydroxyprogesterone
• Adrenocorticotropic Hormone

Topics

• 17-alpha-Hydroxyprogesterone (blood)
• Adrenal Hyperplasia, Congenital (blood, drug therapy, pathology)
• Adrenocorticotropic Hormone (blood)
• Adult
• Aged
• Androstenedione (blood)
• Biomarkers (blood)
• Female
• Follow-Up Studies
• Humans
• Male
• Middle Aged
• Receptors, Corticotropin-Releasing Hormone (antagonists & inhibitors)
• Young Adult