Osilodrostat, a potent oral 11β-hydroxylase inhibitor: 22-week, prospective, Phase II study in Cushing’s disease

Maria Fleseriu*, Rosario Pivonello, Jacques Young, Amir H. Hamrahian, Mark E. Molitch, Chikara Shimizu, Tomoaki Tanaka, Akira Shimatsu, Tracy White, Annie Hilliard, Chuan Tian, Nicholas Sauter, Beverly M.K. Biller, Xavier Bertagna

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

Purpose: 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.

Original languageEnglish (US)
Pages (from-to)138-148
Number of pages11
JournalPituitary
Volume19
Issue number2
DOIs
StatePublished - Apr 1 2016

Keywords

  • 11β-hydroxylase
  • Cortisol
  • Cushing’s
  • LCI699
  • Osilodrostat

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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