Concentration-QTc Relationship from a Single Ascending Dose Study of ANAVEX3-71, a Novel Sigma-1 Receptor and Allosteric M1 Muscarinic Receptor Agonist in Development for the Treatment of Frontotemporal Dementia, Schizophrenia, and Alzheimer's Disease.

Abstract

This is the cardiodynamic evaluation of a single ascending dose study in healthy participants with the primary objective of assessing the effect of ANAVEX3-71, formerly AF710B, on ECG parameters. Twelve-lead ECGs were obtained at 3 time points within 1hour prior to dosing to establish a baseline and then serially postdose. Concentration-QTc analysis of plasma concentrations of ANAVEX3-71 and metabolite M8 was conducted. ANAVEX3-71 at the studied doses did not have a clinically relevant effect on heart rate or on the PR and QRS intervals. ANAVEX3-71 alone was retained in the primary model due to small fit differences between models which included the metabolite M8. The estimated population slope of the concentration-QTcF relationship was small and slightly negative: -0.017ms per µg/L, with a small treatment effect-specific intercept of -0.49ms. An effect on the placebo-corrected, change-from-baseline QTc exceeding 10ms can be excluded within the full observed ranges of plasma concentrations of ANAVEX3-71 and M8 up to ∼996 and ∼58µg/L, respectively. The results from this cardiodynamic evaluation demonstrated that ANAVEX3-71 at single ascending doses of 5-200mg had no clinically relevant effects on any of the studied ECG parameters.