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

According to a new announcement, the FDA has accepted for filing a new drug application (NDA) for Axsome Therapeutics’ investigational agent AXS-12 (reboxetine), a selective norepinephrine reuptake inhibitor, for the treatment of cataplexy in narcolepsy. The company noted that the agency has set a PDUFA target action date of May 1, 2027, and does not currently plan to convene an advisory committee to review the submission.¹

The NDA is supported by positive data from 2 phase 3 controlled trials, dubbed SYMPHONY (NCT05059223) and ENCORE (NCT05113745), both of which met their primary end point of reducing the frequency of cataplexy attacks in patients with narcolepsy. AXS-12, previously granted FDA orphan drug designation, is designed to regulate noradrenergic activity in order to promote wakefulness, sustain muscle tone, and improve cognition.

“Clinical evidence continues to support AXS-12 as a novel treatment option for narcolepsy that has the potential to rapidly and durably ameliorate one of the most debilitating symptoms for patients, cataplexy, while also reducing the severity of excessive daytime sleepiness, and improving cognition and overall function,” Michael Thorpy, MD, director of the Sleep-Wake Disorders Center at Montefiore Medical Center, said in a prior statement.² “Narcolepsy is a complex and heterogeneous condition defined by distinct symptom clusters and there remains great need for options that can address this variety in disease presentation.”

The Phase 3 ENCORE Trial

The ENCORE trial, a 2-part study, comprised a 6-month open-label treatment period followed by a 3-week randomized, placebo-controlled withdrawal. Of 68 enrolled patients with narcolepsy with cataplexy, 42 were randomly assigned 1:1 to continue AXS-12 or switch to placebo. The primary end point of change in weekly cataplexy attacks was met, with those who switched to placebo experiencing a mean increase of 10.29 cataplexy attacks per week compared to a mean increase of 1.32 attacks per week for those randomized to continue AXS-12 treatment, at 3 weeks (P = .017).

With AXS-12 treatment, 72% of patients achieved at least a 50% reduction in weekly cataplexy attacks at 1 month and 82% at 6 months, whereas cataplexy-free days per week increased from 14% at baseline to 61% at 1 month and 70% at 6 months. AXS-12 also had an impact on excessive daytime sleepiness (EDS), as treated patients showed a mean reduction of 5.6 points in Epworth Sleepiness Scale (ESS) by 1 month. This improvement was sustained over the long-term period, with a mean reduction of 7.3 points at 6 months.

In terms of safety, AXS-12 was considered well-tolerated, with no new emerging safety signals identified. During the 6-month open-label period, 17.6% of patients discontinued because of adverse events (AEs), with no individual AE leading to discontinuation by more than 1 patient. The most common AEs throughout that time were nausea (5.9%) and tachycardia (5.9%). During the double-blind period, treatment-related adverse events occurred in 4.5% of AXS-12 patients vs. 15% on placebo, with discontinuation rates because of AEs at 0% and 5%, respectively.

The Phase 3 SYMPONY Trial

The study population of ENCORE included participants who rolled over from the phase 3 SYMPONY trial. SYMPONY was a randomized, double-blind, placebo-controlled, multicenter study that enrolled 90 patients with narcolepsy with cataplexy in a 1:1 ratio over 5 weeks. In the study, AXS-12 achieved its primary end point, demonstrating an 83% reduction in weekly cataplexy attacks vs 66% for placebo (P = .018).

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Additional findings in SYMPONY showed that AXS-12 rapidly reduced weekly cataplexy attacks, demonstrating at week 1 a reduction of 56% compared with a reduction of 31% for placebo (P = .007). In addition to improvements in EDS severity, those treated with AXS-12 showed a decrease in the number of inadvertent naps (54%) at week 5 compared with those on placebo (28%; P = .016). For safety findings, dry mouth, nausea, and constipation were the most commonly reported AES in the SYMPHONY trial.

“The SYMPHONY Phase 3 trial results confirm the promise and potential of AXS-12 for the treatment of narcolepsy,” Herriot Tabuteau, MD, chief executive officer at Axsome, said in a prior statement.³ “Collectively, the data generated in SYMPHONY highlight AXS-12’s positive therapeutic impact and are consistent with the results from the previously completed positive CONCERT trial.”

The Phase 2 CONCERT Trial

In December 2019, Axsome reported that AXS-12 met the prespecified primary end point in the phase 2, randomized, double-blind, placebo-controlled, crossover, multicenter, CONCERT trial (NCT03881852) among patients with narcolepsy.⁴ CONCERT included 21 patients with a diagnosis of narcolepsy with cataplexy who were treated with orally administered AXS-12 followed by placebo, each for 2 weeks, with treatment periods that were separated by 1 week of down-titration and washout.

In CONCERT, the therapy demonstrated a significant reduction as compared with placebo from baseline in the mean weekly number of cataplexy attacks (P <.001). Notably, AXS-12-treated patients showed a mean reduction of 14.6 cataplexy attacks per week compared with a reduction of 2.6 attacks per week for placebo at week 2 (P = .002). At the same time, 76.2% of patients treated with the therapy achieved a 50% or greater reduction in the weekly number of cataplexy attacks compared with 30.0% for placebo (P = .003).

There were no serious AEs reported in the trial, and no discontinuations because of adverse events. In total, 42.9% of patients treated with AXS-12 and 40.0% with placebo who experienced adverse events, with anxiety, constipation, and insomnia the most common for AXS-12. The completion rate was 91% for patients randomized treated with AXS-12 followed by placebo and 100% for those randomized treatment with placebo followed by AXS-12.

REFERENCES
1. Axsome Therapeutics Announces FDA Acceptance of New Drug Application for AXS-12 for the Treatment of Cataplexy in Narcolepsy. News release. Axsome Therapeutics. July 15, 2026. Accessed July 15, 2026. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-announces-fda-acceptance-new-drug-1
2. Axsome Therapeutics Announces AXS-12 Achieves Primary Endpoint in ENCORE Long-Term Phase 3 Trial in Narcolepsy. News release. Axsome Therapeutics. November 26, 2024. Accessed July 15, 2026. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-announces-axs-12-achieves-primary-endpoint-1
3. Axsome Therapeutics Announces AXS-12 Achieves Primary Endpoint in the SYMPHONY Phase 3 Trial in Narcolepsy. News release. March 25, 2024. Accessed July 15, 2026. https://www.globenewswire.com/news-release/2024/03/25/2851469/0/en/Axsome-Therapeutics-Announces-AXS-12-Achieves-Primary-Endpoint-in-the-SYMPHONY-Phase-3-Trial-in-Narcolepsy.html
4. Axsome Therapeutics Announces AXS-12 Achieves Primary Endpoint in CONCERT Phase 2 Trial in Narcolepsy. News Release. Axsome Therapeutics. Published December 3, 2019. Accessed July 15, 2026. https://www.globenewswire.com/en/news-release/2019/12/03/1955366/33090/en/Axsome-Therapeutics-Announces-AXS-12-Achieves-Primary-Endpoint-in-CONCERT-Phase-2-Trial-in-Narcolepsy.html