Axsome Therapeutics’ Reboxetine Promises Long-Term Symptom Relief in Narcolepsy

Axsome Therapeutics has released findings from its ENCORE Phase III trial, demonstrating that their investigational drug AXS-12 (reboxetine) significantly reduces cataplexy attacks, improves excessive daytime sleepiness and enhances overall functioning in individuals with narcolepsy. These results highlight reboxetine’s potential as a comprehensive treatment for this challenging sleep-wake disorder.

Reboxetine, a norepinephrine reuptake inhibitor and cortical dopamine modulator, has been granted Orphan Drug designation for narcolepsy. By enhancing wakefulness and regulating muscle tone, it addresses excessive daytime sleepiness and cataplexy, the disorder’s two hallmark symptoms.

Narcolepsy disrupts sleep-wake regulation, leading to fragmented nighttime sleep, cognitive impairments and sudden muscle weakness triggered by strong emotions. These symptoms significantly affect daily life, underscoring the need for effective therapies.

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The ENCORE trial evaluated reboxetine’s long-term efficacy and safety through a six-month open-label phase followed by a three-week double-blind period. During the double-blind phase, patients continuing reboxetine had an average increase of only 1.32 weekly cataplexy attacks compared to 10.29 for those switched to placebo (p=0.017). Over six months, participants receiving reboxetine experienced a 77 percent reduction in weekly cataplexy attacks, with cataplexy-free days increasing from 14 percent at baseline to 70 percent.

Excessive daytime sleepiness also improved markedly. Epworth Sleepiness Scale scores for participants on reboxetine decreased by 5.6 points at one month and 7.3 points at six months. Clinician assessments showed that 84 percent of patients achieved improvement at one month, with 78 percent maintaining these gains at six months. Cognitive function similarly improved, with 59 percent of patients reporting better focus after six months of treatment.

Overall narcolepsy symptoms improved substantially, with 90 percent of patients showing progress at both one and six months, as measured by the Clinician Global Impression of Change scale. Reboxetine also demonstrated a favorable safety profile, with no new adverse events. The most common side effects, nausea and tachycardia, were reported by fewer than six percent of participants.

Axsome CEO Dr. Herriot Tabuteau confirmed plans to advance AXS-12’s regulatory process, including a pre-New Drug Application (NDA) meeting with the US Food and Drug Administration (FDA). This submission builds on the drug’s efficacy demonstrated across three controlled trials.

In a competitive landscape, reboxetine’s multi-symptom efficacy across cataplexy, daytime sleepiness and cognition distinguishes it from promising and emerging therapies like Takeda’s TAK-861 and Jazz’s Xywav (calcium/magnesium/potassium/sodium oxybates). TAK-861 addresses orexin-deficient narcolepsy type 1, while Jazz’s low-sodium Xywav improves nighttime sleep and daytime functioning but requires nightly dosing. Alkermes’ ALKS 2680, in early development, shows promise as a once-daily orexin agonist for type 2 narcolepsy and idiopathic hypersomnia.

Reboxetine’s long-term efficacy and safety could position it as a versatile option for addressing narcolepsy’s multifaceted challenges.