AXS-14 · program
AXS-14 (esreboxetine) for Fibromyalgia
AXS-14 (esreboxetine) is in Phase 3 development by Axsome Therapeutics for the management of fibromyalgia. The pivotal Phase 3 FORWARD trial (NCT07398417; 'Fibromyalgia Response with Esreboxetine Evaluated Using a Randomized Withdrawal Research Design') is a double-blind, placebo-controlled, multicenter randomized-withdrawal study: a 12-week open-label AXS-14 treatment period followed by 1:1 randomization of responders to continue AXS-14 8 mg once daily or switch to placebo for up to 12 weeks, with the primary endpoint of time from randomization to loss of therapeutic response. The first patient was dosed on/around 2026-01-15 (study start 2026-01-14 actual per ClinicalTrials.gov). AXS-14 was previously developed by Pfizer, which in placebo-controlled fibromyalgia trials reported a positive 8-week Phase 2 study (267 patients; statistically significant improvement vs placebo in weekly mean pain score, p=0.006) and a positive 14-week Phase 3 study (1,122 patients; significant improvements vs placebo in weekly mean pain score across dose levels, p<0.001, p<0.001, p=0.025). Axsome acquired exclusive U.S. rights to these data from Pfizer in January 2020. No FDA expedited designations (e.g., fast track/breakthrough) were found for AXS-14 in fibromyalgia.
Development timeline
- UpcomingTopline results anticipated from the pivotal Phase 3 FORWARD trial (NCT07398417) of AXS-14 (esreboxetine) in fibromyalgia; randomized-withdrawal primary endpoint is time to loss of therapeutic response.
- Axsome initiated the pivotal Phase 3 FORWARD trial (NCT07398417) in fibromyalgia; study start 2026-01-14 (actual), first patient dosed announced 2026-01-15. Randomized-withdrawal design (12-week open-label AXS-14, then 1:1 AXS-14 8 mg QD vs placebo); primary endpoint time to loss of therapeutic response.↗
- Pfizer-era Phase 3 esreboxetine fibromyalgia program (14-week, 1,122 patients) met its primary endpoints with statistically significant improvements vs placebo in weekly mean pain score across dose levels (p<0.001, p<0.001, p=0.025), per the Axsome-Pfizer exclusive license agreement announced 2020-01-13. Development had been discontinued by Pfizer; Axsome acquired U.S. rights to the data.↗
- Pfizer-era Phase 2 study of [S,S]-reboxetine (esreboxetine) in fibromyalgia, NCT00357825 (8-week, randomized, double-blind, placebo-controlled, 246 enrolled; primary endpoint weekly average pain score). Completed March 2007. Per the 2020 Axsome-Pfizer license PR, the Phase 2 program (267 patients) showed a statistically significant improvement vs placebo in weekly mean pain score (p=0.006).
Readouts
- 1H 2028AnticipatedTopline dataNCT07398417
Topline results anticipated from the pivotal Phase 3 FORWARD trial (NCT07398417) of AXS-14 (esreboxetine) in fibromyalgia; randomized-withdrawal primary endpoint is time to loss of therapeutic response.
Clinical trials in Fibromyalgia
NCT07398417Phase 3Recruitingn=620
A Double-Blind, Placebo-Controlled, Randomized Withdrawal Study to Assess the Efficacy and Safety of AXS-14 in the Management of Fibromyalgia (FORWARD)
pendingprimaryTime from randomization to loss of therapeutic response
Primary endpoint of the Phase 3 FORWARD randomized-withdrawal trial: time from randomization to loss of therapeutic response over the 12-week double-blind period (AXS-14 8 mg QD vs placebo in open-label responders). Trial recruiting; no results yet. Estimated primary completion March 2028.
NCT00357825Phase 2Completedn=246
An 8-Week, Randomized, Double-Blind, Placebo-Controlled, Multi-Centre Study of [S,S]-Reboxetine Administered Once Daily in Patients With Fibromyalgia
metprimaryWeekly average pain score from the daily pain diary at Week 8 (0.006)
Pfizer-era Phase 2 study of [S,S]-reboxetine (esreboxetine) in fibromyalgia. Per the 2020 Axsome-Pfizer license PR, the Phase 2 program (267 patients, 8 weeks) showed a statistically significant improvement vs placebo in weekly mean pain score (p=0.006). Originally sponsored by Pfizer; sponsor_company_slug set to axsome-therapeutics as current U.S. rights holder. Reviewer: the 246 enrollment is the CT.gov figure for this specific NCT; the 267 figure in the license PR may aggregate the Phase 2 program.
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| AXS-14 oral (esreboxetine) 8 mg once daily (maintenance dose in the FORWARD Phase 3 randomized-withdrawal trial) | Oral | Once daily | — |
Mechanism of action
Esreboxetine (AXS-14) is a highly selective and potent inhibitor of the norepinephrine (noradrenaline) transporter (NET/SLC6A2), blocking presynaptic reuptake of norepinephrine and thereby increasing noradrenergic signaling in descending pain-modulatory pathways. It is the single (S,S)-(+)-enantiomer of racemic reboxetine; the (S,S)-eutomer is reported to be roughly 24-fold more potent at NET than the (R,R)-distomer, and esreboxetine is described as more selective for NET than the racemate. Reboxetine itself is approximately 20-fold selective for NET over the serotonin transporter (SERT), with low affinity for the dopamine transporter and for muscarinic, histaminergic H1, adrenergic and dopaminergic receptors. Enhanced noradrenergic tone is the proposed basis for analgesic efficacy in fibromyalgia.
| Target | Action | Affinity |
|---|---|---|
| NETprimarySLC6A2 | Reuptake inhibitor | —ⓘ |
| SERTSLC6A4 | Reuptake inhibitor | —ⓘ |
← Full AXS-14 compound page (identity, identifiers, all indications)
Sources
- A Trial Assessing the Effectiveness and Safety of [S,S]-Reboxetine in Patients With Fibromyalgia - NCT00357825 — ClinicalTrials.gov
- Axsome Therapeutics Enters into Exclusive License Agreement with Pfizer Inc. for Reboxetine and Esreboxetine — Pfizer Inc.
- Axsome Therapeutics Initiates FORWARD Phase 3 Trial of AXS-14 for the Management of Fibromyalgia — Axsome Therapeutics / GlobeNewswire
- Fibromyalgia Response With Esreboxetine Evaluated Using a Randomized Withdrawal Research Design (FORWARD) - NCT07398417 — ClinicalTrials.gov
- reboxetine | Ligand page (NET human pKi 8.0; ~20-fold NET-selective over SERT) | IUPHAR/BPS Guide to PHARMACOLOGY — IUPHAR/BPS Guide to Pharmacology