Session Information
Date: Sunday, November 5, 2017
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose:
Filgotinib is a potent and selective Janus kinase 1 (JAK1) inhibitor being developed to treat inflammatory diseases. Safety pharmacology studies and Phase 1 studies indicate that there is a low risk of QT prolongation by filgotinib treatment. This dedicated Phase 1 study was conducted to evaluate the potential effect of filgotinib on the QT interval prolongation in healthy subjects per the International Conference on Harmonization (ICH) E14 guidance.
Methods:
52 healthy adults were randomized to receive a single dose of moxifloxacin 400 mg (positive control) or once daily doses of filgotinib 200 mg (top therapeutic dose), filgotinib 450 mg (supratherapeutic dose), or placebo for 7 days. There was a washout period of 9 days between each dosing period. Digital ECGs were collected in triplicates within 5 minutes at matched time points on the 1st day (predose) and 7th day (postdose) with 24 hours measurements for each treatment on the 7th day. QTc (QTcF and QTcI) were derived and average of triplicates provided time-matched QTc. Subjects with large QTc or QTc change from baseline were summarized. Changes from baseline in time-matched QTc were fit to a mixed effect model, and difference of QTc change between filgotinib treatments or moxifloxacin vs placebo were quantified. PK of filgotinib was evaluated, and safety was monitored throughout study. The 90% confidence intervals (CIs) were constructed for the ratios of geometric least squares means of filgotinib PK parameters (AUCtau, Cmax, and Ctau) for 450 mg vs. 200 mg daily dose. The association between QTc and plasma concentrations of filgotinib was explored.
Results:
46 (88.5%) subjects completed study drug treatments. The mean (range) age of subjects was 38 (20-55) years, 39 (75%) subjects were female, 28 (53.8%) were white and 15 (28.8%) were hispanic or latino.
Lack of QTcF prolongation has been demonstrated at both doses of filgotinib. The upper limits of the 2-sided 90% CI for mean difference in QTcF between 200 mg or 450 mg vs placebo were less than 10 msec (≤ 8.35 msec) at all time points. Similar results were observed with QTcI. Assay sensitivity was demonstrated using moxifloxacin at 400 mg, with the lower 96.7% CI for mean difference in QTcF above 5 msec (≥ 8.32 msec) at 2, 3, and 4 hours post dose. Filgotinib 450 mg provided 2.1-fold higher Cmax than 200 mg. There were no clinically relevant relationships between change from baseline (placebo-corrected) in QTcF/QTcI and plasma concentrations of filgotinib.
Overall, 8 (15.7%), 15 (30.0%), 0 (0.0%), and 5 (10.0%) subjects experienced treatment-related AEs during filgotinib 200 mg, filgotinib 450 mg, placebo, and moxifloxacin treatment periods, respectively. No serious or severe (≥ Grade 3) AEs occurred, and the majority of the AEs reported were Grade 1 (mild) in severity. No Grade 4 laboratory abnormalities occurred. There were no clinically significant trends in vital signs, or safety ECG recordings.
Conclusion:
Filgotinib does not affect QTc interval by definition of a negative thorough QT study per ICH E14 guidance at 200 mg (top therapeutic dose) and 450 mg (supratherapeutic dose; 2.1-fold higher Cmax than 200 mg).
To cite this abstract in AMA style:
Anderson K, Zheng H, Yun C, Kwan E, Qin A, Namour F, Kearney BP, Xin Y. Filgotinib, a Selective Janus Kinase 1 Inhibitor, Has No Effect on QT Interval in Healthy Subjects [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/filgotinib-a-selective-janus-kinase-1-inhibitor-has-no-effect-on-qt-interval-in-healthy-subjects/. Accessed October 23, 2019.« Back to 2017 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/filgotinib-a-selective-janus-kinase-1-inhibitor-has-no-effect-on-qt-interval-in-healthy-subjects/