title: Osilodrostat, a potent oral 11β-hydroxylase inhibitor: 22-week, prospective, Phase II study in Cushing's disease.
abstract: OBJECTIVE
  In a 10-week proof-of-concept study (LINC 1), the potent oral 11β-hydroxylase inhibitor osilodrostat (LCI699) normalized urinary free cortisol (UFC) in 11/12 patients with Cushing's disease. The current 22-week study (LINC 2; NCT01331239) further evaluated osilodrostat in patients with Cushing's disease.
  
  
  METHODS
  Phase II, open-label, prospective study of two patient cohorts. Follow-up cohort: 4/12 patients previously enrolled in LINC 1, offered re-enrollment if baseline mean UFC was above ULN. Expansion cohort: 15 newly enrolled patients with baseline UFC > 1.5 × ULN. In the follow-up cohort, patients initiated osilodrostat twice daily at the penultimate efficacious/tolerable dose in LINC 1; dose was adjusted as needed. In the expansion cohort, osilodrostat was initiated at 4 mg/day (10 mg/day if baseline UFC > 3 × ULN), with dose escalated every 2 weeks to 10, 20, 40, and 60 mg/day until UFC ≤ ULN. Main efficacy endpoint was the proportion of responders (UFC ≤ ULN or ≥50% decrease from baseline) at weeks 10 and 22.
  
  
  RESULTS
  Overall response rate was 89.5% (n/N = 17/19) at 10 weeks and 78.9% (n/N = 15/19) at 22 weeks; at week 22, all responding patients had UFC ≤ ULN. The most common AEs observed during osilodrostat treatment were nausea, diarrhea, asthenia, and adrenal insufficiency (n = 6 for each). New or worsening hirsutism (n = 2) and/or acne (n = 3) were reported among four female patients, all of whom had increased testosterone levels.
  
  
  CONCLUSIONS
  Osilodrostat treatment reduced UFC in all patients; 78.9% (n/N = 15/19) had normal UFC at week 22. Treatment with osilodrostat was generally well tolerated.
authors.affiliation: Northwest Pituitary Center, Departments of Medicine and Neurological Surgery, Oregon Health and Science University, Portland, OR, USA. fleseriu@ohsu.edu.
authors.forename: Maria
authors.initials: M
authors.lastname: Fleseriu
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Pivonello
authors.affiliation: Department of Endocrinology, Hôpital Bicêtre, Université Paris-Sud, Assistance Publique Hôpitaux de Paris, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Young
authors.affiliation: Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Amir H
authors.initials: AH
authors.lastname: Hamrahian
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Molitch
authors.affiliation: Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital, Sapporo, Japan.
authors.forename: Chikara
authors.initials: C
authors.lastname: Shimizu
authors.affiliation: Division of Endocrinology and Metabolism, Chiba University Hospital, Chiba-city, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Shimatsu
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: White
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Hilliard
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: Tian
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Sauter
authors.affiliation: Neuroendocrine Clinical Center, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Beverly M K
authors.initials: BM
authors.lastname: Biller
authors.affiliation: Department of Endocrinology, Centre de Référence des Maladies Rares de la Surrénale, Hôpital Cochin, Faculté de Médecine Paris Descartes, Université Paris 5, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Bertagna
mesh_terms: D000284:Administration, Oral; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000368:Aged; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006854:Hydrocortisone / Q000652:urine; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D047748:Pituitary ACTH Hypersecretion / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects*; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; C553306:Osilodrostat; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone
keywords: 11β-hydroxylase; Cortisol; Cushing’s; LCI699; Osilodrostat