New in Narcolepsy: Pharmacology Updates

With the recent approval of orzeyful (oveporexton) for narcolepsy type 1, review the latest movements in the narcolepsy space.

FDA Approves Oveporexton for Narcolepsy Type 1

The US Food and Drug Administration (FDA) has approved Takeda's Orzeyful (oveporexton) for narcolepsy type 1 in adults, marking the first orexin receptor 2-selective agonist approved for the condition.¹ Approval was based on 2 randomized, double-blind, placebo-controlled 12-week trials enrolling 273 adults, in which patients taking Orzeyful showed improved daytime wakefulness and significant reductions in cataplexy, sleep paralysis, hallucinations, and nighttime sleep disruption compared with placebo.^2,3 The most common adverse effects were insomnia, increased urinary frequency and urgency, and increased salivation, with low discontinuation rates and over 95% of those who completed the trial enrolling in the ongoing long-term extension study. Orzeyful is dosed as an oral 2-mg tablet twice daily and should not be combined with strong CYP3A inhibitors; scheduling under the Controlled Substances Act has been recommended, with a Drug Enforcement Administration decision pending.

FDA Accepts NDA for AXS-12 for the Treatment of Cataplexy in Narcolepsy

Axsome Therapeutics announced that the FDA has accepted the New Drug Application for reboxetine (AXS-12) for cataplexy in narcolepsy, with a PDUFA target action date of May 1, 2027.⁴ AXS-12 is a selective norepinephrine reuptake inhibitor and cortical dopamine modulator intended to stabilize muscle tone during wakefulness while promoting wakefulness and cognitive function. In the phase 3 SYMPHONY trial, 90 participants with narcolepsy type 1 were randomized 1:1 to AXS-12 or placebo for 5 weeks; AXS-12 reduced weekly cataplexy attacks by 83% versus 66% with placebo at week 5 (rate ratio=0.49; P=.018), with complete cataplexy remission in 33% of AXS-12 patients versus 9.5% on placebo.^5,6 Secondary endpoints, including excessive daytime sleepiness severity, inadvertent naps, and cognitive function, also improved with a favorable safety profile.

New AAN Poster Presentation on Alixorexton for Narcolepsy Type 1

New data from the phase 2 Vibrance-1 study of alixorexton, a selective orexin 2 receptor agonist, were presented in a poster at the American Academy of Neurology 2026 Annual Meeting, showing nominally significant, clinically meaningful improvements in patient-reported disease severity, cognitive impairment, and fatigue sustained through 12 to 13 weeks.⁷ In the 92-participant, randomized, placebo-controlled trial, all alixorexton dose groups (4 mg, 6 mg, and 8 mg) showed improvement on the Narcolepsy Severity Scale-Clinical Trials at week 6 versus placebo (P < 0.001), along with early and sustained gains in cognitive function and fatigue measures. More than 95% of the 92 enrolled participants completed both the 6-week double-blind period and the 7-week open-label extension, and alixorexton was generally well tolerated with no serious treatment-emergent adverse events. These findings will support the recently initiated phase 3 Brilliance studies evaluating alixorexton in narcolepsy type 1 and type 2.⁸

Reducing Microsleeps: Oveporexton's Impact on Patient Outcomes

At the SLEEP 2026 Annual Meeting, Takeda presented results from 2 pivotal studies showing that oveporexton (TAK-861) improved daily functioning, cognition, and sleep-related symptoms in narcolepsy type 1, including a reduction in microsleeps, brief sleep episodes lasting 15 seconds or less that are identified by slowing frequency on EEG.^3,9 Elena Koundourakis, PhD, discussed these findings with Psychiatric Times. Microsleeps carry a substantial psychosocial burden; patients report embarrassment when episodes occur publicly, symptom sensitivity to factors such as weather and menstruation, and occasional premonitory sensations like eye discomfort or incoherent speech, though the episodes are typically uncontrollable.¹⁰

References

1. FDA approves first drug to treat the full range of narcolepsy type 1 symptoms. Press release. August 5, 2026. Accessed August 5, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-full-range-narcolepsy-type-1-symptoms

2. A study of TAK-861 for treatment of narcolepsy type 1. ClinicalTrials.gov. July 1, 2025. Accessed August 5, 2026. https://clinicaltrials.gov/study/NCT06470828

3. New pivotal study data show Takeda's oveporexton improved daily function, cognition and nighttime sleep for people with narcolepsy type 1. Press release. June 15, 2026. Accessed August 5, 2026. https://www.takeda.com/newsroom/newsreleases/2026/oveporexton-phase-3-narcolepsy-type-1/

4. Axsome Therapeutics announces FDA acceptance of New Drug Application for AXS-12 for the treatment of cataplexy in narcolepsy. News release. July 15, 2026. Accessed August 10, 2026. https://www.globenewswire.com/news-release/2026/07/15/3327580/33090/en/axsome-therapeutics-announces-fda-acceptance-of-new-drug-application-for-axs-12-for-the-treatment-of-cataplexy-in-narcolepsy.html

5. Thorpy M, Krahn L, Bogan R, et al. AXS-12 for the treatment of narcolepsy: topline results from the phase 3 SYMPHONY trial (PL5.007). Neurology. 2025;104(7 Suppl):1510.

6. Thorpy M, Krahn L, Bogan R, et al. Impact of AXS-12 on symptom severity and functional impairment in narcolepsy: results from the phase three SYMPHONY trial (S3.008). Neurology. 2026;106(11 Suppl):4912.

7. Kuntz L. New AAN poster presentation on alixorexton for narcolepsy type 1: improvement in disease severity, cognitive functioning, and fatigue. Psychiatric Times. April 20, 2026. https://www.psychiatrictimes.com/view/new-aan-poster-presentation-on-alixorexton-for-narcolepsy-type-1

8. Kuntz L. Phase 3 Brilliance studies initiated on alixorexton for the treatment of narcolepsy type 1 and type 2. Psychiatric Times. April 1, 2026. https://www.psychiatrictimes.com/view/phase-3-brilliance-studies-initiated-on-alixorexton-for-the-treatment-of-narcolepsy-type-1-and-type-2

9. Skorucak J, Hertig-Godeschalk A, Schreier DR, et al. Automatic detection of microsleep episodes with feature-based machine learning. Sleep. 2020;43(1):zsz225.

10. Hlodak J, Geckova AM, Veselska ZD, Feketeova E. The burden of narcolepsy symptoms from patients' perspective: a narrative qualitative study. Sleep Breath. 2025;29(4):231.