FDA Accepts NDA for AXS-12 for the Treatment of Cataplexy in Narcolepsy

The FDA accepted the new drug application (NDA) for AXS-12 (Reboxetine; Axsome Therapeutics) for the treatment of cataplexy in narcolepsy. The set Prescription Drug User Fee Act (PDUFA) target action date is May 1, 2027, and the FDA stated that, at the time of the announcement, the agency did not plan to hold an advisory committee meeting to discuss the application.¹

AXS-12 is a selective noradrenergic reuptake inhibitor that acts by binding to the norepinephrine transporter to block the reuptake of extracellular norepinephrine back into terminals. This compound has low affinity for other transporters and receptors. In sleep disorders, it is thought to modulate noradrenergic activity to promote wakefulness, maintain muscle tone, and enhance cognition in patients. The treatment has undergone investigation in depressive disorders and is considered a potential treatment for sleep-related disorders, such as narcolepsy.^1-3

Cataplexy, a physical feature of narcolepsy, is characterized by transient episodes of voluntary muscle weakness precipitated by intense emotion. Subjective descriptions of cataplexy can assist in the identification of narcolepsy, as this symptom is almost unique to the disorder. Although about one-third of patients present with the classic narcolepsy tetrad (eg, cataplexy, excessive daytime sleepiness [EDS], hypnagogic hallucinations, and sleep paralysis), two-thirds of patients with narcolepsy are affected by cataplexy.⁴

AXS-12 Shown to Reduce Narcolepsy Symptom Severity, Improve Other Symptoms

AXS-12 was assessed in SYMPHONY (NCT05059223)⁵, a randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial that assessed the agent’s efficacy and safety when treating cataplexy and EDS in patients with narcolepsy type 1 (NT1). Patients were eligible if they had a diagnosis of narcolepsy—as defined by the International Classification of Sleep Disorders—and exhibited cataplexy- and EDS-related symptoms. Patients enrolled were 15 to 75 years of age and were randomly assigned to receive either AXS-12 or placebo for a 5-week duration.^2,5

The trial’s primary end point was the frequency of cataplexy attacks, which was assessed by the average number of attacks per week. Secondary end points included the Clinical Global Impression of Severity (CGI-S) for narcolepsy, the Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10), and the EuroQol 5-Dimension 5-Level (EQ-5D-5L) anxiety/depression domain.^2,5

A total of 90 participants were enrolled in SYMPHONY. Mean baseline CGI-S and FOSQ-10 scores of about 5.2 and 11.1 (AXS-12 group) and 4.9 and 11.6 (placebo group), respectively. AXS-12 was observed to significantly improve CGI-S (LS mean difference = 0.72 [95% CI, 0.29-1.16]; P = .001) and FOSQ-10 (LS mean difference = 1.66 [95% CI, 0.51-2.82]; P = .005) compared with placebo at the 5-week point. Further, approximately 47.8% of participants treated with AXS-12 and 45.5% withplacebo reported having anxiety or depression (EQ-5D-5L) at baseline. The authors wrote that, numerically, there were more participants who improved 1 or more levels when treated with AXS-12 (55.0%) than when treated with a placebo (31.6%) at the 5-week point (P = .146).⁵

These data from SYMPHONY, as well as the subsequent accepted NDA, further emphasize the potential of AXS-12 when used to treat cataplexy and EDS in NT1. A previous analysis found that AXS-12 reduced the number of cataplexy attacks by approximately 83% compared with placebo (66%) at week 5 (rate ratio = 0.49; P = .018; baseline mean weekly cataplexy attacks: 27.7 and 35.4, respectively). At week 1, reductions were 56% and 31% (rate ratio = 0.65; nominal P = .007), respectively, and cataplexy remission occurred more frequently at week 5 in AXS-12–treated patients (33%) than in those receiving placebo (9.5%; nominal P = .008).⁵

Further, mean percentages of cataplexy-free days at week 5 were approximately 84.5% and 22.6% for the AXS-12 and placebo groups, respectively (nominal P = .014). Changes in CGI-S for EDS at week 5 were −1.8 (AXS-12) compared with −0.9 (placebo; nominal P = .027), and patients who were treated with AXS-12 generally reported fewer inadvertent naps (54%) than their placebo-treated counterparts (28%; nominal P = .016). The investigational agent also led to greater improvements in concentration and memory (1.6 vs 0.7, respectively; nominal P = .004).⁵

What Do Pharmacists Need to Know?

Pharmacists should know that AXS-12 represents a potentially valuable new option for a symptom that significantly impairs the daily functioning and safety of patients with narcolepsy. Pharmacists should also note that AXS-12 has prior investigational history in depressive disorders—meaning its safety and tolerability profile may already have some real-world context—and they should remain vigilant for full safety data as the agent progresses through the approval pipeline. Given the extended timeline to the 2027 PDUFA date, pharmacists have time to build familiarity with AXS-12’s mechanism and trial data, preparing them to effectively counsel patients and collaborate with prescribers if it receives approval and reaches the market.

REFERENCES

1. Axsome Therapeutics Announces FDA Acceptance of New Drug Application for AXS-12 for the Treatment of Cataplexy in Narcolepsy. GlobeNewswire. News release. July 15, 2026. Accessed July 16, 2026. https://www.globenewswire.com/news-release/2026/07/15/3327580/33090/en/axsome-therapeutics-announces-fda-acceptance-of-new-drug-application-for-axs-12-for-the-treatment-of-cataplexy-in-narcolepsy.html

2. Reboxetine Reduces Overall Narcolepsy Symptom Severity and Improves EDS, Mood-Related Symptoms. Pharmacy Times. April 20, 2026. Accessed July 16, 2026. https://www.pharmacytimes.com/view/reboxetine-reduces-overall-narcolepsy-symptom-severity-and-improves-eds-mood-related-symptoms

3. AXS-12 – a potentially new treatment option for narcolepsy. Accessed July 16, 2026. https://www.axsome.com/axs-portfolio/pipeline/about-axs-12/

4. Mirabile VS, Sharma S. Cataplexy. StatPearls [Internet]. Updated June 12, 2023. Accessed July 16, 2026. https://www.ncbi.nlm.nih.gov/books/NBK549782/ 

5. A Study to Assess the Efficacy and Safety of AXS-12 (Reboxetine) in Patients With Narcolepsy (SYMPHONY). ClinicalTrials.gov identifier: NCT05059223. Updated May 28, 2026. Accessed July 16, 2026. https://clinicaltrials.gov/study/NCT05059223