Associate Director, Clinical Pharmacology Sage Therapeutics, Inc. Cambridge, Massachusetts, United States
Background: Zuranolone (ZRN) is a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and neuroactive steroid in development as an oral, once-daily, 14-day treatment course for adults with major depressive disorder and postpartum depression. This study evaluated ZRN effects on cardiac repolarization, as assessed by Fridericia-corrected QT interval (QTcF). Methods: This was a double-blind, double-dummy, placebo- and active-controlled, parallel-group study in healthy adults. In Group 1 (n=32), participants received placebo on day (D) 1 and D9, ZRN 50 mg (therapeutic dose) on D2–7, and ZRN 100 mg (supratherapeutic dose) on D8. In Group 2 (n=32), participants received placebo D1–9 and moxifloxacin 400 mg/placebo for moxifloxacin on D2 or D9 in a crossover manner. Time-matched serial PK and ECG measurements were collected on D2, 7, 8 and 9. The primary endpoint was change from baseline in QTcF (ΔQTcF), by concentration-QTc (C-QTc) modeling. Results: The moxifloxacin C-QTc analysis confirmed assay sensitivity. For ZRN, the slope of the C-QTc model was shallow (0.024 ms per ng/mL). At ZRN Cmax of 98.3 ng/mL (50 mg) and 132.8 ng/mL (100 mg), the predicted placebo-corrected ΔQTcF estimate (ms; 90% confidence interval [CI]) was −0.31 (−4.71, 4.10) and 0.52 (−4.10, 5.13), respectively. The upper bound of the 90% CI remained < 10 ms across the concentration range. ZRN had no QTc effect in the by-timepoint analysis and no effect on heart rate or PR and QRS intervals. Categorical analysis showed no pertinent findings. Most adverse events (95.3%) were mild/moderate. ZRN PK was as expected with observed concentrations covering the anticipated high clinical use scenario. Conclusion: ZRN had no clinically relevant effect on cardiac repolarization at therapeutic and supratherapeutic doses.
