Reboxetine

Cataplexy is a sudden loss of muscle tone set off by strong emotion, which can make a person slump or fall while staying awake^[9]. Most people with narcolepsy with cataplexy have lost the brain cells that make hypocretins, also called orexins, chemicals that help regulate the daily sleep and wake cycle^[9]. Reboxetine blocks the reuptake of norepinephrine, a brain messenger that supports alertness, which leaves more of it active between nerve cells.

Axsome describes AXS-12 as a highly selective and potent norepinephrine reuptake inhibitor that also adjusts dopamine in the outer layer of the brain, and says it is thought to work by adjusting norepinephrine activity to keep muscle tone during wakefulness^[1].

SYMPHONY (NCT05059223) was a 5-week Phase 3 trial that randomly assigned 90 people aged 15 to 75 with narcolepsy with cataplexy to AXS-12 or placebo^[4][2]. Axsome reported that weekly cataplexy attacks fell 83% from the start on AXS-12 against 66% on placebo at week 5, the main measure, and that 33% of people on AXS-12 had full remission of cataplexy at week 5 against 9.5% on placebo^[2].

Axsome also reported a larger drop in daytime sleepiness on a clinician rating scale, 1.8 points against 0.9 on placebo^[2]. ENCORE (NCT05113745) enrolled 68 people from SYMPHONY for 6 months of open-label AXS-12, then randomly assigned 42 of them to keep taking it or switch to placebo for 3 weeks, a design called randomized withdrawal^[3][5].

People switched to placebo had an average of 10.29 more cataplexy attacks a week, against 1.32 more for people who stayed on AXS-12^[3]. Before these, the Phase 2 CONCERT study (NCT03881852) gave 21 adults AXS-12 and placebo in turn for 3 weeks each, and the results posted on ClinicalTrials.gov show weekly attacks fell by about 13 after 2 weeks on AXS-12 against almost no change on placebo^[6].

Every trial compared AXS-12 with placebo, and results have come from Axsome's releases and the registry rather than a full peer-reviewed paper.

In SYMPHONY, Axsome reported no serious adverse events, and the most common side effects on AXS-12 were dry mouth in 6 people, nausea in 6 and constipation in 4, mostly mild to moderate; 1 person in each group stopped because of a side effect^[2]. Over the 6 months of open-label treatment in ENCORE, Axsome reported nausea and a fast heart rate (tachycardia) each in 5.9% of people, and 17.6% stopped treatment because of side effects^[3].

In the small Phase 2 CONCERT study, the side effects posted on ClinicalTrials.gov for the AXS-12 period were anxiety, constipation and insomnia in 4 of 21 people each and dry mouth in 2, against 1, 0, 1 and 0 of 20 on placebo, with no serious adverse events^[6]. A full list of side effects and warnings would come from an FDA label if the drug is approved.

Axsome says the FDA granted AXS-12 Orphan Drug Designation for narcolepsy in October 2018^[2]. ClinicalTrials.gov lists the CONCERT study as running from April to November 2019, SYMPHONY as starting on September 15, 2021, and ENCORE as finishing on November 15, 2024^[6][4][5]. Axsome announced SYMPHONY results on March 25, 2024 and ENCORE results on November 26, 2024^[2][3].

On July 15, 2026, Axsome announced that the FDA had accepted its New Drug Application for cataplexy in narcolepsy, set a target action date of May 1, 2027, and did not plan to hold an advisory committee meeting at that time^[1]. Axsome has not said in that release whether the review is standard or priority. Outside the US, reboxetine is authorised as Edronax for depression; Ireland's medicines regulator lists it as authorised since November 28, 1997 and marketed, and the UK product information lists it for depressive illness^[7][8].