Randomized Trial of Osilodrostat for the Treatment of Cushing Disease.

Abstract

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) excretion ≥ 1.3 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.

• Authors: 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
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 107 Issue 7 Pg. e2882-e2895 (06 16 2022) ISSN: 1945-7197 [Electronic] United States
• PMID: 35325149 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.

Chemical References

• Imidazoles
• Pyridines
• Osilodrostat
• Hydrocortisone

Topics

• Adult
• Double-Blind Method
• Humans
• Hydrocortisone (therapeutic use)
• Imidazoles (therapeutic use)
• Pituitary ACTH Hypersecretion (drug therapy)
• Pyridines
• Treatment Outcome