Crinecerfont Lowers Elevated Hormone Markers in Adults With 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia

J Clin Endocrinol Metab. 2022 Feb 17;107(3):801-812. doi: 10.1210/clinem/dgab749.

Abstract

Context: Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production. Corticotropin-releasing factor type 1 receptor (CRF1R) antagonism may decrease adrenal androgen production.

Objective: This work aimed to evaluate the safety, tolerability, and efficacy of crinecerfont (NBI-74788), a selective CRF1R antagonist, in 21OHD.

Methods: This open-label, phase 2 study, with sequential cohort design (NCT03525886), took place in 6 centers in the United States. Participants included men and women, aged 18 to 50 years, with 21OHD. Interventions included 4 crinecerfont regimens, each administered orally for 14 consecutive days: 50 or 100 mg once daily at bedtime (cohorts 1 and 2, respectively); 100 mg once daily in the evening (cohort 3); and 100 mg twice daily (cohort 4). Participants could enroll in more than 1 cohort. Main outcomes included changes from baseline to day 14 in adrenocorticotropin (ACTH), 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone.

Results: Eighteen participants (11 women, 7 men) were enrolled: cohort 1 (n = 8), cohort 2 (n = 7), cohort 3 (n = 8), cohort 4 (n = 8). Mean age was 31 years; 94% were White. Median percent reductions were more than 60% for ACTH (-66%), 17OHP (-64%), and androstenedione (-64%) with crinecerfont 100 mg twice a day. In female participants, 73% (8/11) had a 50% or greater reduction in testosterone levels; male participants had median 26% to 65% decreases in androstenedione/testosterone ratios.

Conclusion: Crinecerfont treatment for 14 days lowered ACTH and afforded clinically meaningful reductions of elevated 17OHP, androstenedione, testosterone (women), or androstenedione/testosterone ratio (men) in adults with 21OHD. Longer-term studies are required to evaluate the effects of crinecerfont on clinical end points of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD.

Keywords: 17-hydroxyprogesterone; 21-hydroxylase deficiency; NBI-74788; congenital adrenal hyperplasia; crinecerfont.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 17-alpha-Hydroxyprogesterone / blood
  • Administration, Oral
  • Adolescent
  • Adrenal Hyperplasia, Congenital* / blood
  • Adrenal Hyperplasia, Congenital* / diagnosis
  • Adrenal Hyperplasia, Congenital* / drug therapy
  • Adrenocorticotropic Hormone / blood
  • Adult
  • Androstenedione / blood
  • Azabicyclo Compounds* / administration & dosage
  • Biomarkers / blood
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Male
  • Middle Aged
  • Oxadiazoles* / administration & dosage
  • Receptors, Corticotropin-Releasing Hormone* / antagonists & inhibitors
  • Testosterone / blood
  • Treatment Outcome
  • Young Adult

Substances

  • 17-alpha-Hydroxyprogesterone
  • Adrenocorticotropic Hormone
  • Androstenedione
  • Azabicyclo Compounds
  • Biomarkers
  • CRF receptor type 1
  • NBI 77860
  • Oxadiazoles
  • Receptors, Corticotropin-Releasing Hormone
  • Testosterone
  • crinecerfont

Supplementary concepts

  • Congenital adrenal hyperplasia due to 21 hydroxylase deficiency

Associated data

  • ClinicalTrials.gov/NCT03525886