title: LCI699, a potent 11β-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing's disease: results from a multicenter, proof-of-concept study.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  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 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.
  
  
  CONCLUSIONS
  LCI699 was efficacious and well tolerated in patients with Cushing's disease enrolled in this proof-of-concept study.
authors.affiliation: 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.
authors.forename: Xavier
authors.initials: X
authors.lastname: Bertagna
authors.forename: Rosario
authors.initials: R
authors.lastname: Pivonello
authors.forename: Maria
authors.initials: M
authors.lastname: Fleseriu
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhang
authors.forename: Paul
authors.initials: P
authors.lastname: Robinson
authors.forename: Ann
authors.initials: A
authors.lastname: Taylor
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Watson
authors.forename: Mario
authors.initials: M
authors.lastname: Maldonado
authors.forename: Amir H
authors.initials: AH
authors.lastname: Hamrahian
authors.forename: Marco
authors.initials: M
authors.lastname: Boscaro
authors.forename: Beverly M K
authors.initials: BM
authors.lastname: Biller
mesh_terms: D000328:Adult; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000652:urine*; D007093:Imidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D047748:Pituitary ACTH Hypersecretion / Q000188:drug therapy* / Q000652:urine*; D011725:Pyridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012016:Reference Values; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D016482:Urinalysis / Q000592:standards
chemical_list: D007093:Imidazoles; D011725:Pyridines; C553306:Osilodrostat; D013252:Steroid 11-beta-Hydroxylase; D006854:Hydrocortisone