D. A. Tatosian,1 N. Cardillo Marricco,2 X. Glasgow,1 B. DeGroot,3 K. Dunnington,3 L. George,1 I. Gendrano,1 A. O. Johnson-Levonas,1 D. Swearingen,4 E. Kauh1; 1Merck, Whitehouse Station, NJ, 2Celerion, Montreal, QC, Canada, 3Celerion, Lincoln, NE, 4Celerion, Tempe, AZ
BACKGROUND: Omarigliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor being developed as a once-weekly treatment for type 2 diabetes. Plasma concentration-QTc analysis was performed using data from the first in human single-ascending dose trial, and predicted a clinically insignificant 2.8 msec QTc prolongation at 10 μM, a concentration ~15-20-fold higher than the therapeutic Cmax.
METHODS: This double-blind, double-dummy, randomized, placebo- and active-comparator-controlled, 3-period, balanced crossover study definitively evaluated the effects of a supratherapeutic omarigliptin dose on the QTc interval. A population-specific correction of QT interval (QTcP) was used for the primary analysis. Healthy subjects (n=60) received treatments separated by ~28-day washout: A) single-dose 25 mg omarigliptin on Day 1, single-dose 175 mg omarigliptin on Day 2; B) placebo on Day 1, single-dose 400 mg moxifloxacin on Day 2; C) placebo on Days 1 and 2. Day 2 QTcP intervals were analyzed. The primary hypothesis was supported if the 90% CIs for the least squares mean differences between omarigliptin 175 mg and placebo in QTcP interval change from baseline were all <10 msec at every post-dose time point on Day 2.
RESULTS: The upper bounds of the 90% CIs for the true mean differences (omarigliptin-placebo) in QTcP change from baseline for omarigliptin 175 mg were <10 msec at all post-dose time points on Day 2.
CONCLUSION: A supratherapeutic dose of omarigliptin does not prolong the QTcP interval to a clinically meaningful degree relative to placebo, confirming the results of the earlier concentration-QTc analysis. These results support the early usage of first in human concentration-QTc analysis as a valid approach to assess QTc risk.