LCI699, a potent 11β-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing's disease: results from a multicenter, proof-of-concept study
| Autor: | Mario Maldonado, Rosario Pivonello, Maria Fleseriu, Catherine Watson, Ann Taylor, Marco Boscaro, Beverly M. K. Biller, Yiming Zhang, Xavier Bertagna, Amir H. Hamrahian, Paul Robinson |
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| Přispěvatelé: | Bertagna, X, Pivonello, Rosario, Fleseriu, M, Zhang, Y, Robinson, P, Taylor, A, Watson, Ce, Maldonado, M, Hamrahian, Ah, Boscaro, M, Biller, B. M., Biller, Bm |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Adult
Male medicine.medical_specialty Hydrocortisone Pyridines Endocrinology Diabetes and Metabolism Urinary system Clinical Biochemistry Urinalysis Biochemistry Endocrinology Reference Values Internal medicine Urinary free cortisol medicine Clinical endpoint Humans In patient Pituitary ACTH Hypersecretion Osilodrostat Dose-Response Relationship Drug Adult patients business.industry Biochemistry (medical) Imidazoles Cushing's disease Middle Aged medicine.disease Treatment Outcome Cortisol synthesis Feasibility Studies Steroid 11-beta-Hydroxylase Female business |
| Popis: | 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] levels1.5 × 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 wasULN 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. |
| Databáze: | OpenAIRE |
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