Osilodrostat Treatment of Cushing Syndrome in Real-World Clinical Practice: Findings From the ILLUSTRATE study

Abstract

Context: In clinical trials, osilodrostat (11β-hydroxylase inhibitor) effectively reduced cortisol levels in patients with endogenous Cushing syndrome (CS).

Objectives: A real-world study (ILLUSTRATE) was conducted evaluating osilodrostat use in patients with various etiologies of CS in the United States.

Methods: A retrospective chart-review study was conducted of adults with CS treated with osilodrostat between May 1, 2020, and October 29, 2021.

Results: A total of 42 patients (Cushing disease, n = 34; CS due to adrenal adenoma, n = 5; ectopic adrenocorticotropin syndrome [EAS], n = 3) were included. Starting doses were 2 mg twice daily in 27/42 patients (64.3%), maintenance doses were 2 mg twice daily in 6 of 9 patients (66.7%) attaining them. During osilodrostat treatment, urinary free cortisol (UFC) decreased below the upper limit of normal (ULN) in 14 of 20 patients (70.0%) with pretreatment UFC greater than the ULN. Osilodrostat response was observed across a range of doses (2-20 mg/day). In Cushing disease, median UFC and late-night salivary cortisol decreased from 3.03 and 2.39 × ULN, respectively, to 0.71 and 1.13 × ULN at last assessment in those with available data (n = 17 and 8, respectively). UFC decreased in all patients with adrenal CS or EAS with available data (n = 2 each). There were no unexpected safety signals; the most common adverse events (incidence ≥20%) were fatigue, nausea, and lower-extremity edema. Glucocorticoid withdrawal syndrome and/or adrenal insufficiency were reported in 12 of 42 patients (28.6%) after osilodrostat initiation, resulting in treatment discontinuation in 4.

Conclusion: In routine practice with dosing individualized according to clinical condition, response, and tolerability, osilodrostat was effective and well tolerated regardless of CS etiology and severity.

Keywords: Cushing disease; adrenal Cushing syndrome; ectopic adrenocorticotropin syndrome; osilodrostat; real world; retrospective.

Figure 1.

A, Total osilodrostat daily starting dose* in all patients (n = 42) and B, dose changes postinitiation (by etiology) in patients with at least one clinical encounter after initiating osilodrostat (n = 40). *Osilodrostat starting doses were given twice daily in all except 3 patients with Cushing disease (initiated on 1 mg once daily, 2 mg once daily, and 4 mg once daily) and 1 patient with adrenal CS (initiated on 1 mg once daily).

Figure 2.

Changes in A, UFC; B, LNSC; and C, morning serum cortisol in individual patients. *In patient 23, the first and last doses recorded were both 2 mg twice daily; during the follow-up period, 2 changes in dose were recorded the same day on 2 separate occasions.

Figure 3.

Individual osilodrostat dosing, UFC, and serum cortisol levels during the study period in illustrative patients. ULN for UFC was 50 μg/24 hours for patients 11, 4, and 1 and 42 μg/24 hours for patient 2. *ULN for serum cortisol was not provided for this patient, so it was estimated to be approximately 18 µg/dL.