Abstract
Objective: To investigate the long-term efficacy and tolerability of osilodrostat, a potent oral 11β-hydroxylase inhibitor, for treating Cushing's disease (CD). Design/methods: A total of 137 adults with CD and mean 24-h urinary free cortisol (mUFC) > 1.5 × upper limit of normal (ULN) received osilodrostat (starting dose 2 mg bid; maximum 30 mg bid) during the prospective, Phase III, 48-week LINC 3 (NCT02180217) core study. Patients benefiting from osilodrostat at week 48 could enter the optional extension (ending when all patients had received ≥ 72 weeks of treatment or discontinued). Efficacy and safety were assessed for all enrolled patients from the core study baseline. Results: Median osilodrostat exposure from the core study baseline to study end was 130 weeks (range 1-245) and median average dose was 7.4 mg/day (range 0.8-46.6). The reduction in mean mUFC achieved during the core was maintained during the extension and remained ≤ ULN. Of 106 patients, 86 (81%) patients who entered the extension had mUFC ≤ ULN at week 72. Improvements in cardiovascular/metabolic-related parameters, physical manifestations of hypercortisolism (fat pads, central obesity, rubor, striae, and hirsutism in females), and quality of life in the core study were also maintained or improved further during the extension. No new safety signals were reported; 15/137 (10.9%) and 12/106 (11.3%) patients discontinued for adverse events during the core and extension, respectively. Mean testosterone in females decreased towards baseline levels during the extension. Conclusions: Data from this large, multicentre trial show that long-term treatment with osilodrostat sustains cortisol normalisation alongside clinical benefits in most patients with CD and is well tolerated.
| Original language | English |
|---|---|
| Pages (from-to) | 531-541 |
| Number of pages | 11 |
| Journal | European Journal of Endocrinology |
| Volume | 187 |
| Issue number | 4 |
| Early online date | 16 Sept 2022 |
| DOIs | |
| Publication status | Published - Oct 2022 |
Bibliographical note
Funding Information:Janssen Pharmaceuticals, Crinetics Pharmaceuticals, OMass Therapeutics, Quest Diagnostics, Adrenas Therapeutics, and PhaseBio. C S reports occasional consulting honoraria from HRA, ?ovartis, Recordati, Pfizer, and Sandoz. Z B has no conflicts of interest to disclose. R A F reports research grants from Strongbridge and Corcept Therapeutics and consultancy fees from Recordati Rare Diseases and Corcept Therapeutics. G V reports serving as a speaker and consultant for Novartis, HRA Pharma, and Recordati and as a research investigator for Novartis, Corcept, and Recordati. G H reports serving as a consultant for ?ovartis. R W has no conflicts of interest to disclose. M I and M R are employees of Novartis. A M P and A P are employees of Recordati. B M K B reports research grants to her institution from Novartis, Strongbridge, and Millendo and occasional consulting honoraria from HRA Pharma, Recordati Rare Diseases, and Sparrow; she served as a member of the LINC 3 steering committee.
Publisher Copyright:
© 2022 The authors Published by Bioscientifica Ltd.
