Axsome's AXS-12 Meets Primary Goal in Phase 3 Narcolepsy Study

Axsome Therapeutics, Inc., a biopharmaceutical company specializing in treatments for central nervous system disorders, has announced that their drug AXS-12 (reboxetine) has achieved significant results in a Phase 3 trial (ENCORE) for treating narcolepsy patients with cataplexy. AXS-12, a norepinephrine reuptake inhibitor and cortical dopamine modulator, was found to significantly reduce cataplexy attacks compared to a placebo, meeting its primary endpoint.

The ENCORE trial was designed to evaluate the long-term efficacy and safety of AXS-12. This multi-center trial included a 6-month open-label treatment period with AXS-12, followed by a 3-week double-blind, placebo-controlled, randomized withdrawal period. It enrolled 68 patients, who were treated with AXS-12 for the initial 6 months. Subsequently, 42 patients were randomized to either continue the AXS-12 treatment or switch to a placebo.

The results showed that discontinuing AXS-12 led to a significant increase in cataplexy attacks compared to those who continued with the treatment. Specifically, patients switching to the placebo experienced an average weekly increase of 10.29 cataplexy attacks, compared to an increase of just 1.32 attacks for those who remained on AXS-12 (p=0.017).

Beyond reducing cataplexy attacks, AXS-12 demonstrated additional benefits. It significantly improved cognition and overall narcolepsy symptoms compared to the placebo, as measured by the Narcolepsy Symptom Assessment Questionnaire (NSAQ) and the Patient Global Impression of Change (PGI-C). For instance, a greater proportion of patients on the placebo reported worsening in their ability to concentrate (52.6% versus 14.3%) at the end of the 3 weeks (p=0.011).

AXS-12 also showed a positive impact on excessive daytime sleepiness (EDS). Patients receiving long-term treatment with AXS-12 had notable reductions in EDS, which was assessed using the Clinician Global Impression of Change (CGI-C) scale. At one month, 84% of patients reported improvement, and this was sustained at 78% by the sixth month.

During the open-label treatment phase, substantial and sustained improvements were noted. Patients experienced a 71% reduction from baseline in mean weekly cataplexy attacks after one month, which further improved to a 77% reduction at six months. Additionally, 72% of patients achieved a cataplexy response (defined as a ≥50% reduction in weekly attacks) within one month, and this response rate increased to 82% at six months. The percentage of cataplexy-free days per week also rose from 14% at baseline to 61% after one month and reached 70% at six months.

Treatments with AXS-12 also resulted in significant improvements in cognition and overall narcolepsy symptoms, with 55% of patients reporting better concentration at one month, and 59% by six months, as per the NSAQ. Similarly, 67% of patients reported improved concentration at one month, and this increased to 70% by six months, according to the PGI-C.

Overall improvements in narcolepsy and patient functioning were also observed. By the first month, 90% of patients showed overall improvement, which was maintained at six months. Patient-reported functionality, measured using the Work Productivity and Activity Impairment Questionnaire (WPAI), indicated a substantial decrease in work-related impairment from 53% at baseline to 34% at one month, further reducing to 24% at six months.

AXS-12 proved to be well-tolerated, with a safety profile consistent with previous trials. The most common adverse events during the 6-month period were nausea and tachycardia, each reported by 5.9% of patients. Discontinuation due to adverse events occurred in 17.6% of patients, but no single event led to more than one patient discontinuing. During the double-blind period, the rates of treatment-related adverse events were 4.5% in the AXS-12 group and 15% in the placebo group.

AXS-12 has been granted Orphan Drug Designation for narcolepsy treatment by the FDA, which could provide Axsome Therapeutics with exclusive marketing rights in the U.S. for seven years upon approval. The drug is protected by patents extending at least until 2039.