Changes in Adrenal and Gonadal Androgens After 14-Day Treatment With CRF1 Receptor Antagonist, Crinecerfont (NBI-74788), in Men With Classic 21-Hydroxylase Deficiency

Background: Congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency (21OHD) causes cortisol insufficiency and androgen excess. A phase 2 trial of crinecerfont, a CRF1 receptor antagonist, in 18 adults with 21OHD showed prominent decreases in ACTH, 17-hydroxyprogesterone, and androstenedione (A4), and in women, testosterone (T), after 14 days of treatment. In men with 21OHD, T derives from both adrenals and testes; in poor disease control, A4/T ratio is elevated due to disproportionately increased adrenal A4 production and decreased testicular T production. We sought to determine the impact of crinecerfont on both adrenal and gonadal androgen production in men with 21OHD in this phase 2 trial. Methods: A4 and T data were analyzed for 7 men who completed 1 or more of 4 oral dosing regimens: Cohort 1, 50 mg QHS, n=4; Cohort 2, 100 mg QHS, n=2; Cohort 3, 100 mg QPM, n=5; and Cohort 4, 100 mg BID, n=3 (14 total treatment periods). Mean 0600-1000 4-hour morning window (M4hMW) and mean 24-hour (M24h) A4, T, and A4/T ratios were analyzed from serial serum samples at baseline and on day 15. Results: Dose-dependent reductions in M4hMW A4 were observed [median (range)] in men, consistent with previously presented data in all subjects:Cohort 1: -21% (-84 to -12%);Cohort 2: -37% (-51% to -23%);Cohort 3: -43% (-85% to +140%);Cohort 4: -62% (-90% to -33%). In contrast, M4hMW T showed inconsistent changes [median (range)]: Cohort 1: +18% (-40% to +82%);Cohort 2: -4% (-4.3% to -3.8%);Cohort 3: +9% (-11 to +24%);Cohort 4: +9% (-3% to +27%). Thus, M4hMW A4/T ratios decreased with dose. Values at baseline, on day 15, and percent changes [median (range)] were, respectively:Cohort 1: 0.9 (0.3–2.6), 0.6 (0.1–2.1), -26% (-91% to +23%);Cohort 2: 5.0 (4.8–5.2), 3.3 (2.5–4.2), -35% (-49% to -20%);Cohort 3: 0.6 (0.1–6.9), 0.3 (0.1–2.7), -54% (-85% to +178%);Cohort 4: 3.9 (0.6–5.9), 0.4 (0.3–2.1), -65% (-92% to -31%). M24h A4/T ratios similarly declined in all cohorts. Values at baseline, on day 15, and percent changes [median (range)] were, respectively:Cohort 1: 1.0 (0.3–2.3), 0.4 (0.1–1.9), -33% (-92% to +2%);Cohort 2: 4.3 (3.8–4.9), 2.7 (2.4–3.0), -36% (-51% to -22%);Cohort 3: 0.5 (0.1–4.7), 0.4 (0.1–2.4), -59% (-78% to +310%);Cohort 4: 3.2 (0.4–4.1), 0.4 (0.3–1.7), -58% (-89% to -31%). Conclusions: Following crinecerfont therapy, A4 and A4/T decreased in a dose-dependent manner in men with 21OHD. In contrast to reductions in T observed in women with 21OHD, T did not change consistently and rose in some men. Preserved T values despite marked A4 reductions suggests testicular T production increased during crinecerfont therapy, perhaps due to release of gonadotropin suppression from adrenal-derived androgens. Long term studies are needed to determine if crinecerfont treatment improves additional measures of testicular function in men with 21OHD. Reference: RJ Auchus, et al. J Endocr Soc 2020;4(Suppl 1):OR25-03.