Phase 3 Trial of AXS-12 for Narcolepsy Meets Primary Endpoint


The treatment significantly reduced the frequency of cataplexy attacks in patients with narcolepsy compared with placebo.



The SYMPHONY phase 3 trial1 evaluating the efficacy of AXS-12 (reboxetine) for the treatment of narcolepsy has achieved positive results by meeting its primary endpoint. The trial revealed that AXS-12, a highly selective norepinephrine reuptake inhibitor and cortical dopamine modulator2 that was granted Orphan Drug Designation for the treatment of narcolepsy in 2018,3 successfully met its primary endpoint by significantly reducing the frequency of cataplexy attacks in patients with narcolepsy compared with placebo.2

“AXS-12 is a novel therapeutic approach to the treatment of narcolepsy as evidenced by the strong clinical results generated from the phase 3 SYMPHONY trial, including a rapid and significant reduction in cataplexy events compared to placebo,” said Michael Thorpy, MD, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center and professor of neurology at Albert Einstein College of Medicine, in a press release.

“Despite the existence of multiple approved narcolepsy treatments, significant unmet need still exists, given the high rates of persistent symptoms reported by patients. Based on the concurrent improvements observed on cataplexy, severity of excessive daytime sleepiness, cognition, and overall function, I believe AXS-12 represents a meaningful enhancement to the treatment armamentarium for narcolepsy patients and clinicians and will be a welcome treatment option in our fight against the devastating impact of narcolepsy on patients and their loved ones.”

The SYMPHONY trial, a phase 3 multicenter study, enrolled 90 patients diagnosed with narcolepsy with cataplexy who were randomized to receive either AXS-12 or placebo for a duration of 5 weeks. Results demonstrated a noteworthy reduction in weekly cataplexy attacks with AXS-12 compared with placebo, with a reduction of 83% versus 66%, respectively, at week 5 (p=0.018). Additionally, AXS-12 exhibited rapid reduction in cataplexy attacks as early as week 1, with a reduction of 56% versus 31% for placebo (p=0.007).2

Furthermore, AXS-12 demonstrated the induction of remission of cataplexy, defined as a 100% reduction from baseline, in 33% of treated patients compared with 9.5% of placebo patients at week 5 (p=0.008). Remission was observed as early as week 2 in 24% of AXS-12-treated patients compared with 4.5% of placebo patients (p=0.008). AXS-12 also led to a significant increase in the percentage of cataplexy-free days per week compared with placebo, with 84.5% versus 22.6% respectively (p=0.014).2

In addition to reducing cataplexy attacks, AXS-12 demonstrated a significant reduction in the severity of excessive daytime sleepiness compared with placebo at week 5 (p=0.027). This improvement was evident as early as week 1 (p=0.006). AXS-12 also showed concurrent improvements in excessive daytime sleepiness and cataplexy response compared with placebo, with 57% of AXS-12-treated patients achieving concurrent response at week 5 compared with 33% of placebo patients (p=0.029).2

AXS-12 also exhibited improvements in cognitive function, overall narcolepsy severity, patient function, and quality of life compared with placebo. Notably, AXS-12 was well tolerated in the trial, with dry mouth, nausea, and constipation being the most commonly reported adverse events.2

“The SYMPHONY Phase 3 trial results confirm the promise and potential of AXS-12 for the treatment of narcolepsy,” said Herriot Tabuteau, MD, CEO of AXS-12 developer Axsome Therapeutics, in a press release.

“Treatment with AXS-12 resulted in rapid and substantial reduction of cataplexy events, the primary endpoint of the SYMPHONY trial, while evidencing improvement across a range of validated global clinical, patient-reported, quality of life, and functional outcome measures. 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. As a next step, we look forward to completing the ongoing open-label safety extension trial of AXS-12 as we work to bring this treatment to individuals living with narcolepsy.”

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Note: This article was prepared with the assistance of ChatGPT.


1. A study to assess the efficacy and safety of AXS-12 (reboxetine) in patients with narcolepsy (SYMPHONY). Updated March 7, 2023. Accessed March 26, 2024.

2. Axsome Therapeutics announces AXS-12 achieves primary endpoint in the SYMPHONY phase 3 trial in narcolepsy. GlobeNewswire. News release. March 25, 2024. Accessed March 26, 2024.

3. AXS-12: a potentially new treatment option for narcolepsy. Axsome Therapeutics. Accessed March 26, 2024.

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