Poster
42
(#42) ENCORE: Topline Results of a Phase 3 Open-Label Extension and Randomized-Withdrawal Trial of AXS-12 in Narcolepsy
Psych Congress 2025
Abstract: Introduction
AXS-12 (reboxetine) is a highly selective norepinephrine reuptake inhibitor and cortical dopamine modulator under development for narcolepsy. The ENCORE study evaluated long-term efficacy and safety of AXS-12 in participants with narcolepsy type 1 who completed the Phase 3 SYMPHONY study.
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.
Conclusion
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.
Short Description: ENCORE was a Phase 3 study evaluating the long-term efficacy and safety of AXS-12 in participants with narcolepsy type 1. Over the 6-month open-label period, weekly cataplexy frequency, cataplexy response, and percentage of cataplexy-free days improved. Following double-blind randomized withdrawal, participants remaining on AXS-12 demonstrated maintenance of effect, while those randomized to placebo demonstrated significant worsening of cataplexy attack frequency. AXS-12 was well-tolerated with no new safety signals, supporting its positive therapeutic impact for narcolepsy.
Name of Sponsoring Organization(s): Axsome Therapeutics, Inc.
AXS-12 (reboxetine) is a highly selective norepinephrine reuptake inhibitor and cortical dopamine modulator under development for narcolepsy. The ENCORE study evaluated long-term efficacy and safety of AXS-12 in participants with narcolepsy type 1 who completed the Phase 3 SYMPHONY study.
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.
Conclusion
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.
Short Description: ENCORE was a Phase 3 study evaluating the long-term efficacy and safety of AXS-12 in participants with narcolepsy type 1. Over the 6-month open-label period, weekly cataplexy frequency, cataplexy response, and percentage of cataplexy-free days improved. Following double-blind randomized withdrawal, participants remaining on AXS-12 demonstrated maintenance of effect, while those randomized to placebo demonstrated significant worsening of cataplexy attack frequency. AXS-12 was well-tolerated with no new safety signals, supporting its positive therapeutic impact for narcolepsy.
Name of Sponsoring Organization(s): Axsome Therapeutics, Inc.
