Axsome Therapeutics announced topline SYMPHONY trial results, which show AXS-12 significantly improves key narcolepsy symptoms, including cataplexy and cognitive function.

Summary:

In the SYMPHONY phase 3 trial, Axsome Therapeutics’ AXS-12 significantly reduced weekly cataplexy attacks and improved symptoms of narcolepsy, including excessive daytime sleepiness, cognitive function, and overall disease severity, compared to placebo. The study, which involved 90 patients, also observed remission of cataplexy in a third of AXS-12 treated patients. The company plans to present detailed findings at upcoming scientific meetings.

Key Points: 

  • AXS-12 statistically significantly reduced cataplexy attacks compared to placebo.
  • AXS-12 achieved statistically significant remission of cataplexy compared to placebo.
  • AXS-12 statistically significantly reduced excessive daytime sleepiness severity.
  • AXS-12 statistically significantly improved concentration and memory compared to placebo.
  • AXS-12 statistically significantly reduced the overall severity of narcolepsy compared to placebo.
  • AXS-12 statistically significantly improved overall function and quality of life compared to placebo.

In the SYMPHONY phase 3 trial, Axsome Therapeutics’ AXS-12 (reboxetine), a highly selective and potent norepinephrine reuptake inhibitor and cortical dopamine modulator, met its primary endpoint by significantly reducing the frequency of cataplexy attacks in narcolepsy patients.

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 five weeks.

“The SYMPHONY phase 3 trial results confirm the promise and potential of AXS-12 for the treatment of narcolepsy,”  says Herriot Tabuteau, MD, CEO of Axsome Therapeutics, in a release. “Treatment with AXS-12 resulted in rapid and substantial reduction of cataplexy events, the primary endpoint of the SYMPHONY trial, while evidencing improvement across a range of validated global clinical, patient-reported, quality of life, and functional outcome measures.” 

SYMPHONY Phase 3 Trial Results

  • 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 (p=0.018). AXS-12 rapidly reduced weekly cataplexy attacks, demonstrating at week 1 a reduction of 56% compared to a reduction of 31% for placebo (p=0.007).
  • 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 (p=0.008). Achievement of remission was rapid, being experienced at week 2 by 24% of AXS-12 treated patients compared to 4.5% of placebo patients (p=0.008). 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 (p=0.014).
  • AXS-12 significantly reduced excessive daytime sleepiness severity, assessed by the Clinician Global Impression of Severity scale for excessive daytime sleepiness, compared to placebo at week 5 with mean reductions of 1.8 points for AXS-12 compared to 0.9 points for placebo (p=0.027). Rapid improvement on the Clinician Global Impression of Severity scale for excessive daytime sleepiness was seen as early as Week 1 compared to placebo (p=0.006). 
  • AXS-12 concurrently improved excessive daytime sleepiness and cataplexy as compared to placebo. Concurrent excessive daytime sleepiness and cataplexy response was achieved at week 5 by 57% of patients treated with AXS-12 compared to 33% of placebo patients (p=0.029). Concurrent EDS and cataplexy response was defined as a ≥30% reduction in inadvertent naps (excessive daytime sleepiness response), and a ≥50% reduction in cataplexy attacks (cataplexy response).
  • 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 (p=0.016), 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 ≥3-point improvement from baseline on the Epworth Sleepiness Scale 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 (p=0.004). 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 (p=0.016). Response was defined by an increase in days patients rated their Ability to Concentrate as very good or good (cognitive response), and a ≥50% reduction in cataplexy attacks (cataplexy response).
  • 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 (p=0.007), with improvements observed as early as Week 1 (p<0.001). AXS-12 demonstrated significant improvement in overall patient function and quality of life as measured by the Functional Outcomes of Sleep Questionnaire total score as compared to placebo at Week 5 (p=0.005).
  • 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 EuroQol was achieved by 55% of patients treated with AXS-12 compared to 32% of placebo patients (p=0.146).
  • AXS-12 was well tolerated in the trial. The most commonly reported adverse events in the AXS-12 arm were dry mouth (n=6), nausea (n=6), and constipation (n=4), which were overall mild to moderate. The rates of discontinuation due to adverse events was low (n=1 in each of AXS-12 and placebo arms). There were no serious adverse events in the trial.

AXS-12 was granted Orphan Drug Designation for the treatment of narcolepsy in October 2018. 

“Collectively, the data generated in SYMPHONY highlight AXS-12’s positive therapeutic impact and are consistent with the results from the previously completed positive CONCERT trial. As a next step, we look forward to completing the ongoing open-label safety extension trial of AXS-12 as we work to bring this treatment to individuals living with narcolepsy,” says Herriot Tabuteau, MD, CEO of Axsome Therapeutics, in a release.

Axsome plans to present the detailed results of the SYMPHONY trial at upcoming scientific meetings.

“Despite the existence of multiple approved narcolepsy treatments, significant unmet need still exists given the high rates of persistent symptoms reported by patients. Based on the concurrent improvements observed on cataplexy, severity of excessive daytime sleepiness, cognition and overall function, I believe AXS-12 represents a meaningful enhancement to the treatment armamentarium for narcolepsy patients and clinicians and will be a welcome treatment option in our fight against the devastating impact of narcolepsy on patients and their loved ones,”  says Michael Thorpy, MD, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center and professor of neurology at Albert Einstein College of Medicine. 

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