PI-051 - CONCENTRATION-QTC ANALYSIS TO ASSESS THE EFFECT OF THE GS-5718 ON CARDIAC REPOLARIZATION.

E. Weber¹, K. Anderson², I. Younis³, L. Dong¹, O. Gurtovaya¹, A. Othman¹; ¹Gilead Sciences, Foster City, CA, USA, ²EQRx International, Inc., Cambridge, MA, USA, ³Gilead Sciences, Herndon, VA, USA.

Background: GS-5718 is a potent and selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor in clinical development for treatment of inflammatory diseases. The objective of this work is to characterize the relationship between GS-5718 plasma concentrations and any potential changes in QT interval using data from the first-in-human study.

Methods: Cardiac safety assessments in healthy participants (N=79) administered GS-5718 as single (15 to 450 mg) or multiple (15 to 150 mg) doses or placebo, were performed with intensive, time-matched, 12-lead ECGs. Effects of GS-5718 on baseline-adjusted Fridericia’s corrected QT interval (ΔQTcF) were determined using linear mixed-effects models. The predicted placebo-corrected ΔQTcF (ΔΔQTcF) and 90% confidence intervals (CIs) were obtained from the linear mixed-effect model to evaluate the potential risk of QT prolongation. Plasma samples were collected over 144 hours and GS-5718 concentrations were determined using a validated LC-MS/MS method.

Results: At the highest evaluated single- (450 mg) and multiple-dose (150 mg, QD) in the first-in-human study, the predicted ΔΔQTcF (90%CI) were 1.77 (-0.14, 3.67) and 2.00 (-0.01, 4.01) msec, respectively. The upper bound of the predicted ΔΔQTcF 90% CI was below the 10 msec threshold of regulatory concern at these doses which are expected to cover supratherapeutic exposures of GS-5718.

Conclusion: GS-5718 does not prolong QT interval at exposures associated with expected therapeutic or supratherapeutic doses.