Levoketoconazole in the Treatment of Endogenous Cushing’s Syndrome: a Double-Blind, Placebo-Controlled, Randomized Withdrawal Study

The current study (LOGICS) evaluated the drug-specificity of cortisol normalization in adults with endogenous Cushing’s syndrome (CS) by randomly withdrawing levoketoconazole (L-KTZ) versus continuing the drug. Notably, efficacy and safety of L-KTZ was previously demonstrated in a phase 3, open-label study (SONICS).

Methods:

LOGICS was a phase 3, double-blind, placebo (PBO)-controlled, randomized withdrawal (RW) study that investigated L-KTZ in adults with CS via an open-label titration-maintenance (TM) phase (14-19 wk) followed by a double-blind RW phase (8 wk) and a restoration phase (8 wk). The primary endpoint was the proportion of patients with loss of mean urinary free cortisol (mUFC) response during RW. Secondary endpoints included mUFC normalization at the end of RW and changes in comorbidity biomarkers.

Results:

79 patients with CS (mean mUFC: 5.4× ULN; Cushing’s disease: n=70) received ascending doses of L-KTZ, as needed, to normalize mUFC; 39 patients on a stable dose (for ~4 wk or more) proceeded to RW. These 39 patients and 5 SONICS study completers (without dose titration) were randomly assigned to receive L-KTZ (n=22) or PBO (n=22). During RW, 21 patients on PBO (95.5%) met the primary endpoint of loss of mUFC response versus 9 continuing L-KTZ (40.9%); treatment difference: -54.5% (95% CI: -75.7, -27.4; P=0.0002). At the end of RW, mUFC normalization was observed among 11 patients (50.0%) receiving L-KTZ and 1 patient (4.5%) receiving PBO; treatment difference: 45.5% (95% CI: 19.2, 67.9; P=0.0015). Restoration of L-KTZ therapy reversed loss of cortisol control in most patients who had received PBO. Mean change from RW baseline to end of RW in total cholesterol was -0.04 mmol/L for L-KTZ and +0.9 mmol/L for PBO (P=0.0004); mean change in LDL cholesterol was -0.006 mmol/L and +0.6 mmol/L, respectively (P=0.0056). Mean increases in cholesterol observed in the PBO group during RW were reversed during the restoration phase. The most common adverse events (AEs) during L-KTZ treatment (all phases combined) were nausea (29%) and hypokalemia (26%). Prespecified AEs of special interest with L-KTZ were liver-related (10.7%), QT interval prolongation (10.7%), and adrenal insufficiency (9.5%).

Discussion/Conclusion:

Treatment with L-KTZ benefitted patients with CS of different etiologies and a wide range in UFC elevations at baseline by normalization of mUFC in half of the patients and concurrent improvements in serum cholesterol. These benefits were established as L-KTZ–specific via loss of therapeutic effect upon withdrawal to PBO and restoration upon reintroduction of L-KTZ. No new safety signals of L-KTZ treatment were identified, and known risks were manageable with appropriate monitoring.