0837 Evaluation of Cardiac Safety Profile of ALKS 2680 in Healthy Subjects: Concentration-QTc Relationship of ALKS 2680

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Abstract Introduction ALKS 2680 is a highly potent, orally bioavailable, and selective orexin 2 receptor agonist being developed as a once-daily treatment for narcolepsy and idiopathic hypersomnia. Cardiac safety is an important consideration for drugs in clinical development. This cardiodynamic evaluation assessed the effects of ALKS 2680 on the corrected QT (QTc) interval using the Fridericia method (QTcF), and other electrocardiogram (ECG) parameters (heart rate [HR] and cardiac conduction [PR and QRS intervals]). Methods Single-ascending dose (SAD) data from 42 ALKS 2680-treated healthy volunteers (6 subjects in each of 7 dose cohorts ranging from 1 to 50 mg powder-in-capsule [PIC] and nanosuspension [NS] formulations) and 14 placebo subjects, and multiple-ascending dose (MAD) data from 23 ALKS 2680-treated healthy volunteers (5-6 subjects in each of 4 dose cohorts ranging from 3 to 25 mg PIC formulation) and 8 placebo subjects, were analyzed. Twelve-lead ECGs were extracted from Holter recordings at baseline and prespecified post-dose time points in the SAD (Day 1) and MAD (Day 10) cohorts. The primary analysis was based on concentration-QTc (C-QTc) modeling of the relationship between change-from-baseline QTcF and ALKS 2680 plasma concentrations using a linear mixed-effects modeling approach to exclude an effect on the QTc interval ≥10 ms. Other endpoints included HR and PR and QRS intervals. Results For the SAD and MAD cohorts, the by-timepoint analysis showed that the mean change-from-baseline HR followed the pattern observed on placebo for all doses. In the C-QTc analysis based on the pooled SAD and MAD cohorts, the estimated slope of the concentration-QTc relationship was negative (−0.113 [90% CI: −0.179 to −0.047] ms per ng/mL). An effect on placebo-corrected change-from-baseline QTcF exceeding 10 ms can be excluded within the full observed ALKS 2680 plasma concentration range up to ~94.4 ng/mL. No clinically relevant effects were observed in the by-timepoint analysis on placebo-corrected change-from-baseline PR and QRS intervals. Conclusion The high precision QT analysis confirms a lack of any effects of ALKS 2680 (up to 50 mg) on QTc prolongation, heart rate, or cardiac conduction. Support (if any) Alkermes, Inc.

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