ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 63 GP166 | DOI: 10.1530/endoabs.63.GP166

Results from the phase 3 multicenter SONICS study of levoketoconazole: subgroup analysis of Cushing's syndrome patients with diabetes mellitus

Maria Fleseriu1, Rosario Pivonello2, Atanaska Elenkova3, Roberto Salvatori4, Richard J. Auchus5, Richard A. Feelders6, Eliza B. Geer7, Yona Greenman8, Przemyslaw Witek9, Frederic Cohen10 & Beverly MK Biller11

1Oregon Health and Science University, Portland, OR, USA; 2University of Naples Federico II, Naples, Italy; 3Medical University Sofia, Sofia, Bulgaria; 4Johns Hopkins University, Baltimore, MD, USA; 5University of Michigan Medical School, Ann Arbor, MI, USA; 6Erasmus Medical Center, Rotterdam, Netherlands; 7Memorial Sloan Kettering Cancer Center, New York, NY, USA; 8Tel Aviv University, Tel Aviv, Israel; 9Military Institute of Medicine, Warsaw, Poland; 10Strongbridge Biopharma, Trevose, PA, USA; 11Massachusetts General Hospital, Boston, MA, USA.

Background: Cushing’s syndrome (CS) has numerous comorbidities, including diabetes mellitus (DM). Levoketoconazole is a ketoconazole stereoisomer in clinical trials for treatment of CS.

Methods: SONICS is a prospective, open-label, phase 3 maintenance-of-benefit study in adults with confirmed CS and mean urinary free cortisol (mUFC) of ≥1.5x upper limit of normal (ULN). Repeated hospitalization due to hyperglycemia or any complication related to DM during the previous 12 months were exclusion criteria. There were 3 study phases: dose-titration (DT; to normalize mUFC; 2–21 weeks), maintenance (M; 6 months), and extension (6 months). The study met the primary end point of mUFC normalization at the end of M (EoM) without a preceding dose increase during M as recently described (Fleseriu M, et al. ICE 2018). Secondary end points included measures of glycemic control: fasting blood glucose (FBG) and hemoglobin A1c (HbA1c). This analysis compares patients with DM to overall study population.

Results: Intention-to-treat (ITT) population comprised 94 patients; 77 completed DT, 61 completed M. At baseline, overall median (range) age was 44 (18–75) years; 82% were female; 85% had Cushing’s disease (CD); and 38% had DM at screening. In 36 patients with DM: median (range) age was 48 (22–75) years; 92% were female; 81% had CD. Median (range) baseline mUFC was similar for the DM subset (2.6x [1.2x–30x] ULN) and ITT population (3.0x [1.2x–30x] ULN). At EoM, 30% (95% CI, 21%–40%) of ITT population achieved the primary end point; DM was not a significant factor in the mUFC normalization model (odds ratio 1.25; P=0.6058). In the DM subset, 34% had mUFC normalization (95% CI, 19%–53%). Patients with versus without DM had mean baseline FBG of 123 mg/dL versus 92 mg/dL, and HbA1c of 6.9% versus 5.5%; at EoM, mean FBG was 105 mg/dL versus 84 mg/dL, and mean HbA1c was 6.2% versus 5.3%. Adverse events (AEs) were reported for 97% of DM and 98% of ITT patients; 11% with DM and 13% of ITT discontinued due to AEs. The most common AEs in DM patients were nausea (58%), vomiting (19%), and urinary tract infection (17%); and in ITT population were nausea (32%), headache (28%), and peripheral edema (19%).

Conclusions: In this prospective trial, levoketoconazole at a stable therapeutic dose maintained mUFC normalization for 6 months in 34% of patients with DM versus 30% in the ITT population. Improvements in HbA1c were more notable among patients with DM.