SAT-452 Results from the Phase 3 Multicenter SONICS Study of Levoketoconazole: Subgroup Analysis of Cushing's Syndrome (CS) Patients with Diabetes Mellitus (DM)

Abstract

Background: Cushing’s syndrome (CS) has numerous comorbidities, including diabetes mellitus (DM).1 Levoketoconazole is a ketoconazole stereoisomer in clinical trials for the 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 last 12 mo were exclusion criteria. There were 3 phases: dose-titration (DT; to normalize mUFC; 2-21 weeks), maintenance (M; 6 mo), and extension (6 mo). 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.2 The key secondary end points were changes in DM control, using fasting blood glucose (FBG) and hemoglobin A1c (HbA1c). This analysis compares patients with baseline (BL) DM to the overall study population. Results: Of 201 screened, 94 enrolled, constituting the intention-to-treat (ITT) population; 77 completed DT, 61 completed M. At BL, overall median (range) age was 44 (18-75) y; 82% were female; 85% had Cushing disease (CD); and 38% had DM at screening. In those with DM: median (range) age was 48 (22-75) y; 92% were female; 81% had CD. The median (range) BL mUFC for the DM subset of 2.6x (1.2x-30x) ULN was similar to the ITT population of 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 DM and those without DM had mean BL FBG of 123 mg/dL:92 mg/dL and HbA1c of 6.9%:5.5%; at EoM, the mean FBG was 105 mg/dL:84 mg/dL and the mean HbA1c was 6.2%:5.3%. In the overall M population, mean BL FBG was 104 mg/dL and mean BL HbA1c was 6.0%; at EoM, mean FBG was 91 mg/dL and mean HbA1c was 5.6%. Treatment-emergent adverse events (TEAEs) were reported for 97% of DM and 98% of ITT, with 42% and 43%, respectively, reporting ≥1 probably/definitely drug-related TEAE. Overall, 11% with DM and 13% of ITT discontinued due to TEAEs. Most common TEAEs in DM were nausea (58%), vomiting (19%), and urinary tract infection (17%); among ITT 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 mo in 34% of patients with DM at screening vs 30% in the ITT population. Improvements in HbA1c in the M population were more notable among patients with DM. The rate of discontinuation due to TEAEs was low regardless of DM, but those with DM reported nausea, vomiting, and urinary tract infection more frequently.