Evaluation Of The Effect Of Idelalisib On The QT/QTc Interval In Healthy Subjects

Idelalisib (IDELA) is a potent competitive inhibitor of the ATP binding site of the PI3K p110δ catalytic domain, which has been shown to be prominently expressed in cells of hematopoietic origin. IDELA displayed no significant inhibition of hERG channel activity for in vitro studies (IC50 ≥ 50 μM). ECG assessments in clinical studies indicated no evidence of QT interval prolongation or relationships between IDELA concentrations and QT or PR interval parameters over a dose range of 17 mg to 400 mg. A Phase 1, thorough QT study was performed in accordance with ICH E14 requirements for clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential of non-antiarrhythmic drugs. This study evaluated the effect of therapeutic and supratherapeutic doses of IDELA on QTc interval in healthy subjects, relative to matched placebo and active control.

A total of 48 subjects were enrolled in the study and randomized to one of two cohorts, each with a 4 x 4 Williams square design, to receive IDELA single dose at 150 (therapeutic dose) or 400 mg (supratherapeutic dose), placebo, or moxifloxacin at 400 mg (positive control) with 10 days of washout between each treatment. Multiple 12-lead time-matched ECGs were collected in triplicate at various time points over 24hours after each treatment and ECGs collected were obtained digitally using a Mortara H12+ Holter monitor. Time matched blood samples were collected and levels of IDELA and GS-563117 were measured using LC/MS/MS. Parametric analyses of covariance (ANCOVA) using a mixed-effects model were used to assess the change of QTc from predose baseline and proportionality of IDELA PK. A linear mixed effects model was used to quantify the relationship between IDELA plasma concentration and the DDQTc (time-matched, baseline-adjusted, placebo corrected QTc). Safety assessments were performed throughout the study.

A total of 48 subjects were enrolled into this study. The majority of subjects were Black or African-American (58.3%) or White (33.3%), with even distribution of female (47.9%) and male (52.1%), and with a mean age of 33 years (range, 20 to 45 years).  Study treatments were generally well tolerated.  The majority of AEs were reported as Grade 1 (mild) in severity. There were no clinically relevant changes in any hematology or chemistry parameter for any treatment (including IDELA 150 and 400 mg, placebo, and moxifloxacin). The majority of treatment-emergent laboratory abnormalities were Grade 1. Idelalisib was generally well-tolerated at therapeutic (150 mg) and supratherapeutic (400 mg) doses.

Plasma exposures IDELA and its major circulating metabolite GS-563117 were slightly less than dose-proportional between the 400 mg vs 150 mg (over a 2.7-fold dose range, IDELA and GS-563117 C_max increased ∼1.7- and ∼1.8-fold respectively; corresponding values for AUC_infincreased ∼2.3 and 2.4-fold, respectively). Following moxifloxacin treatment, the lower bound of the 2-sided 90% CI for the mean difference in QTcF between moxifloxacin and placebo was greater than 5 msec at 2 time points (3 and 4 hours) after dosing, thereby establishing assay sensitivity. Following IDELA treatment, the upper bounds of the 2-sided 90% CIs for the mean difference in QTcF between therapeutic or supratherapeutic doses of IDELA and placebo were below 10 msec at all time points after dosing, meeting the definition of a “negative” thorough QT study. Results from the analyses of secondary endpoints QTcB, QTcN, and QTcI were consistent with those from the primary QTcF analysis. There were no relevant relationships between time-matched, baseline-adjusted, placebo-corrected QTcF and IDELA or GS-563117 plasma concentrations.

In a study with demonstrated assay sensitivity, IDELA 150 mg and 400 mg administration did not affect QTc interval in healthy adults, and met the definition of a negative thorough QT study as defined by ICH guidance. There were no relevant relationships between time-matched, baseline-adjusted, placebocorrected QTcF and IDELA or GS-563117 plasma concentrations. Single oral doses of IDELA 150 mg and 400 mg were well tolerated.

Jin:Gilead Sciences: Employment, Equity Ownership. Robeson:Gilead Sciences: Employment, Equity Ownership. Zhou:Gilead Sciences: Employment, Equity Ownership. Nichols:Gilead Sciences: Employment. Ramanathan:Gilead Sciences: Employment, Equity Ownership.