138: A Thorough QT Study Using C-QTc to Evaluate the Effects of Centanafadine on Cardiac Repolarization

Statement of Purpose: Centanafadine is a potent norepinephrine, dopamine, and serotonin reuptake inhibitor in development for treatment of attention-deficit/hyperactivity disorder (ADHD). The effect of centanafadine on cardiac repolarization in healthy subjects from a thorough QT (TQT) trial is reported.

Description of Methods & Materials: This was a single-center, double-blind, randomized, placebo- and active-controlled, 3-period crossover TQT trial. Adults of nonchildbearing potential aged 18-65 years were randomized to 1 of 6 dosing sequences to receive a supratherapeutic dose of centanafadine (800 mg total daily dose: 4 x 100 mg tablets in the morning and 5 hours later), centanafadine placebo (4 placebo tablets in the morning and 5 hours later), and the active control moxifloxacin (400 mg + centanafadine placebo in the morning and centanafadine placebo 5 hours later) administered in covered cups. Morning doses were separated by 72 hours. Plasma for pharmacokinetic analyses was collected for 24 hours following dosing; continuously recorded electrocardiograph (ECG) data were extracted at the same time points. Effects of centanafadine on ECG parameters (QT interval with Fridericia’s correction factor [QTcF], PR and QRS intervals, and T- and U-wave morphology), and heart rate (HR) were assessed. C-QTc, the relationship between drug concentration and placebo-corrected change from baseline in QTcF (ΔΔQTcF), was the primary analysis. ΔΔQTcF was assessed and categorical analyses of ECG parameters were conducted for changes in QTcF, PR, and QRS intervals and HR. Treatment-emergent adverse events (TEAEs) were summarized.

Data & Results: Of 30 subjects enrolled, 17 (56.7%) were male and most were White (86.7%). Mean (SD) age was 37.6 (14.5) years; mean (SD) BMI was 26.4 (3.4) kg/m². Centanafadine had no clinically meaningful effect on cardiac repolarization. The slope (90% CI) of the C-QTc relationship for centanafadine was −0.001 (−0.003, 0.00002) msec/[ng/mL] and not significant. The predicted ΔΔQTcF (90% CI) at the geometric mean C_max of 800 mg centanafadine was −2.72 (−6.92, 1.48) msec. Assay sensitivity was confirmed by a significant slope (90% CI) of the C-QTc relationship for moxifloxacin (0.004 [0.002, 0.006] msec/[ng/mL]) and a predicted ΔΔQTcF (90% CI) at the geometric mean C_max of moxifloxacin 400 mg above 5 (11.75 [8.25, 15.24]) msec. No ΔΔQTcF ≥10 msec was observed for centanafadine at any postdose time point; all upper limits of 90% CIs of ΔΔQTcF were < 10 msec. The by-time-point analysis showed the maximum least squares mean difference in ΔQTcF (90% CI) between centanafadine and placebo was 1.64 (−1.40, 4.68) msec at 24 hours postdose. No centanafadine-treated subjects had a QTcF increase of >30 msec; no relevant increases in PR or QRS interval or HR were observed. Four subjects had >25% decrease in HR and < 50 beats per minute. No abnormal U waves were observed; 1 subject had abnormal T-wave morphology. No serious TEAEs or deaths were reported. The most frequently reported TEAEs with centanafadine were nausea (24.1%), dizziness (24.1%) and decreased appetite (13.8%).

Interpretation, Conclusion or Significance: In this TQT trial, centanafadine, a norepinephrine, dopamine, and serotonin reuptake inhibitor being evaluated for the treatment of ADHD, had no clinically meaningful effect on cardiac repolarization and was generally safe and well tolerated.

Disclosures: Osman Turkoglu, Xiaofeng Wang, Jennifer Repella Gordon and Susan E. Shoaf are employees of Otsuka Pharmaceutical Development & Commercialization Inc.