Axsome Therapeutics says AXS-12 achieves primary endpoint in SYMPHONY trial

Axsome Therapeutics announced that AXS-12, a highly selective and potent norepinephrine reuptake inhibitor and cortical dopamine modulator, achieved the primary endpoint and significantly reduced the frequency of cataplexy attacks as compared to placebo in patients with narcolepsy in the SYMPHONY Phase 3 trial. AXS-12 also reduced excessive daytime sleepiness severity, improved cognitive function, and reduced overall narcolepsy severity as compared to placebo. SYMPHONY was a Phase 3 multicenter, randomized, double-blind, placebo-controlled trial in which 90 patients with a diagnosis of narcolepsy with cataplexy were randomized to treatment with AXS-12 or placebo for 5 weeks. AXS-12 met the primary endpoint by demonstrating a substantial and statistically significant reduction from baseline in weekly cataplexy attacks compared to placebo at Week 5, with reductions of 83% for AXS-12 and 66% for placebo. AXS-12 rapidly reduced weekly cataplexy attacks, demonstrating at Week 1 a reduction of 56% compared to a reduction of 31% for placebo. AXS-12 induced remission of cataplexy and increased cataplexy-free days compared to placebo. Remission of cataplexy, defined as a 100% reduction from baseline, was achieved at Week 5 by 33% of AXS-12 treated patients compared to 9.5% of placebo patients. Achievement of remission was rapid, being experienced at Week 2 by 24% of AXS-12 treated patients compared to 4.5% of placebo patients AXS-12 increased the percentage of cataplexy-free days per week, defined as days with zero cataplexy attacks, to 84.5% at Week 5 compared to 22.6% for placebo. AXS-12 significantly reduced excessive daytime sleepiness severity, assessed by the Clinician Global Impression of Severity scale for EDS, compared to placebo at Week 5 with mean reductions of 1.8 points for AXS-12 compared to 0.9 points for placebo. Rapid improvement on the CGI-S for EDS was seen as early as Week 1 compared to placebo. AXS-12 concurrently improved EDS and cataplexy as compared to placebo. Concurrent EDS and cataplexy response was achieved at Week 5 by 57% of patients treated with AXS-12 compared to 33% of placebo patients. Concurrent EDS and cataplexy response was defined as a greater than or equal to30% reduction in inadvertent naps, and a greater than or equal to50% reduction in cataplexy attacks. A decrease in the number of inadvertent naps was experienced by 54% of AXS-12 patients at Week 5 compared to 28% of placebo patients, assessed by the Narcolepsy Symptom Assessment Questionnaire. Improvement on the Epworth Sleepiness Scale was numerically greater for AXS-12 than for placebo, with mean reductions from baseline of 4.7 points for AXS-12 compared to 3.4 points for placebo. A greater than or equal to3-point improvement from baseline on the ESS was achieved by 60% of AXS-12 patients who had a cataplexy response. AXS-12 significantly improved concentration and memory as measured by the Cognitive Function Items of the Functional Outcomes of Sleep Questionnaire at Week 5. AXS-12 concurrently improved cognition and cataplexy as compared to placebo. Concurrent cognitive and cataplexy response was achieved at Week 5 by 41% of patients treated with AXS-12 compared to 17% of placebo patients. Response was defined by an increase in days patients rated their Ability to Concentrate as very good or good, and a greater than or equal to50% reduction in cataplexy attacks. AXS-12 improved narcolepsy overall disease condition, and patient function and quality of life. Clinicians reported a rapid and significant reduction in overall narcolepsy severity for patients treated with AXS-12 compared to placebo at Week 5, with improvements observed as early as Week 1. AXS-12 demonstrated significant improvement in overall patient function and quality of life as measured by the FOSQ-10 total score as compared to placebo at Week 5. Anxiety and depression, known common narcolepsy co-morbidities, was reported by 45% of study participants at baseline, as assessed by the EuroQol. Improvement from baseline in the Anxiety/Depression domain of the EQ-5D-5L was achieved by 55% of patients treated with AXS-12 compared to 32% of placebo patients. AXS-12 was well tolerated in the trial. The most commonly reported adverse events in the AXS-12 arm were dry mouth, nausea, and constipation, which were overall mild to moderate. The rates of discontinuation due to adverse events was low. There were no serious adverse events in the trial.