A Pooled Analysis of Three Randomized Phase I/IIa Clinical Trials Confirms Absence of a Clinically Relevant Effect on the QTc Interval by Umibecestat

Abstract

Umibecestat, an orally active β-secretase inhibitor, reduces the production of amyloid beta-peptide that accumulates in the brain of patients with Alzheimer's disease. The echocardiogram effects of umibecestat, on QTcF (Fridericia-corrected QT), on PR and QRS and heart rate (HR), were estimated by concentration-effect modeling. Three phase I/II studies with durations up to 3 months, with 372 healthy subjects over a wide age range, including both sexes and 2 ethnicities, were pooled, providing a large data set with good statistical power. No clinically relevant effect on QTcF, PR interval, QRS duration, or HR were observed up to supratherapeutic doses. The upper bound of 90% confidence intervals of the ∆QTcF was below the 10 ms threshold of regulatory concern for all concentrations measured. Prespecified sensitivity analysis confirmed the results in both sexes, in those over and below 60 years, and in Japanese subjects. All conclusions were endorsed by the US Food and Drug Administration (FDA).

Figure 1. Analysis of QTcF interval change vs. umibecestat plasma concentration

(a, b) Changes from baseline in QTcF vs. plasma concentrations for the pooled data set. (c) Analysis of QTcF interval change from baseline on day 1 (ECG/pharmacokinetic analysis set). The solid regression line describes the linear relationship between umibecestat plasma concentration (zero concentration for placebso) and ΔQTcF, estimated from a linear mixed effects model. The shaded area is the corresponding two‐sided 90% confidence band. The vertical dashed lines are drawn at the mean C_max at steady‐state of selected doses of umibecestat (35 mg and 85 mg after 13 weeks, 300 mg after 2 weeks) C_max, maximum concentration; ECG electrocardiography; QTcF, Fridericia corrected QT; ΔQTcF, QTcF change from baseline.

Figure 2

Hysteresis analysis on data from the first‐in‐human study for a single dose of 300 mg. (a) Hysteresis plots by timepoints. The graph shows the time profiles using mean QTcF change from baseline (ΔQTcF) by timepoint (blue line, y‐axis left) and concentration of umibecestat (red line, y‐axis right). The x‐axis represents the timepoints. (b) Hysteresis loop plots of QTcF change from baseline (ΔQTcF) and plasma concentrations of umibecestat by dose. The y‐axis represents the ΔQTcF (ms) and the x‐axis represents the plasma concentrations of umibecestat (ng/mL). The circles represent timepoints (in hours) postdosing on day 1. QTcF, Fridericia corrected QT; ΔQTcF, QTcF change from baseline.

Figure 3

Scatter plots of QT and QTcF against RR (ECG/PK analysis set). Diagnostic plots showing the correlation between QT and RR intervals measured at baseline in the ECG/PK analysis set on (a) Holter ECG data and (b) standard 12‐lead ECG data. These plots include data from all timepoints included in the ECG‐PK analysis (i.e., baseline and postdose timepoints). A regression line has been added to visualize trends in the data.ECG electrocardiography; PK, pharmacokinetic; QTcF, Fridericia corrected QT.

Figure 4

Analysis of changes from baseline for heart rate, PR interval and QRS interval. Changes from baseline in (a) HR, (b) PR interval, and (c) QRS duration, versus umibecestat plasma concentrations (ECG/PK analysis set). The solid regression line describes the linear relationship between umibecestat plasma concentration (zero concentration for placebo) and change from baseline, estimated from a linear mixed effects model. The shaded area is the corresponding two‐sided 90% confidence band. The vertical dashed lines are drawn at the mean C_max at the steady state of selected doses of umibecestat (35 mg and 85 mg after 13 weeks, 300 mg after 2 weeks). bpm, beats per minute; C_max, maximum concentration; ECG electrocardiography; HR, heart rate; ms, millisecond.