Randomized Trial of Osilodrostat for the Treatment of Cushing Disease

Mônica Gadelha*, Marie Bex, Richard A. Feelders, Anthony P. Heaney, Richard J. Auchus, Aleksandra Gilis-Januszewska, Przemyslaw Witek, Zhanna Belaya, Yerong Yu, Zhihong Liao, Chih Hao Chen Ku, Davide Carvalho, Michael Roughton, Judi Wojna, Alberto M. Pedroncelli, Peter J. Snyder

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

40 Citations (Scopus)
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Context: Cushing disease, a chronic hypercortisolism disorder, is associated with considerable morbidity and mortality. Normalizing cortisol production is the primary treatment goal.

Objective: We aimed to evaluate the safety and efficacy of osilodrostat, a potent, orally available 11βhydroxylase inhibitor, compared with placebo in patients with Cushing disease.

Methods: LINC 4 was a phase III, multicenter trial comprising an initial 12-week, randomized, double-blind, placebo-controlled (osilodrostat:placebo, 2:1) period followed by a 36-week, open-label treatment period (NCT02697734). Adult patients (aged 18-75 years) with confirmed Cushing disease and mean urinary free cortisol (mUFC) excretion1.3 times the upper limit of normal (ULN) were eligible. The primary endpoint was the proportion of randomized patients with mUFC≤ULN at week 12. The key secondary endpoint was the proportion achieving mUFC≤ULN at week 36 (after 24 weeks' open-label osilodrostat).

Results: Seventy-three patients (median age, 39 years [range, 19-67]; mean/median mUFC, 3.1×ULN/2.5×ULN) received randomized treatment with osilodrostat (n=48) or placebo (n=25). At week 12, significantly more osilodrostat (77%) than placebo (8%) patients achieved mUFC≤ULN (odds ratio 43.4; 95% CI 7.1, 343.2; P<0.0001). Response was maintained at week 36, when 81% (95% CI 69.9, 89.1) of all patients achieved mUFC≤ULN. The most common adverse events during the placebo-controlled period (osilodrostat vs placebo) were decreased appetite (37.5% vs 16.0%), arthralgia (35.4% vs 8.0%), and nausea (31.3% vs 12.0%).

Conclusion: Osilodrostat rapidly normalized mUFC excretion in most patients with Cushing disease and maintained this effect throughout the study. The safety profile was favorable.

Original languageEnglish
Pages (from-to)E2882-E2895
JournalJournal of Clinical Endocrinology and Metabolism
Issue number7
Early online date23 Mar 2022
Publication statusPublished - 1 Jul 2022

Bibliographical note

Publisher Copyright:
© 2022 The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.


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