Investigational AXS-12 Reduces Cataplexy in Narcolepsy Patients

Summary: Axsome Therapeutics’ AXS-12 (reboxetine) achieved significant results in the ENCORE phase 3 trial for narcolepsy with cataplexy, reducing cataplexy attacks by 77% over six months and improving excessive daytime sleepiness, cognition, and overall narcolepsy symptoms. The trial demonstrated AXS-12’s long-term safety and efficacy, with minimal adverse effects. The company plans to file a New Drug Application (NDA) with the US Food and Drug Administration (FDA) and intends to request a pre-NDA meeting.

Key Takeaways:

Significant Reduction in Cataplexy: AXS-12 reduced weekly cataplexy attacks by 77% after six months, with 82% of patients achieving a ≥50% reduction and an increase in cataplexy-free days from 14% to 70%.
Broad Symptom Improvements: The treatment also improved excessive daytime sleepiness, cognition, and overall narcolepsy status, as assessed by clinician and patient-reported measures.
Favorable Safety Profile: AXS-12 was well tolerated, with a low rate of adverse events and no new safety concerns, supporting its potential as a long-term treatment option for narcolepsy.

Axsome Therapeutics Inc announced that AXS-12 (reboxetine), a highly selective and potent norepinephrine reuptake inhibitor and cortical dopamine modulator, achieved the primary endpoint in the ENCORE phase 3 trial, demonstrating a statistically significant improvement in the frequency of cataplexy attacks compared to placebo.

AXS-12 was also well tolerated with long-term dosing with a safety profile consistent with that observed in previously completed trials. ENCORE was a multi-center, two-period phase 3 trial evaluating the long-term efficacy and safety of AXS-12 in patients with narcolepsy with cataplexy, consisting of a 6-month open-label AXS-12 treatment period, followed by a three-week double-blind, placebo-controlled, randomized withdrawal period.

The trial enrolled 68 patients in the six-month AXS-12 treatment period. Patients (n=42) were then randomized in a 1:1 ratio to continue treatment with AXS-12 or to discontinue AXS-12 and switch to placebo for three weeks.

Significant Reduction in Cataplexy

AXS-12 met the primary endpoint of the change from randomization in the frequency of cataplexy attacks as compared to placebo at week 3 of the double-blind period. Patients randomized to switch to placebo experienced a statistically significant worsening in the average weekly number of cataplexy attacks compared with patients randomized to continue AXS-12 treatment, with an increase of 10.29 attacks per week with placebo versus 1.32 with AXS-12, at 3 weeks (p=0.017).

“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,” says Michael Thorpy, MD, ChB, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center and professor of neurology at Albert Einstein College of Medicine, in a release.

Thorpy continues, “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.”

AXS-12 resulted in statistically significant benefit 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% versus 14.3%) at three weeks (p=0.011). A significantly greater proportion of patients randomized to switch to placebo also reported worsening in their ability to concentrate, as assessed by the PGI-C, compared to those continuing on AXS-12 (57.9% versus 22.2%) at 3 weeks (p=0.029).

AXS-12 resulted in statistically significant benefit in narcolepsy overall compared to placebo, as assessed by the PGI-C. A significantly greater proportion of patients randomized to switch to placebo reported worsening of their narcolepsy, as assessed by the PGI-C, compared to those continuing on AXS-12 (52.6% versus 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,” says Herriot Tabuteau, MD, CEO of Axsome Therapeutics, in a release. “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 Benefits in Narcolepsy Symptoms

During the long-term open-label treatment portion of the trial, patients experienced substantial and sustained improvement of cataplexy with AXS-12 treatment. Patients experienced a 71% reduction from baseline in mean weekly cataplexy attacks at one month with AXS-12 treatment, which was sustained with long-term treatment resulting in a 77% reduction at six months.

Cataplexy response, defined as ≥50% reduction from baseline in weekly cataplexy attacks, was achieved by 72% of patients at one month and by 82% of patients at six months with AXS-12 treatment. Treatment with AXS-12 also substantially increased the percentage of cataplexy-free days (days with zero cataplexy attacks) per week from 14% at baseline to 61% at one month and 70% at six months.

Long-term open-label treatment with AXS-12 resulted in substantial improvements in excessive daytime sleepiness, assessed 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 one month, with this improvement maintained with long-term treatment resulting in a mean reduction of 7.3 points at six months.

Clinicians reported improvement in excessive daytime sleepiness in a substantial proportion of patients on the CGI-C scale, with 84% of patients achieving excessive daytime sleepiness improvement at one month and 78% of patients at six months with AXS-12 treatment.

A substantial proportion of patients reported improvement in cognition with AXS-12 which was sustained with long-term open-label treatment. Improvement in cognition, assessed by the NSAQ Ability to Concentrate item, was reported by 55% of patients at one month and 59% at six months with AXS-12 treatment. Change in the ability to concentrate was also assessed using the PGI-C scale. The proportion of patients reporting improvement in the ability to concentrate on the PGI-C was 67% at one month and 70% at six months with AXS-12 treatment.

Long-term open-label treatment with AXS-12 was also associated with improvement in overall narcolepsy status and patient functioning, assessed using the CGI-C, the PGI-C, and the Work Productivity and Activity Impairment Questionnaire (WPAI). On the CGI-C, clinicians reported overall improvement in narcolepsy in 90% of patients at one month and also 90% of patients at six months with AXS-12 treatment. Results were similar with the patient-reported PGI-C.

Impairment due to narcolepsy while working was assessed after treatment with AXS-12 using the WPAI. The percentage of time impaired while working decreased substantially with AXS-12 treatment from 53% at baseline to 34% at one month and 24% at six months.

Favorable Safety Profile

AXS-12 was well tolerated with long-term dosing. The safety profile with long-term dosing was consistent with prior trials of AXS-12 with no new safety signals identified. During the six-month open-label treatment period, the most common adverse events (≥5%) were nausea (5.9%) and tachycardia (5.9%). Over the six-month treatment period, 17.6% of patients discontinued due to adverse events, with no individual adverse event leading to discontinuation by more than one 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.

Orphan Drug Designation and Future Plans

AXS-12 has been granted Orphan Drug Designation for the treatment of narcolepsy. Orphan Drug Designation is granted to promising drugs intended for the safe and effective treatment of rare diseases, defined as those affecting fewer than 200,000 people in the US.

This designation may entitle Axsome to a period of seven years of marketing exclusivity in the US upon FDA approval and a waiver of the company’s obligation to pay the FDA application user fees for the product as required by the Prescription Drug User Fee Act. AXS-12 is covered by issued patents providing protection to at least 2039.