Crinecerfont 降低 21-羟化酶缺乏症先天性肾上腺皮质增生症成人中升高的激素标志物。
Crinecerfont Lowers Elevated Hormone Markers in Adults With 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia.
机构信息
Departments of Pharmacology and Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Department of Pediatrics, Division of Pediatric Endocrinology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
出版信息
J Clin Endocrinol Metab. 2022 Feb 17;107(3):801-812. doi: 10.1210/clinem/dgab749.
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.
背景
由于 21-羟化酶缺乏症（21OHD）导致的经典先天性肾上腺增生症的特征是皮质醇合成受损和雄激素过量产生。促肾上腺皮质激素释放因子 1 型受体（CRF1R）拮抗剂可能会减少肾上腺雄激素的产生。
目的
本研究旨在评估选择性 CRF1R 拮抗剂 crinecerfont（NBI-74788）在 21OHD 中的安全性、耐受性和疗效。
方法
这是一项在美国 6 个中心进行的开放标签、两阶段研究，采用序贯队列设计（NCT03525886）。参与者包括年龄在 18 至 50 岁之间的男性和女性，患有 21OHD。干预措施包括 4 种 crinecerfont 方案，每种方案连续 14 天口服给药：分别为 50 或 100 mg 睡前每日一次（队列 1 和 2）；每晚 100 mg 一次（队列 3）；和每日两次 100 mg（队列 4）。参与者可以参加多个队列。主要结局指标包括从基线到第 14 天促肾上腺皮质激素（ACTH）、17-羟孕酮（17OHP）、雄烯二酮和睾酮的变化。
结果
共有 18 名参与者（11 名女性，7 名男性）入组：队列 1（n=8）、队列 2（n=7）、队列 3（n=8）、队列 4（n=8）。平均年龄为 31 岁；94%为白人。与 crinecerfont 100 mg 每日两次相比，ACTH（-66%）、17OHP（-64%）和雄烯二酮（-64%）的中位百分比降低超过 60%。在女性参与者中，73%（8/11）的睾酮水平降低 50%或更多；男性参与者的雄烯二酮/睾酮比值中位数降低 26%至 65%。
结论
在患有 21OHD 的成年人中，使用 crinecerfont 治疗 14 天可降低 ACTH，并可显著降低升高的 17OHP、雄烯二酮、睾酮（女性）或雄烯二酮/睾酮比值（男性）。需要进行更长时间的研究来评估 crinecerfont 对 21OHD 患者类固醇生成紊乱和糖皮质激素暴露的临床终点的影响。
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