Axsome to File NDA Following Positive Phase 3 Results of AXS-12 in Narcolepsy

Michael Thorpy, MD

New findings from the phase 3 ENCORE trial revealed that treatment with AXS-12 (Axsome Therapeutics), an investigational agent for narcolepsy, achieved its primary end point in reducing the number of cataplexy attacks compared with placebo. Coupled with other benefits in excessive daytime sleepiness, cognition, and work productivity, Axsome plans to move towards a new drug application (NDA) filing for AXS-12 and intends to request a pre-NDA meeting with the FDA.

The ENCORE trial, a 2-part study, comprised a 6-month open-label treatment period followed by a 3-week randomized, placebo-controlled withdrawal. Of 68 enrolled patients with narcolepsy with cataplexy, 42 were randomly assigned 1:1 to continue AXS-12 or switch to placebo. The primary end point of change in weekly cataplexy attacks was met, with those who switched to placebo experiencing a mean increase of 10.29 cataplexy attacks per week compared to a mean increase of 1.32 attacks per week for those randomized to continue AXS-12 treatment, at 3 weeks (P = .017).

Additional data from the double-blind portion revealed that a significantly greater proportion of patients randomized to switch to placebo experienced worsening on the NSAQ Ability to Concentrate item compared with those who continued on AXS-12 (52.6% vs 14.3%) at 3 weeks (P = .011). At 3 weeks, significantly more patients switching to placebo reported worsening in concentration (57.9% vs. 22.2%; p=0.029) and overall narcolepsy symptoms (52.6% vs. 16.7%; p=0.024) compared to those continuing AXS-12, per PGI-C assessments.

"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," Michael Thorpy, MD, director of the Sleep-Wake Disorders Center at Montefiore Medical Center and professor of neurology at the Albert Einstein College of Medicine, said in a statement.¹ "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, a selective norepinephrine reuptake inhibitor, is designed to regulate noradrenergic activity in order to promote wakefulness, sustain muscle tone, and improve cognition. In the open-label portion of the trial, patients experienced a 71% drop in mean weekly cataplexy attacks at 1 month with AXS-12 treatment, which was sustained with long-term treatment resulting in a 77% reduction at 6 months.

With AXS-12 treatment, 72% of patients achieved at least a 50% reduction in weekly cataplexy attacks at 1 month and 82% at 6 months, while cataplexy-free days per week increased from 14% at baseline to 61% at 1 month and 70% at 6 months. AXS-12 also had an impact on excessive daytime sleepiness (EDS), as treated patients showed a mean reduction of 5.6 points in Epworth Sleepiness Scale (ESS) by 1 month. This improvement was sustained over the long-term period, with a mean reduction of 7.3 points at 6 months.

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In the study, 55% of patients reported an improvement in cognition at 1 month, explained by the NSAQ Ability to Concentrate item. This figure increased slightly to 59% at 6 months. AXS-12 treatment was also associated with an improvement in the ability to concentrate, assessed by the PGI-C, with 67% of patients reporting improvement at 1 month, and 70% reporting improvement at 6 months.

Herriot Tabuteau

"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," Herriot Tabuteau, chief executive officer at Axsome, said in a statement.¹ "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."

In terms of safety, AXS-12 was considered well-tolerated, with no new emerging safety signals identified. During the 6-month open-label period, 17.6% of patients discontinued because of adverse events (AEs), with no individual AE leading to discontinuation by more than 1 patient. The most common AEs throughout that time were nausea (5.9%) and tachycardia (5.9%). During the double-blind period, treatment-related adverse events occurred in 4.5% of AXS-12 patients vs. 15% on placebo, with discontinuation rates due to adverse events at 0% and 5%, respectively.

The study population of ENCORE included participants who rolled over from the phase 3 SYMPONY trial (NCT5059223). Earlier this year, Axsome announced that AXS-12 achieved its primary end point in SYMPHONY, demonstrating an 83% reduction in weekly cataplexy attacks vs 66% for placebo (P = .018). AXS-12 also rapidly reduced weekly cataplexy attacks, demonstrating at week 1 a reduction of 56% compared with a reduction of 31% for placebo (P = .007). In addition to improvements in EDS severity, those treated with AXS-12 showed a decrease in the number of inadvertent naps (54%) at week 5 compared with those on placebo (28%; P = .016).²

REFERENCES
1. Axsome Therapeutics Announces AXS-12 Achieves Primary Endpoint in ENCORE Long-Term Phase 3 Trial in Narcolepsy. News release. Axsome Therapeutics. November 26, 2024. Accessed November 27, 2024. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-announces-axs-12-achieves-primary-endpoint-1
2. Axsome Therapeutics Announces AXS-12 Achieves Primary Endpoint in the SYMPHONY Phase 3 Trial in Narcolepsy. News release. March 25, 2024. Accessed November 27, 2024. https://www.globenewswire.com/news-release/2024/03/25/2851469/0/en/Axsome-Therapeutics-Announces-AXS-12-Achieves-Primary-Endpoint-in-the-SYMPHONY-Phase-3-Trial-in-Narcolepsy.html