ECE2020 Audio ePoster Presentations Adrenal and Cardiovascular Endocrinology (121 abstracts)
Crinecerfont (NBI-74788), a novel CRF1 receptor antagonist, reduces adrenal androgens and precursors in patients with classic congenital adrenal hyperplasia: Results from a phase 2, multiple-dose study
Richard Auchus 1 , Kyriakie Sarafoglou 2 , Patricia Fechner 3 , Maria Vogiatzi 4 , Nagdeep Giri 5 , Eiry Roberts 5 , Julia Sturgeon 5 & Robert Farber 5
1University of Michigan Medical School, Ann Arbor, United States; 2University of Minnesota Masonic Children’s Hospital, Minneapolis, United States; 3University of Washington School of Medicine, Seattle Children’s Hospital, Seattle, United States; 4The Children’s Hospital of Philadelphia, Philadelphia, United States; 5Neurocrine Biosciences, Inc., San Diego, United States
Introduction: Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD CAH) is a rare genetic disorder resulting in impaired cortisol biosynthesis, increased steroid precursors, and excess androgen production. Inhibition of adrenocorticotropic hormone (ACTH) release via antagonism of the corticotropin-releasing factor-1 (CRF1) receptor could reduce adrenal androgen production, thereby reducing the amount of exogenous glucocorticoids required for androgen control. This Phase 2 study evaluated the pharmacodynamic effects of a novel, non-steroidal, and selective CRF1 receptor antagonist, crinecerfont (NBI-74788), on adrenal androgens and precursors in adults with 21OHD CAH.
Methods: In a sequential-cohort design, 16 subjects (18–50 yrs) with 21OHD CAH received crinecerfont open-label for 14 consecutive days in one or more of 4 oral dosing regimens: 50 mg QHS (Cohort1); 100 mg QHS (Cohort2); 100 mg QPM (Cohort3); and 100 mg BID (Cohort4). ACTH, 17-hydroxy-progesterone (17OHP), and androstenedione (A4) were measured Q2H during the peak morning period (0600, 0800, 1000 hrs) and averaged at baseline and Day14.
Results: Demographics are provided in the table. Substantial reductions from baseline in peak-morning ACTH, 17OHP, and A4 after 14 days of crinecerfont treatment were observed across Cohorts 1 through 4 (Table). A dose-response in A4 was observed with 100 mg dosing regimens showing superiority over the 50mg dose cohort. Adverse events were mostly mild. There were no clinically significant findings from routine laboratory tests, vital signs, or electrocardiograms.
Conclusions: This study ofcrinecerfont, a novel, selective CRF1 receptor antagonist, demonstrated clinically meaningful reductions of elevated ACTH, 17OHP, and A4 and was well tolerated after 14 days of treatment in adults with 21OHD CAH. Further studies are warranted to evaluate the effects of chronic crinecerfont therapy on adrenal steroid production, clinical endpoints of disordered steroidogenesis, and reduction of supraphysiologic glucocorticoid dosing in adult and pediatric patients with 21OHD CAH.
| Cohort1 | Cohort2 | Cohort3 | Cohort4 | |||
| Demographics | ||||||
| Female/Male (n) | 4/4 | 5/2 | 3/5 | 2/2 | ||
| Age (mean± | 31.1 ± 9.4 | 32.9 ± 9.7 | 30.9 ± 10.5 | 30.8 ± 7.6 | ||
| Median ACTH (pg/ml) normal range: female 6–58; male 7–69 | ||||||
| Baselinea | 151 | 232 | 470 | 363 | ||
| Day14 (%Reduction)a | 114 (−54%) | 53 (−67%) | 40 (−69%) | 169 (−62%) | ||
| Median 17OHP (ng/dl) normal range: female <207; male <139 | ||||||
| Baselinea | 5352 | 12821 | 6451 | 12214 | ||
| Day14 (%Reduction)a | 2090 (−60%) | 3710 (−75%) | 2695 (−55%) | 6092 (−60%) | ||
| Median A4 (ng/dl) normal range: ≤39 yrs (female 26–214; male 33–134), >39 yrs (female 13–82; male 23–89) | ||||||
| Baselinea | 270 | 597 | 299 | 737 | ||
| Day14 (%Reduction)a | 109 (s−21%) | 346 (−47%) | 90 (−43%) | 395 (−52%) | ||
| aBased on peak morning period (0600, 0800, 1000 hrs) average. | ||||||
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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