PI-016 - SELTOREXANT DOES NOT PROLONG THE QT INTERVAL: A PLACEBO- AND POSITIVE-CONTROLLED, SINGLE DOSE PHASE 1 STUDY IN HEALTHY ADULTS

V. Sinha¹, A. Russu², H. Crauwels³, J. Ariyawansa⁴, J. Natarajan⁴, S. Mesens⁵, G. Pandina⁶, D. Damayanthi⁷; ¹Janssen Research & Development, LLC, Spring House, PA, USA, Janssen Research & Development, LLC, Spring House, PA, USA, ²Janssen-Cilag S.p.A., Milan, Italy, Janssen-Cilag S.p.A., Milan, Italy, ³Janssen Research & Development, Belgium, Beerse, Antwerp, Belguim, ⁴Janssen Research & Development, LLC, Raritan, NJ, USA, Janssen Research & Development, LLC, Raritan, NJ, USA, ⁵Janssen Research & Development, LLC, Beerse, Antwerp, Belguim, Janssen Research & Development, LLC, Beerse, Antwerp, Belgium, ⁶Janssen Research & Development, LLC, Titusville, NJ, USA, Janssen Research & Development, LLC, Titusville, NJ, United states, ⁷Janssen Research & Development, LLC, Raritan, NJ, USA, Janssen Research & Development, LLC, Raritan, NJ, USA.

Background: Seltorexant, a selective human orexin-2 receptor antagonist, is being developed for adjunctive treatment of major depressive disorder in patients with insomnia symptoms. This phase 1 study evaluated the effects of supratherapeutic seltorexant doses on the QT/QTc interval in healthy participants.

Methods: This was a randomized, double-blind, 4-way crossover, placebo- and positive-controlled study. Eligible participants (n=52) were randomized to receive a single oral dose of seltorexant 40 mg (2x therapeutic dose [20 mg]) or 100 mg (5x therapeutic dose), the active control moxifloxacin 400 mg, or placebo, each in 1 of the 4 treatment periods. All treatments were taken fasted in the morning of Day 1 of each treatment session. Serial electrocardiograms (pharmacodynamics [PD]) and pharmacokinetics (PK) were obtained over 48 hours. The primary endpoint was Fridericia-corrected QT interval (QTcF). Secondary endpoints included safety and PK.

Results: Mean changes from baseline in QTcF on Day 1 were similar for seltorexant 40 mg or 100 mg, as compared to placebo. The upper limits of the 2-sided 90% CIs for ΔΔQTcF between seltorexant and placebo were below the 10-ms limit at all time points for both doses of seltorexant, thus demonstrating noninferiority of seltorexant to placebo. The highest upper limit of the 2-sided 90% CIs for ΔΔQTcF was 3.18 milliseconds (ms; 40 minutes) for the seltorexant 40 mg dose and 3.97 ms (10 hours) for the 100 mg dose. Therefore, seltorexant has no potential to inhibit cardiac repolarization. The assay sensitivity was confirmed by observing that the difference between moxifloxacin and placebo in change from baseline QTcF (ΔΔQTcF) on Day 1 was greater than 5 ms at the prespecified time points (smallest lower limit was 7.07 ms). No relevant PK/PD relationship was observed between plasma concentrations of seltorexant or its metabolites (M12 and M16) and ΔΔQTcF. The tolerability of a single morning fasted dose of 40 mg or 100 mg seltorexant in healthy participants was similar to observations in other morning dose seltorexant phase 1 studies and did not show any new safety findings. Additionally, no significant findings were observed in other ECG parameters.

Conclusion: Seltorexant showed no evidence of QT/QTc interval prolongation in healthy participants.