C. H. Nelson, L. Fang, F. Cheng, L. Wang, M. Hepner, J. Lin, S. Ramanathan; Gilead Sciences, Foster City, CA
BACKGROUND: GS-4997, an apoptosis signal-regulating kinase-1 inhibitor, is in development to treat diabetic kidney disease and pulmonary arterial hypertension. A first-in-human study entailed pharmacokinetic and time-matched triplicate electrocardiograms (ECGs) evaluation. The effect of GS-4997 on QTc intervals was determined using concentration-QTc modeling.
METHODS: Healthy subjects (N=81) received single or multiple GS-4997 doses (1 to 100 mg once daily) or placebo in a randomized, double-blinded study. ECG acquisition, review, and analysis were performed consistent with thorough QT study standards. Concentration-ΔQTcF relationship was evaluated with linear mixed effects models. Bootstrapped 90% confidence intervals (CIs) of predicted baseline-adjusted, placebo-corrected QTcF (ΔΔQTcF) at therapeutic (18 mg) and supratherapeutic (100 mg; based on intrinsic and extrinsic factors) GS-4997 levels were determined. False-positive and false-negative rates (using Monte Carlo simulations [N=1000]), sensitivity and goodness-of-fit analyses were performed.
RESULTS: Per primary hypothesis testing, the predicted ΔΔQTcF (90% CI) at the geometric mean Cmax of GS-4997 at doses up to 100 mg were below 10 msec threshold; estimated slope for concentration-ΔΔQTcF was near zero (0.0009 msec/ng/mL). Consistent results were obtained with sensitivity analyses using reduced models. Goodness-of-fit model evaluations, including residual plots, supported overall model fit. The power to detect a positive QTcF effect was 93.5% and false-positive rate was 0%.
CONCLUSION: The results of the concentration-QTc analyses indicate that GS-4997 does not have a QT prolongation effect.