Axsome Therapeutics, Inc., a clinical-stage biopharmaceutical company developing novel therapies for the management of central nervous system (CNS) disorders, 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), and improved cognitive function, sleep quality and sleep-related symptoms. Narcolepsy is a debilitating, neurological condition characterized by EDS and cataplexy, a sudden loss of muscle tone triggered by strong emotions. AXS-12 has been granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) for the treatment of narcolepsy. CONCERT was a Phase 2, randomized, double-blind, placebo-controlled, crossover, multicenter, U.S. 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 (p<0.001). At Week 2, AXS-12 demonstrated a mean reduction of 14.6 cataplexy attacks per week compared to a reduction of 2.6 attacks per week for placebo (p=0.002), representing mean reductions of 48.8% and 8.6% from baseline, 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 improvement in cataplexy was rapid with AXS-12 demonstrating significant benefit over placebo as early as Week 1 (p<0.001).
AXS-12 significantly improved EDS symptoms compared to placebo, as measured by the Epworth Sleepiness Scale (ESS) and by the frequency of inadvertent naps. The improvement on the ESS with AXS-12 treatment was twice that observed with placebo, with reductions from baseline in the ESS score of 6.0 and 3.1, respectively for AXS-12 and placebo (p=0.003). AXS-12 treatment 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<0.001) 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=0.038).
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<0.001). For this assessment, patients rated their ability to concentrate on a 5-point scale (1=very good to 5=very poor). At the end of treatment, 42.9% of patients had an ability to concentrate that was “good” to “very 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 as early as Week 1 (p=0.007).
AXS-12 significantly improved sleep quality, as measured by overall improvement and by number of awakenings at night, and reduced sleep-related symptoms, as compared to placebo. 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 5.3% of patients with placebo (p=0.044). AXS-12 treatment also resulted in greater proportions of patients with reductions in sleep paralysis episodes, and in hypnagogic hallucinations, as compared to placebo (p=ns).
“Narcolepsy is a neurological disorder that interferes with mental and social functioning, increases work and driving related accidents, and results in a nearly two-fold higher mortality rate,”
said Dr. Michael J. Thorpy, Professor of Neurology at Albert Einstein College of Medicine.
“Medications that have the potential to reduce cataplexy symptoms, promote wakefulness, and enhance cognitive function, such as AXS-12, if borne out in Phase 3 trials, could provide new treatment options for patients living with this debilitating disorder.”
AXS-12 was safe and well tolerated. There were no serious adverse events reported in the trial, and no discontinuations due to adverse events. The overall percentage of patients experiencing adverse events was 42.9% with AXS-12 and 40.0% with placebo, with the most commonly reported adverse events with AXS-12 treatment being anxiety, constipation, and insomnia. The completion rate was 91% for patients randomized to treatment sequence 1 (AXS-12 followed by placebo) and 100% for those randomized to sequence 2 (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,”
said Herriot Tabuteau, MD, Chief Executive Officer of Axsome.
“Based on these positive results, Axsome intends to initiate Phase 3 trials of AXS-12 in 2020 with the goal of bringing this differentiated experimental medicine to narcolepsy patients as soon as possible.”
“The CONCERT trial exemplifies Axsome’s commitment to accelerating the innovation of effective treatments for difficult-to-treat CNS disorders such as narcolepsy. Our approach uses innovative clinical trial designs to effectively assess the potential of our product candidates to address unmet medical needs,”
said Cedric O’Gorman, MD, Senior Vice President of Clinical Development and Medical Affairs of Axsome.
“Existing treatment options for narcolepsy are few, do not address all key symptoms, may not be well tolerated, and are mostly controlled substances. If successfully developed, AXS-12 may overcome these limitations and could make it a candidate as foundational therapy to meaningfully improve the lives of the many narcolepsy patients.”
Axsome plans to present the detailed results of the CONCERT trial at upcoming scientific meetings.