Department of Endocrinology (X.B.), Centre de Référence des Maladies Rares de la Surrénale, Hôpital Cochin, Faculté de Médecine Paris Descartes, Université Paris 5, Paris 75014, France; Dipartimento di Medicina Clinica e Chirurgia (R.P.), Università Federico II di Napoli, IT-80131, Naples, Italy; Department of Medicine and Neurological Surgery (M.F.), Northwest Pituitary Center, Oregon Health and Science University, Portland, Oregon 97239-3098; Novartis Pharmaceuticals Corporation (Y.Z.), East Hanover, New Jersey 07936; Novartis Pharmaceuticals UK Limited (P.R.), Horsham, West Sussex, RH12 5AB, United Kingdom; Novartis Institutes for BioMedical Research (A.T., C.E.W.), Cambridge, Massachusetts 02139; Clinical Development (M.M.), Oncology Business Unit, Novartis Pharma AG, CH-4002 Basel, Switzerland; Department of Endocrinology, Diabetes, and Metabolism (A.H.H.), Cleveland Clinic Foundation, Cleveland, Ohio 44106; Division of Endocrinology (M.B.), Polytechnic University of Marche, 60121 Ancona, Italy; and Neuroendocrine Clinical Center (B.M.K.B.), Massachusetts General Hospital, Boston, Massachusetts 02114.
J Clin Endocrinol Metab. 2014 Apr;99(4):1375-83. doi: 10.1210/jc.2013-2117. Epub 2013 Dec 11.
The clinical features and increased mortality associated with Cushing's syndrome result from a chronic excess of circulating cortisol. As LCI699 potently inhibits 11β-hydroxylase, which catalyzes the final step of cortisol synthesis, it is a potential new treatment for Cushing's disease, the most common cause of endogenous Cushing's syndrome.
Adult patients with moderate-to-severe Cushing's disease (urinary free cortisol [UFC] levels >1.5 × ULN [upper limit of normal]) received oral LCI699 for 10 weeks in this proof-of-concept study. LCI699 was initiated at 4 mg/d in two equal doses; the dose was escalated every 14 days to 10, 20, 40, and 100 mg/d until UFC normalized, whereupon the dose was maintained until treatment ended (day 70). The primary endpoint was UFC ≤ ULN or a ≥50% decrease from baseline at day 70.
Twelve patients were enrolled and completed the study. Baseline UFC ranged over 1.6-17.0 × ULN. All 12 patients achieved UFC ≤ULN or a ≥50% decrease from baseline at day 70; 11 (92%) had normal UFC levels at that time. After treatment discontinuation (day 84), UFC was >ULN in 10 patients with available measurements. Mean 11-deoxycortisol, 11-deoxycorticosterone, and adrenocorticotropic hormone levels increased during treatment and declined after discontinuation. Mean systolic and diastolic blood pressure decreased from baseline by 10.0 and 6.0 mmHg, respectively. LCI699 was generally well tolerated; most adverse events (AEs) were mild or moderate. The most common AEs included fatigue (7/12), nausea (5/12), and headache (3/12). No serious drug-related AEs were reported.
LCI699 was efficacious and well tolerated in patients with Cushing's disease enrolled in this proof-of-concept study.
库欣综合征的临床特征和死亡率升高是由于循环皮质醇持续过量所致。LCI699 可强效抑制 11β-羟化酶，该酶催化皮质醇合成的最后一步，因此它可能成为治疗库欣病（内源性库欣综合征最常见的病因）的一种新疗法。
这项概念验证研究纳入了中重度库欣病患者（尿游离皮质醇[UFC]水平＞1.5×正常值上限[ULN]），他们接受口服 LCI699 治疗 10 周。LCI699 起始剂量为每日 4mg，分两次服用；每 14 天递增剂量，直至达到 10、20、40 和 100mg/d，直至 UFC 正常，此后维持剂量直至治疗结束（第 70 天）。主要终点是第 70 天 UFC≤ULN 或较基线下降≥50%。
共纳入 12 例患者并完成了研究。基线 UFC 范围为 1.6-17.0×ULN。所有 12 例患者在第 70 天达到 UFC≤ULN 或较基线下降≥50%；11 例（92%）当时 UFC 水平正常。在停药（第 84 天）后，10 例有可测量 UFC 的患者 UFC ＞ULN。治疗期间 11-脱氧皮质醇、11-脱氧皮质酮和促肾上腺皮质激素水平升高，停药后下降。收缩压和舒张压分别较基线下降 10.0 和 6.0mmHg。LCI699 总体耐受性良好；大多数不良事件（AE）为轻度或中度。最常见的 AE 包括疲劳（7/12）、恶心（5/12）和头痛（3/12）。未报告严重与药物相关的 AE。
在这项概念验证研究中，LCI699 治疗库欣病患者有效且耐受性良好。
