ENCORE: Topline Results of a Phase Three Open-label Extension and Randomized-withdrawal Trial of AXS-12 in Narcolepsy
Richard Bogan1, Michael Thorpy2, Lois Krahn3, Bruce Corser4, Colin Shapiro5, Dan Chen6, Angad Chhabra6, Eileen Leary7, Herriot Tabuteau6
1Medical University of South Carolina, 2Montefiore Medical Center, Sleep-Wake Disorders Center, 3Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, 4Intrepid Research, 5University of Toronto, 6Axsome Therapeutics, Inc., 7Formerly of Axsome Therapeutics, Inc.
Objective:
The ENCORE study evaluated long-term efficacy and safety of AXS-12 (reboxetine) in participants with narcolepsy type 1 (NT1) who completed the Phase 3 SYMPHONY study.
Background:
AXS-12 is a highly selective norepinephrine reuptake inhibitor and cortical dopamine modulator under development for narcolepsy. In the Phase 3 SYMPHONY study, AXS-12 met the primary endpoint, significantly reducing weekly cataplexy attack frequency versus placebo.
Design/Methods:
ENCORE included a 24-week open-label period (OLP) of continued AXS-12 treatment, and a 3-week double-blind, randomized withdrawal period (DBRWP) during which participants were randomized to continue AXS-12 or switch to placebo. The primary endpoint was change from randomization in weekly cataplexy attack frequency versus placebo at DBRWP week 3.
Results:
ENCORE enrolled 68 participants; 42 completed the OLP and entered the DBRWP (AXS-12, n=22; placebo, n=20). In SYMPHONY, baseline median weekly cataplexy attack frequency was 19.9 pretreatment. At DBRWP randomization in ENCORE, mean weekly cataplexy attack frequency was 4.2 (AXS-12) and 6.9 (placebo). Participants randomized to placebo experienced a mean increase of 10.29 weekly cataplexy attacks versus 1.32 for AXS-12 at DBRWP end (p=0.017). At OLP month 1 and 6, cataplexy response (≥50% reduction) was achieved by 72% and 82%, and cataplexy-free days increased from 14% to 61% and 70%. OLP adverse events (AEs; ≥5%) were nausea and tachycardia (both 5.9%); no new safety signals were detected. Discontinuations due to AEs occurred in 17.6% of participants in the OLP.
Conclusions:
AXS-12 was well-tolerated and demonstrated maintenance of efficacy with long-term open-label use. Switching to placebo resulted in significant worsening of cataplexy attack frequency relative to continued AXS-12 treatment. These results support the therapeutic impact of AXS-12 for narcolepsy.
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