Levoketoconazole in the Treatment of Patients With Cushing's Syndrome and Diabetes Mellitus: Results From the SONICS Phase 3 Study

Abstract

Background: Cushing's syndrome (CS) is associated with numerous comorbidities, including diabetes mellitus (DM). Levoketoconazole, an orally administered ketoconazole stereoisomer, is in clinical trials for the treatment of CS.

Methods: SONICS, a prospective, open-label, phase 3 study in adults with confirmed CS and mean 24-h urinary free cortisol (mUFC) ≥1.5× ULN, included dose-titration, 6-month maintenance, and 6-month extension phases. This subanalysis evaluated the efficacy of levoketoconazole in patients with DM (n = 28) or without DM (n = 49) who entered the maintenance phase. Safety was evaluated in the overall population (N = 94) during the dose-titration and maintenance phases.

Results: Normalization of mUFC at the end of maintenance phase (EoM), without a dose increase during maintenance (SONICS primary endpoint) was observed in 46% of patients with DM (95% CI, 28 to 66%; P = 0.0006 vs null hypothesis of ≤20%) and 33% of patients without DM (95% CI, 20 to 48%; P = 0.0209). At EoM, mean HbA1c decreased from 6.9% at baseline to 6.2% in patients with DM and from 5.5 to 5.3% in patients without DM. Mean fasting blood glucose decreased from 6.85 mmol/L (123.4 mg/dl) to 5.82 mmol/L (104.9 mg/dl) and from 5.11 mmol/L (92.1 mg/dl) to 4.66 mmol/L (84.0 mg/dl) in patients with and without DM, respectively. Adverse events that were more common in patients with DM included nausea (58.3%), vomiting (19.4%), and urinary tract infection (16.7%); none prompted study drug withdrawal.

Conclusions: Treatment with levoketoconazole led to sustained normalization of mUFC and improvement in glycemic control that was more pronounced in patients with DM.

Clinical trial registration: (ClinicalTrials.gov), NCT01838551.

Keywords: Cushing’s disease; Cushing’s syndrome; diabetes mellitus; hypercortisolism; levoketoconazole.

Conflict of interest statement

The authors declare that this study was funded by Cortendo AB (a subsidiary of Strongbridge Biopharma). Strongbridge Biopharma was involved in the study design and implementation, data collection and analysis, and critical review of the report. RP reports serving as the principal investigator of research grants to Federico II University from Corcept Therapeutics, Novartis, and Strongbridge Biopharma and receiving consulting honoraria from Novartis and Strongbridge Biopharma. AE reports serving as the principal investigator/sub-investigator of clinical trials for Corcept Therapeutics and Novartis and receiving consulting honoraria from Novartis. MF reports serving as an investigator with research grants to OHSU for Novartis and Strongbridge and serving as an occasional consultant to Novartis and Strongbridge. RF reports receiving research grants from Novartis and serving on the speakers’ bureau for HRA Pharma and Novartis. PW reports receiving travel grants from Ipsen and Novartis and receiving personal fees as a clinical investigator from Ipsen, Novartis, Novo Nordisk, and Strongbridge Biopharma. YG reports serving as the principal investigator of research grants to Tel Aviv-Sourasky Medical Center from Chiasma, Novartis, and Strongbridge Biopharma and receiving lecture fees from Medison, Novartis, and Pfizer. EG reports serving as an investigator for research grants to MSKCC from Ionis, Novartis, and Strongbridge Biopharma and serving as an occasional consultant to Novartis and Strongbridge Biopharma. LS reports receiving lecture fees from Novartis and receiving travel grants from Medison and Novartis. FC is an employee of Strongbridge Biopharma. GA reports receiving lecture fees from Novartis and Otsuka and receiving consulting honoraria from HRA Pharma. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Pivonello, Elenkova, Fleseriu, Feelders, Witek, Greenman, Geer, Perotti, Saiegh, Cohen and Arnaldi.

Figures

Figure 1

Patient disposition. ITT population included all patients who received ≥1 dose of study medication. Maintenance population consisted of all patients who entered the maintenance phase and received ≥1 dose of study medication during this phase. DM, diabetes mellitus; ITT, intent-to-treat.

Figure 2

Measures of glycemic control over time, (A) hemoglobin A1c and (B) fasting blood glucose (maintenance population). D, day; DM, diabetes mellitus; FBG, fasting blood glucose; HbA1c, hemoglobin A1c; M, month; SE, standard error.