Axsome Therapeutics Inc announced that AXS-12 (reboxetine) met the prespecified primary endpoint and significantly reduced the number of cataplexy attacks as compared to placebo in patients with narcolepsy in the CONCERT Phase 2 trial. AXS-12 also significantly reduced excessive daytime sleepiness (EDS), as well as improved cognitive function, sleep quality, and sleep-related symptoms. AXS-12 has been granted Orphan Drug Designation by the US Food and Drug Administration (FDA) for the treatment of narcolepsy. CONCERT was a Phase 2, randomized, double-blind, placebo-controlled, crossover, multicenter, US trial in which 21 patients with a diagnosis of narcolepsy with cataplexy were all treated with orally administered AXS-12 for 2 weeks, and with placebo for 2 weeks, with the treatment periods separated by 1 week of down-titration and washout.
AXS-12 met the prespecified primary endpoint by demonstrating a highly statistically significant reduction from baseline in the mean weekly number of cataplexy attacks, averaged for the 2-week treatment period (overall treatment effect), as compared to placebo (pSummary of Topline Results of the CONCERT Trial
Effect on Cataplexy

  • AXS-12 was associated with a statistically significant reduction from baseline in the mean weekly number of cataplexy attacks, averaged for the 2-week treatment period, as compared to placebo (p
  • At Week 2, AXS-12 was associated with a statistically significant mean reduction from baseline in the weekly number of cataplexy attacks of 14.6 attacks per week for AXS-12 compared to a reduction of 2.6 attacks for placebo (p=0.002), representing mean reductions from baseline of 48.8% and 8.6%, respectively.
  • The proportion of patients achieving a 50% or greater reduction in the weekly number of cataplexy attacks was 76.2% for AXS-12, compared to 30.0% for placebo (p=0.003) at Week 2.
  • The effect of AXS-12 on cataplexy was rapid with AXS-12 demonstrating a statistically significant improvement in the frequency of cataplexy as compared to placebo as early as Week 1 (p

Effect on Excessive Daytime Sleepiness (EDS)

  • AXS-12 was associated with a statistically significant mean reduction in Epworth Sleepiness Scale (ESS) score from baseline as compared to placebo, with mean reductions of 6.0 and 3.1 points, respectively for AXS-12 and placebo (p=0.003).
  • AXS-12 was associated with a statistically significant reduction from baseline in the weekly number of inadvertent naps as compared to placebo, with a mean reduction of 31.8% for AXS-12 versus 5.3% for placebo (p
  • The improvements in EDS symptoms were rapid with AXS-12 demonstrating significantly greater reductions than placebo in the number of inadvertent naps at Week 1 (p=0.038).

Effect on Cognitive Function

  • AXS-12 significantly improved cognitive function compared to placebo over the 2-week treatment period as measured by the Ability to Concentrate item of the Narcolepsy Symptom Assessment Questionnaire (NSAQ), which was assessed daily (p
  • At the end of treatment, 42.9% of patients had an ability to concentrate that was “very good” or “good” with AXS-12 treatment, compared to 25.0% of patients with placebo, and 0% of patients at baseline.
  • The improvement in the ability to concentrate was rapid with AXS-12 demonstrating significant improvement over placebo at Week 1 (p=0.007).

Effect on Sleep Quality and Sleep-related Symptoms

  • AXS-12 treatment resulted in 45.0% of patients reporting improved sleep quality versus 5.3% of patients with placebo (p=0.007).
  • AXS-12 treatment resulted in 30.0% of patients reporting a reduction in the number of awakenings at night versus 5% of patients with placebo (p=0.044).
  • AXS-12 treatment also resulted in greater proportions of patients with reductions in sleep paralysis episodes (55.0% vs. 26.3%), and in hypnagogic hallucinations (40.0% vs. 26.3%), as compared to placebo (p=ns).

Safety and Tolerability

  • AXS-12 was safe and well tolerated. There were no serious adverse events, and no discontinuations due to adverse events.
  • The overall rate of adverse events was 42.9% for patients treated with AXS-12 and 40.0% for patients treated with placebo, with the most commonly reported adverse events with AXS-12 treatment being anxiety, constipation, and insomnia.