Axsome Therapeutics has announced positive results from its Phase 3 ENCORE trial, demonstrating the long-term efficacy and safety of AXS-12 (reboxetine) in patients with narcolepsy. The trial met its primary endpoint, showing a statistically significant reduction in the frequency of cataplexy attacks compared to placebo. These findings suggest AXS-12 could offer a substantial and sustained benefit for individuals suffering from this debilitating condition.
The ENCORE trial was a multi-center study consisting of a 24-week open-label period followed by a 3-week double-blind, randomized withdrawal period. It evaluated the long-term efficacy and safety of AXS-12 in patients with narcolepsy with cataplexy. Sixty-eight participants were enrolled in the open-label period, receiving AXS-12 (5 mg) once daily for the first week, followed by twice-daily dosing for the next 23 weeks. Of these, 42 patients completed the open-label treatment and were then randomized (1:1) to either continue on AXS-12 or switch to placebo.
Reduction in Cataplexy Attacks
The primary endpoint was the change from randomization in the frequency of cataplexy attacks compared to placebo at week 3 of the double-blind period. Patients who switched to placebo experienced a statistically significant worsening in the average weekly number of cataplexy attacks compared to those who continued AXS-12 treatment. Specifically, there was an increase of 10.29 attacks per week with placebo versus 1.32 with AXS-12 at 3 weeks (P = 0.017).
Improvements in Cognition and Overall Narcolepsy Symptoms
AXS-12 also demonstrated statistically significant benefits in cognition compared to placebo, as assessed by the Narcolepsy Symptom Assessment Questionnaire (NSAQ) and the Patient Global Impression of Change (PGI-C). A significantly greater proportion of patients randomized to switch to placebo experienced worsening on the NSAQ Ability to Concentrate item compared to those continuing on AXS-12 (52.6% vs 14.3%) at 3 weeks (P = 0.011). Similarly, more patients switching to placebo reported worsening in their ability to concentrate, as assessed by the PGI-C, compared to those continuing on AXS-12 (57.9% vs 22.2%) at 3 weeks (P = 0.029).
Furthermore, a significantly greater proportion of patients randomized to switch to placebo reported worsening of their narcolepsy overall, as assessed by the PGI-C, compared with those on AXS-12 (52.6% vs 16.7%) at 3 weeks (P = 0.024).
Long-Term Benefits and Safety
In the long-term open-label treatment portion of the trial, participants treated with AXS-12 experienced substantial and sustained improvement of cataplexy, seeing a 71% reduction from baseline in mean weekly cataplexy attacks at 1 month with AXS-12 treatment. This was sustained with long-term treatment, resulting in a 77% reduction at 6 months. Cataplexy response, or ≥50% reduction from baseline in weekly cataplexy attacks, was achieved with AXS-12 treatment by 72% of patients at 1 month and by 82% of patients at 6 months. Treatment with AXS-12 also substantially increased the number of participants’ cataplexy-free days per week (14% at baseline to 61% at 1 month and 70% at 6 months).
AXS-12 also resulted in substantial improvements in excessive daytime sleepiness (EDS), assessed by investigators using the Epworth Sleepiness Scale (ESS) and the Clinician Global Impression of Change (CGI-C) scale. Mean ESS scores were reduced by 5.6 points at 1 month and 7.3 points at 6 months. On the CGI-C scale, approximately 84% of participants achieved EDS improvement at 1 month and 78% of patients at 6 months with AXS-12 treatment.
Regarding safety, AXS-12 was well-tolerated with long-term dosing. During the 6-month open-label treatment period, the most common adverse events (≥5%) were nausea (5.9%) and tachycardia (5.9%). Approximately 17.6% of patients discontinued due to adverse events, with no single adverse event leading to discontinuation by more than 1 patient. Treatment-related adverse events during the double-blind period were reported in 4.5% of patients in the AXS-12 group and 15% of patients in the placebo group. Rates of discontinuation due to adverse events in the double-blind period were 0% and 5% in the AXS-12 and placebo groups, respectively.
Expert Commentary
"Clinical evidence continues to support AXS-12 as a novel treatment option for narcolepsy that has the potential to rapidly and durably ameliorate one of the most debilitating symptoms for patients, cataplexy, while also reducing the severity of excessive daytime sleepiness, and improving cognition and overall function," said 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.
Regulatory Plans
"The results of the ENCORE trial confirm the efficacy of AXS-12 in patients with narcolepsy with cataplexy, which has now been demonstrated in three positive controlled trials, and indicate that the potential benefits of AXS-12 are substantial and sustained with long-term treatment," said Herriot Tabuteau, MD, CEO of Axsome Therapeutics. The company plans to move expeditiously towards an NDA filing for AXS-12 and intends to request a pre-NDA meeting with the FDA.
