Exposure-QT analysis for sonidegib (LDE225), an oral inhibitor of the hedgehog signaling pathway, for measures of the QT prolongation potential in healthy subjects and in patients with advanced solid tumors.

PURPOSE: Sonidegib prevents activation of the Hedgehog signal transduction pathway. This PK-QT analysis has been performed to test for potential prolongation of the QT/QTc interval during extended use, and to understand the exposure-QT relationship for sonidegib in patients and in healthy volunteers (HV).

METHODS: A pooled analysis of the change in QT interval corrected for heart rate according to Fridericia's formula was conducted across four patient studies from a total of 341 patients (n = 211, 102, 21, and 7 from the phase II pivotal study A2201, study X2101, study X1101, and study B2209, respectively), and across four healthy volunteer studies from a total of 204 healthy volunteers (n = 146, 36, 16, and 6 from study A2114, study A1102, study A2108, and study A2110, respectively). A PK/ECG subgroup of 62 patients from the pivotal study A2201 was also analyzed to assess the QT prolongation risk at steady-state exposures. Sonidigib PK and ECG data were matched to determine the change from baseline in QTcF using a linear mixed-effect model.

RESULTS: Clinical data indicate sonidegib does not cause QTc prolongation. ΔQTcF at steady-state concentrations for both 200 and 800-mg doses were all below 5 ms. The highest mean ΔQTcF at steady state was -3.9 ms at week 17 pre-dose in the sonidegib 200-mg group and 2.7 ms at 2-h post-dose in the sonidegib 800-mg group. The upper one-sided 95 % confidence interval of the estimated ΔQTcF at steady-state concentrations from the linear mixed-effect models were all <10 ms. No cases of ventricular arrhythmia or torsades de pointes and no deaths associated with QT prolongation have been reported in the sonidegib clinical development program.

CONCLUSIONS: Based on these analyses, there is no evidence of QT prolongation associated with sonidegib 200 or 800 mg in solid tumor patients and HV.