Robinson, Paul, Watson, Catherine, Taylor, Ann, Maldonado-Lutomirsky, Mario, Zhang, Yiming, Bertagna, Xavier, Pivonello, Rosario, Fleseriu, Maria, Hamrahian, Amir H, Boscaro, Marco and Biller, Beverly MK (2014) LCI699, a potent 11β-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing’s disease: results from a multicenter, proof-of-concept study. Journal of Clinical Endocrinology and Metabolism.

Abstract

Introduction: The clinical features and increased mortality associated with Cushing’s syndrome results 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 syndrome.
Methods: Adult patients with moderate-to-severe Cushing’s disease (urinary free cortisol [UFC] levels >1.5 fold above ULN) received oral LCI699 for 10 weeks in this proof-of-concept, open-label study. LCI699 was initiated at 4 mg/day in two divided doses, then the dose was escalated every 14 days to 10, 20, 40 and 100 mg/day until UFC normalized, whereupon the dose was maintained until active treatment ended (day 70). Patients were monitored until day 84. The primary endpoint was UFC≤ULN or a ≥50% decrease from baseline at day 70.
Results: 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. After treatment discontinuation (day 84), UFC was >ULN in all 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; the most common adverse events included fatigue (7/12), nausea (5/12) and headache (3/12). No serious drug-related adverse events were reported.
Conclusion: LCI699 was efficacious and well tolerated in patients with Cushing’s disease enrolled in this proof-of-concept study.

Item Type:	Article
Keywords:	LCI699, 11β-hydroxylase, Cushing’s
Date Deposited:	26 Apr 2016 23:46
Last Modified:	26 Apr 2016 23:46
URI:	https://oak.novartis.com/id/eprint/9928