Narcolepsy Treatment AXS-12 Achieves Primary Endpoint in Long-Term Phase 3 Trial

auremar/AdobeStock

Axsome Therapeutics announced that reboxetine (AXS-12), a highly selective and potent norepinephrine reuptake inhibitor and cortical dopamine modulator, achieved the primary endpoint in the phase 3 ENCORE trial, demonstrating a statistically significant improvement in the frequency of cataplexy attacks when compared with placebo. Long-term dosing with AXS-12 was also well tolerated with a safety profile consistent with previous trials.^1,2

“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. “Narcolepsy is a complex and heterogeneous condition defined by distinct symptom clusters and there remains great need for options that can address this variety in disease presentation. The results from the ENCORE study support AXS-12 as a potentially important new option for physicians and patients.”

ENCORE

ENCORE (Evaluating Continued Treatment with Reboxetine)—a multicenter phase 3 trial that consisted of a 24-week open-label period followed by a 3-week, double-blind, randomized withdrawal period—evaluated the efficacy and long-term safety of AXS-12 in participants with narcolepsy. Investigators evaluated 68 participants who rolled over from the SYMPHONY phase 3 trial of AXS-12, then enrolled into the open-label period and were treated with AXS-12 (5 mg) once-daily for the first week, followed by twice daily dosing for the next 23 weeks. The participants who completed the open-label treatment period (n=42) were then randomized in a 1:1 ratio to continue on AXS-12 (n=22) or to switch to placebo (n=20). The mean number of cataplexy attacks at baseline was 31.3, whereas the mean number of cataplexy attacks at randomization was 4.2 (AXS-12) and 6.9 (placebo).

AXS-12 met the primary endpoint: change from randomization in the frequency of cataplexy attacks as compared with placebo at week 3 of the double-blind period. Compared with participants taking AXS-12, participants who were randomized to switch to placebo experienced a statistically significant worsening in the average weekly number of cataplexy attacks, seeing an increase of 10.29 attacks per week with placebo vs 1.32 with AXS-12, at 3 weeks (P=0.017).

AXS-12 also showed improvement in participants across a range of other measures. For example, AXS-12 resulted in statistically significant benefit in cognition compared with placebo. Investigators assessed cognition using 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 with those on AXS-12 (52.6% vs 14.3%) at 3 weeks (P=0.011); and a 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).

Additionally, a significantly greater proportion of patients randomized to switch to placebo reported worsening of their narcolepsy, as assessed by the PGI-C, compared with those on AXS-12 (52.6% vs 16.7%) at 3 weeks (P=0.024).

“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. “We are pleased by the improvements not only in cataplexy, but also in excessive daytime sleepiness and cognition reported by a majority of patients in the trial with long-term AXS-12 treatment. Importantly, these improvements were accompanied by a favorable long-term safety and tolerability profile. We plan to move expeditiously towards an NDA filing for AXS-12 and intend to request a pre-NDA meeting with the FDA.”

Long-Term Treatment

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.

Participant improvement in cognition with AXS-12 treatment, assessed by the NSAQ Ability to Concentrate item, was reported by 55% at 1 month and 59% at 6 months. Patients reporting improvement in the ability to concentrate on the PGI-C was 67% at 1 month and 70% at 6 months with AXS-12 treatment.

For overall improvement in narcolepsy with AXS-12 treatment, on the CGI-C, clinicians reported improvement in 90% of patients at 1 month and also 90% of patients at 6 months. Patient-reported PGI-C Results were similar. Impairment due to narcolepsy while working was assessed after treatment with AXS-12 using the Work Productivity and Activity Impairment Questionnaire. The percentage of time impaired while working decreased substantially with AXS-12 treatment from 53% at baseline to 34% at 1 month and 24% at 6 months.

Safety Profile

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.

References

1. Axsome Therapeutics announces AXS-12 achieves primary endpoint in ENCORE long-term phase 3 trial in narcolepsy. News release. November 26, 2024. https://www.globenewswire.com/news-release/2024/11/26/2987364/33090/en/Axsome-Therapeutics-Announces-AXS-12-Achieves-Primary-Endpoint-in-ENCORE-Long-Term-Phase-3-Trial-in-Narcolepsy.html

2. Bratulic A. Phase III win puts Axsome's narcolepsy drug on fast track for US filing. FirstWord Pharma. November 26, 2024. https://firstwordpharma.com/story/5916592