PMID- 24423285
OWN - NLM
STAT- MEDLINE
DCOM- 20140603
LR  - 20220309
IS  - 1945-7197 (Electronic)
IS  - 0021-972X (Linking)
VI  - 99
IP  - 4
DP  - 2014 Apr
TI  - LCI699, a potent 11beta-hydroxylase inhibitor, normalizes urinary cortisol in 
      patients with Cushing's disease: results from a multicenter, proof-of-concept 
      study.
PG  - 1375-83
LID - 10.1210/jc.2013-2117 [doi]
AB  - INTRODUCTION: The clinical features and increased mortality associated with 
      Cushing's syndrome result from a chronic excess of circulating cortisol. As 
      LCI699 potently inhibits 11beta-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 x 
      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 x 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.
FAU - Bertagna, Xavier
AU  - Bertagna X
AD  - Department of Endocrinology (X.B.), Centre de Reference des Maladies Rares de la 
      Surrenale, Hopital Cochin, Faculte de Medecine Paris Descartes, Universite Paris 
      5, Paris 75014, France; Dipartimento di Medicina Clinica e Chirurgia (R.P.), 
      Universita 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.
FAU - Pivonello, Rosario
AU  - Pivonello R
FAU - Fleseriu, Maria
AU  - Fleseriu M
FAU - Zhang, Yiming
AU  - Zhang Y
FAU - Robinson, Paul
AU  - Robinson P
FAU - Taylor, Ann
AU  - Taylor A
FAU - Watson, Catherine E
AU  - Watson CE
FAU - Maldonado, Mario
AU  - Maldonado M
FAU - Hamrahian, Amir H
AU  - Hamrahian AH
FAU - Boscaro, Marco
AU  - Boscaro M
FAU - Biller, Beverly M K
AU  - Biller BM
LA  - eng
SI  - ClinicalTrials.gov/NCT01331239
PT  - Clinical Trial
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20131211
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - 0 (Imidazoles)
RN  - 0 (Pyridines)
RN  - 5YL4IQ1078 (Osilodrostat)
RN  - EC 1.14.15.4 (Steroid 11-beta-Hydroxylase)
RN  - WI4X0X7BPJ (Hydrocortisone)
SB  - IM
CIN - Nat Rev Endocrinol. 2014 Mar;10(3):127. PMID: 24393783
CIN - J Clin Endocrinol Metab. 2014 Apr;99(4):1157-60. PMID: 24702012
MH  - Adult
MH  - Dose-Response Relationship, Drug
MH  - Feasibility Studies
MH  - Female
MH  - Humans
MH  - Hydrocortisone/*urine
MH  - Imidazoles/pharmacokinetics/*therapeutic use
MH  - Male
MH  - Middle Aged
MH  - Pituitary ACTH Hypersecretion/*drug therapy/*urine
MH  - Pyridines/pharmacokinetics/*therapeutic use
MH  - Reference Values
MH  - Steroid 11-beta-Hydroxylase/*antagonists & inhibitors
MH  - Treatment Outcome
MH  - Urinalysis/standards
EDAT- 2014/01/16 06:00
MHDA- 2014/06/04 06:00
CRDT- 2014/01/16 06:00
PHST- 2014/01/16 06:00 [entrez]
PHST- 2014/01/16 06:00 [pubmed]
PHST- 2014/06/04 06:00 [medline]
AID - 10.1210/jc.2013-2117 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 2014 Apr;99(4):1375-83. doi: 10.1210/jc.2013-2117. Epub 
      2013 Dec 11.