FDA Accepts NDA for AXS-12 in Cataplexy Associated With Narcolepsy
Key Clinical Summary:
- The US Food and Drug Administration (FDA) accepted Axsome Therapeutics’ NDA for AXS-12 (reboxetine) for cataplexy in narcolepsy, with a PDUFA target action date of May 1, 2027, and no advisory committee meeting currently planned.
- In the phase 3 SYMPHONY trial, AXS-12 significantly reduced weekly cataplexy attacks versus placebo at week 5 and improved remission, excessive daytime sleepiness, cognition, narcolepsy severity, function, and quality of life.
- Continued AXS-12 treatment maintained cataplexy control versus placebo withdrawal in the phase 3 ENCORE trial, with long-term data showing sustained symptom improvements and no new safety signals.
The US Food and Drug Administration (FDA) has accepted a New Drug Application for AXS-12 (reboxetine) for the treatment of cataplexy in narcolepsy, announced manufacturer Axsome Therapeutics.
If approved, AXS-12 would provide a new therapeutic option for individuals experiencing cataplexy, a symptom of narcolepsy characterized by sudden episodes of muscle weakness or loss of muscle tone while awake. Seen in an estimated 70% of patients with narcolepsy, these episodes are typically triggered by strong emotions, including fear, anger, stress, laughter, or excitement.
Phase 3 Evidence
The NDA is supported by findings from the phase 3 SYMPHONY and ENCORE trials. In the 5-week, multicenter, randomized, double-blind, placebo-controlled SYMPHONY trial, 90 patients with narcolepsy with cataplexy were randomized to AXS-12 or placebo. AXS-12 met the primary endpoint, reducing weekly cataplexy attacks by 83% from baseline at week 5 compared with 66% for placebo (p = 0.018). Cataplexy remission, defined as a 100% reduction from baseline, occurred in 33% of patients receiving AXS-12 versus 9.5% receiving placebo (p = 0.008).
AXS-12 also significantly improved measures of excessive daytime sleepiness (EDS) severity, concentration and memory, overall narcolepsy severity, and function and quality of life compared with placebo.
In the phase 3 ENCORE trial, which included a 6-month open-label treatment period followed by a 3-week randomized withdrawal period, patients switched to placebo experienced a greater increase in weekly cataplexy attacks than those who continued AXS-12, with 10.29 versus 1.32 attacks per week at 3 weeks respectively (p = 0.017). Long-term treatment was associated with sustained reductions in cataplexy attacks and improvements in EDS, cognition, overall narcolepsy status, and work-related impairment.
Safety and Investigational Status
In SYMPHONY, AXS-12 was well tolerated, with the most commonly reported adverse events including dry mouth, nausea, and constipation. No serious adverse events were reported. In ENCORE, long-term dosing showed a safety profile consistent with prior trials, with no new safety signals identified.
AXS-12 has been granted FDA Orphan Drug Designation for the treatment of narcolepsy. The agency has set a Prescription Drug User Fee Act (PDUFA) target action date of May 1, 2027, and currently does not plan to hold an advisory committee meeting as part of its review.
