Y. Xin, S. Jun, L. Moorehead, E. Kwan, M. Hepner, S. Ramanathan; Gilead Sciences, Inc, Foster City, CA
BACKGROUND: Momelotinib (MMB, GS-0387) is a selective small molecule inhibitor of JAK1 and 2 currently being evaluated to treat myelofibrosis. The effect of MMB 200 mg (therapeutic) and 800 mg (supratherapeutic) on QTc interval were evaluated in healthy adults.
METHODS: 48 healthy adults were enrolled into 1 of 2 cohorts (each a 4x4 Williams square) to receive MMB 200 or 800 mg single dose, placebo, or moxifloxacin (positive control) with a 9-day washout between treatments. Time-matched ECGs were collected in triplicate over 24 hours after each treatment. Plasma levels of MMB were determined. Change from baseline in QTc for MMB or moxifloxacin vs. placebo was determined. Pharmacokinetics and exposure-QT relationships were evaluated. Safety was monitored throughout the study.
RESULTS: Subjects were mainly White (87.5%) or Black/African-American (12.5%), with slightly more males (58.3%) than females (41.7%). Adverse events and laboratory abnormalities were generally Grade 1 in severity, except for one Grade II dermatitis acneiform in MMB 800 mg group. The lower bound of the 2-sided 90% CI for mean difference in QTcF for moxifloxacin vs placebo was > 5 msec at 3 and 4 hours post-dose, establishing assay sensitivity. The upper bound of the 2-sided 90% CIs for mean difference in QTcF between 200 or 800 mg dose vs. placebo was below 10 msec at all time points post-dose. Similar results were observed with QTcI. Peak plasma levels of MMB were 70-80% higher at 800 mg vs. 200 mg. There were no clinically relevant relationships between change from baseline (placebo-corrected) in QTcF/QTcI and plasma levels of MMB.
CONCLUSION: MMB does not affect QTc interval in healthy adults and met the definition of a negative thorough QT study per ICH E14 guidance.