AXS-12 · program

AXS-12 (reboxetine) for Narcolepsy

Filed (NDA)ActiveAxsome Therapeutics, Inc. (AXSM)
  • Orphan Drug

AXS-12 (reboxetine) is in late-stage development by Axsome Therapeutics for the treatment of cataplexy (and associated excessive daytime sleepiness) in narcolepsy. The program comprises the positive Phase 3 SYMPHONY trial (NCT05059223; primary endpoint met, cataplexy attack rate ratio 0.49, p=0.018), the positive Phase 3 ENCORE long-term open-label-extension/randomized-withdrawal trial (NCT05113745; randomized-withdrawal primary endpoint met, p=0.017) and an earlier positive Phase 2 crossover study, CONCERT (NCT03881852; p<0.001). On 2025-12-31 Axsome announced that, based on pre-NDA meeting minutes, the FDA agreed its regulatory data package would be sufficient to support an NDA for AXS-12 for cataplexy in narcolepsy, and the company guided to completing the NDA submission in January 2026. AXS-12 holds FDA Orphan Drug Designation for narcolepsy. NOTE: formal NDA submission/acceptance and a PDUFA date were not confirmable as of 2026-06-25.

Data current as of

Development timeline

Filed (NDA)Dec 2025 – Jan 2026
  1. UpcomingAxsome guided to completing an NDA submission to the FDA for AXS-12 for cataplexy in narcolepsy in January 2026, after the FDA confirmed via pre-NDA meeting minutes that the regulatory data package would be sufficient.↗
  2. Axsome announced FDA pre-NDA meeting minutes confirming its regulatory data package would be sufficient to support an NDA for AXS-12 for cataplexy in narcolepsy; company guided to completing the NDA submission in January 2026. AXS-12 holds Orphan Drug Designation for narcolepsy. Formal NDA submission/acceptance and PDUFA date not yet confirmed in a press release as of 2026-06-25.↗
Phase 3Mar 2024 – Nov 2024
  1. metLong-term Phase 3 ENCORE trial met its randomized-withdrawal primary endpoint: patients switched to placebo had significantly greater worsening of cataplexy than those continuing AXS-12 (p=0.017), with significant worsening of cognition (p=0.011) and overall narcolepsy (p=0.024).↗
  2. metPhase 3 SYMPHONY trial met its primary endpoint: AXS-12 significantly reduced weekly cataplexy attacks vs placebo at Week 5 (rate ratio 0.49, p=0.018), with cataplexy remission in 33% vs 9.5% and improved EDS severity.↗
Phase 2Nov 2019
  1. Phase 2 CONCERT crossover study (NCT03881852) in cataplexy/EDS in narcolepsy completed; AXS-12 reduced weekly cataplexy attacks vs placebo (p<0.001). Primary completion 2019-11-27 per ClinicalTrials.gov.

Readouts

  • January 2026AnticipatedRegulatory

    Axsome guided to completing an NDA submission to the FDA for AXS-12 for cataplexy in narcolepsy in January 2026, after the FDA confirmed via pre-NDA meeting minutes that the regulatory data package would be sufficient. ↗

  • 2024-11-26ReportedTopline datametNCT05113745

    Long-term Phase 3 ENCORE trial met its randomized-withdrawal primary endpoint: patients switched to placebo had significantly greater worsening of cataplexy than those continuing AXS-12 (p=0.017), with significant worsening of cognition (p=0.011) and overall narcolepsy (p=0.024). ↗

  • 2024-03-25ReportedTopline datametNCT05059223

    Phase 3 SYMPHONY trial met its primary endpoint: AXS-12 significantly reduced weekly cataplexy attacks vs placebo at Week 5 (rate ratio 0.49, p=0.018), with cataplexy remission in 33% vs 9.5% and improved EDS severity. ↗

Clinical trials in Narcolepsy

NCT05113745AXS-12-302Phase 3Completedn=68

A Study to Assess the Long-term Efficacy and Safety of AXS-12 in the Treatment of Cataplexy and Excessive Daytime Sleepiness in Subjects With Narcolepsy (ENCORE)

Started Oct 2021· Primary completion Nov 2024· 📍 25 sites across 2 countries (United States, Canada)

metprimaryIncrease in weekly cataplexy attacks during the 3-week double-blind randomized-withdrawal period (placebo vs continued AXS-12) — Mean increase of 10.29 weekly attacks (placebo) vs 1.32 (AXS-12) over 3 weeks; 42 randomized (AXS-12 n=22, placebo n=20) (0.017)

Met the primary endpoint: following a 24-week open-label AXS-12 period (n=68), patients randomized to placebo experienced significantly greater worsening of cataplexy than those continuing AXS-12 in the randomized-withdrawal phase.

metsecondaryWorsening of ability to concentrate (NSAQ) at Week 3 of randomized withdrawal — Worsening in 52.6% (placebo) vs 14.3% (AXS-12) (0.011)

Significantly greater cognitive worsening on the NSAQ concentration item in patients switched to placebo vs continued AXS-12.

metsecondaryWorsening of overall narcolepsy (PGI-C) at Week 3 of randomized withdrawal — Worsening reported by 52.6% (placebo) vs 16.7% (AXS-12) (0.024)

Significantly greater proportion of placebo-switched patients reported overall narcolepsy worsening on the PGI-C vs those continuing AXS-12.

NCT05059223Phase 3Completedn=90

A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Assess the Efficacy and Safety of AXS-12 in the Treatment of Cataplexy and Excessive Daytime Sleepiness in Subjects With Narcolepsy (SYMPHONY)

Started Sept 2021· Primary completion Mar 2024· 📍 50 sites across 2 countries (United States, Canada)

metsecondaryExcessive daytime sleepiness severity (CGI-S) reduction at Week 5 — Mean reduction 1.8 points (AXS-12) vs 0.9 (placebo) (0.027)

AXS-12 significantly improved clinician-rated EDS severity vs placebo; consistent improvement also reported on the Epworth Sleepiness Scale (reviewer should re-verify exact ESS figures against the source).

metprimaryChange from baseline in average number of cataplexy attacks per week at Week 5 — Rate ratio 0.49 (AXS-12 reduced attacks 83% vs 66% with placebo at Week 5) (0.018)

Met the primary endpoint: AXS-12 significantly reduced weekly cataplexy attacks vs placebo at Week 5. Dosed 5 mg once daily Week 1 then twice daily Weeks 2-5.

metsecondaryCataplexy remission (100% reduction in attacks) at Week 5 — 33% (AXS-12) vs 9.5% (placebo) in remission (0.008)

Significantly greater proportion of AXS-12 patients achieved complete cataplexy remission vs placebo.

NCT03881852Phase 2Completedn=21

A Multi-center, Randomized, Double-blind, Placebo-controlled, 3-Week Crossover Study to Assess the Efficacy and Safety of AXS-12 in Subjects With Cataplexy and Excessive Daytime Sleepiness in Narcolepsy (CONCERT)

Started Apr 2019· Primary completion Nov 2019· 📍 14 sites across 1 country (United States)

metprimaryChange from baseline in the weekly average total number of cataplexy attacks — AXS-12 reduced attacks by approximately 13 per week vs minimal change with placebo (<0.001)

Met the primary endpoint in this Phase 2 crossover proof-of-concept study: AXS-12 significantly reduced cataplexy attacks vs placebo.

Formulations

FormulationRouteRegimenPharmacokinetics
AXS-12 oral tablet (reboxetine)
5 mg once daily for the first week, then 5 mg twice daily (Phase 3 narcolepsy dosing)
OralTwice dailyt½ 13 h · Tmax 2 h · F 94%

Mechanism of action (compound-wide)

Reboxetine (AXS-12) is a highly selective and potent inhibitor of the norepinephrine (noradrenaline) transporter (NET/SLC6A2), blocking presynaptic reuptake of norepinephrine and thereby increasing noradrenergic signaling. It is roughly 20-fold selective for NET over the serotonin transporter (SERT) and has low affinity for the dopamine transporter and for muscarinic, histaminergic H1, adrenergic alpha-1 and dopaminergic D2 receptors. Enhanced noradrenergic tone is thought to suppress cataplexy and reduce excessive daytime sleepiness in narcolepsy; Axsome additionally characterizes AXS-12 as a 'cortical dopamine modulator.'

TargetActionAffinity
NETprimarySLC6A2Reuptake inhibitorpKi 8ⓘ
SERTSLC6A4Reuptake inhibitor—ⓘ

← Full AXS-12 compound page (identity, identifiers, all indications)

Sources

  1. A Study to Assess the Efficacy and Safety of AXS-12 (Reboxetine) in Patients With Narcolepsy — ClinicalTrials.gov
  2. A Study to Assess the Long-term Efficacy and Safety of AXS-12 (Reboxetine) in Subjects With Narcolepsy (ENCORE) — ClinicalTrials.gov
  3. Axsome Therapeutics Announces AXS-12 Achieves Primary Endpoint in ENCORE Long-Term Phase 3 Trial in Narcolepsy — Axsome Therapeutics / GlobeNewswire
  4. Axsome Therapeutics Announces AXS-12 Achieves Primary Endpoint in ENCORE Long-Term Phase 3 Trial in Narcolepsy — BioSpace / Axsome Therapeutics
  5. Axsome Therapeutics Announces AXS-12 Achieves Primary Endpoint in the SYMPHONY Phase 3 Trial in Narcolepsy — Axsome Therapeutics / BioSpace
  6. Axsome Therapeutics Announces FDA Pre-NDA Meeting Minutes for AXS-12 in Narcolepsy Supporting NDA Submission — Axsome Therapeutics / GlobeNewswire
  7. Clinical Outcomes in Narcolepsy and Cataplexy: An Evaluation of Reboxetine Treatment (CONCERT) — ClinicalTrials.gov
  8. reboxetine | Biological activity (NET human pKi 8.0) | IUPHAR/BPS Guide to PHARMACOLOGY — IUPHAR/BPS Guide to Pharmacology
  9. reboxetine | Ligand page (NET human pKi 8.0; ~20-fold NET-selective over SERT) | IUPHAR/BPS Guide to PHARMACOLOGY — IUPHAR/BPS Guide to Pharmacology