The phase 3 SYMPHONY trial assessing AXS-12, a selective norepinephrine reuptake inhibitor for narcolepsy, was initially expected in the third quarter of 2023.
In a recent corporate presentation, Axsome Therapeutics announced that the readout for the phase 3 SYMPHONY trial (NCT05059223) investigating AXS-12 (reboxetine), a selective norepinephrine reuptake inhibitor in development for narcolepsy, will be postponed until the fourth quarter of 2023.1 The agent, granted FDA orphan drug designation, is designed to regulate noradrenergic activity in order to promote wakefulness, sustain muscle tone, and improve cognition.2
SYMPHONY a phase 3, randomized, double-blind, multicenter, placebo-controlled trial assessing the efficacy and safety of AXS-12, began recruitment in September 2021, with the goal of approximately 90 patients randomized in a 1:1 ratio to treatment with either AXS-12 or placebo for 5 weeks. The primary end point is the frequency of cataplexy attacks with other symptoms of narcolepsy and safety explored as well.
“The advancement of AXS-12 into phase 3 testing for narcolepsy demonstrates Axsome’s commitment to developing important new medicines for patients living with serious CNS conditions,” said Herriot Tabuteau, MD, chief executive officer at Axsome, said in a statement at the time of enrollment.3 “Narcolepsy impairs almost every aspect of a patient’s life including cognitive, psychological, social, and emotional functioning. If successfully developed, AXS-12 may address multiple symptoms of this debilitating condition.”
In December 2019, AXS-12 met the prespecified primary end point in the phase 2, randomized, double-blind, placebo-controlled, crossover, multicenter, CONCERT trial (NCT03881852) of 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 the therapy achieved a 50% or greater reduction in the weekly number of cataplexy attacks compared with 30.0% for placebo (P = .003).
From baseline, AXS-12 and placebo-treated patients saw reductions of 6.0 and 3.1, respectively, in Epworth Sleepiness Scale score (P = .003). Treatment with AXS-12 resulted in a 31.8% mean reduction from baseline in the average weekly number of inadvertent naps versus a 5.3% mean reduction for placebo (P < .001) at week 2. The improvement in frequency of inadvertent naps was rapid with AXS-12 demonstrating significant benefit over placebo as early as week 1 (P = .038).
The improvement in the ability to concentrate was rapid with those treated with AXS-12 as the patients demonstrated significant improvement over placebo as early as week 1 (P =.007) on the Ability to Concentrate item of the Narcolepsy Symptom Assessment Questionnaire. Treatment with AXS-12 resulted in 45.0% of patients reporting improvements in sleep quality compared with 5.3% of patients on placebo (P = .007). The agent resulted in 30.0% of patients reporting a reduction in the number of awakenings at night versus 5.3% of patients with placebo (P = .044).
There were no serious adverse events 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.
“We are very pleased with the results of the CONCERT trial, which demonstrated a strong effect of AXS-12 on both cataplexy and excessive daytime sleepiness symptoms, as well as on cognitive function, in narcolepsy patients. The improvement in the ability to concentrate with AXS-12 is especially relevant because the cognitive impairment associated with narcolepsy is one of the most distressing aspects of the disease for patients, as highlighted in the FDA’s The Voice of the Patient report on Narcolepsy,” Tabuteau said in a statement.4