QT effect of semagacestat at therapeutic and supratherapeutic doses

This thorough QT/ QT interval corrected for heart rate (QTc) study was designed to assess the potential of semagacestat, a functional gamma-secretase inhibitor, to delay cardiac repolarization.

In this Phase I, single-dose, randomized, 4-period crossover study, semagacestat was compared with placebo in 54 healthy male and female subjects between the ages of 19 and 63 years, inclusive. Each study period included single oral-dose administrations of semagacestat 140 mg, semagacestat 280 mg, moxifloxacin 400 mg, or placebo. Study subjects and the investigator were blinded to the identity of semagacestat and placebo; however, moxifloxacin was administered as open-label. Moxifloxacin was compared with placebo for assay sensitivity analysis. Pharmacokinetic parameters were also assessed.

For each QTc, the upper bound of the 2-sided 90% confidence interval (CI) for the least squares mean difference between semagacestat (at both the 140- and 280-mg dose levels) and placebo was < 10 msec at all time points, and thus, within the limits set for clinical relevance in regulatory guidelines.

The results of this study indicate that single doses of 140 and 280 mg semagacestat did not prolong QTc to a clinically significant degree.