Data presented at World Sleep 2025 from two global narcolepsy type 1 phase III trials, FirstLight (TAK‑861‑3001) (NCT06470828) and RadiantLight (TAK‑861‑3002)1,2, evaluating oveporexton (TAK‑861), an investigational oral orexin receptor 2 (OX2R)‑selective agonist for narcolepsy type 1 (NT1). These trials met all primary and secondary endpoints at week 12, with both waking and cataplexy symptoms significantly improved compared to placebo. The data mark an important advance toward more effective, disease‑targeted therapies in NT1.1
Data presented at World Sleep 2025 2,3
Wakefulness
- Statistically significant improvement in mean sleep latency (Maintenance of Wakefulness Test [MWT]).
- Significant improvements in Epworth Sleepiness Scale (ESS) scores at week 12.
- Majority of participants on 2/2 mg dose achieved wakefulness in the normative range (≥20 minutes on MWT).
- ~85% of participants achieved ESS scores ≤10, comparable to healthy individuals.
Cataplexy
- More than 80% median reduction in weekly cataplexy rate over 12 weeks, across doses.
- Median cataplexy-free days increased from 0 days at baseline to 4–5 days per week at week 12.
- Cataplexy is a defining symptom of NT1, marked by sudden loss of muscle tone triggered by strong emotions.
Symptom severity
- Statistically significant improvement in NSS-CT total score compared to placebo.
- More than 70% of participants reported the lowest severity level (mild; score 0–14).
- 97% of participants reported improvements in overall narcolepsy symptoms (PGI-C).
Quality of life
- Statistically significant improvements on the Short Form-36-item (SF-36) survey, reaching scores in the normative range.
- Supported by significant improvements on the exploratory EuroQol 5-Dimension 5-Level (EQ-5D-5L) measure.
Safety Profile
- Oveporexton was generally well-tolerated.
- No treatment-related serious adverse events were observed.
- Most common adverse events: insomnia, urinary urgency, and urinary frequency.
- Most adverse events were mild to moderate in severity.
Implications: Oveporexton may become the first disease-targeted oral therapy for NT1, addressing the underlying orexin deficit with broad efficacy and a favourable safety profile. Regulatory filings are expected in 2025.2,3
Wakefulness and sleepiness improvements
In both trials, participants treated with oveporexton at doses of 1 mg twice daily and 2 mg twice daily showed statistically significant gains in wakefulness via the Maintenance of Wakefulness Test (MWT), alongside improvements on the Epworth Sleepiness Scale (ESS). At week 12, many on the 2 mg BID dose achieved MWT times within the normative range (≥ 20 minutes), while approximately 85% reached ESS scores comparable to healthy individuals (≤ 10). These results highlight oveporexton’s potential to substantially reduce excessive daytime sleepiness (EDS) in NT1.
Dramatic reductions in cataplexy
Cataplexy, a hallmark feature of NT1 characterised by sudden muscle tone loss triggered by emotions, also saw major improvements. Across doses, the weekly cataplexy rate dropped by over 80% from baseline versus placebo. Participants reported 4‑5 cataplexy‑free days per week at week 12, compared to none at baseline. These findings suggest oveporexton may meaningfully reduce burden from this debilitating symptom.
Symptom severity, symptom relief & quality of life
The trials also assessed symptom severity using the Narcolepsy Severity Scale‑Clinician and/or Caregiver‑rated Tool (NSS‑CT) and the self‑rated Patient Global Impression of Change (PGI‑C). More than 70% of treated participants reported symptom severity levels in the “mild” category (score 0‑14), and an impressive ~97% indicated overall improvement. Quality of life metrics, including the Short Form‑36 (SF‑36) and EQ‑5D‑5L, also showed significant improvement, with scores reaching normative ranges in many participants.
Safety and tolerability
Oveporexton was generally well tolerated. No serious treatment‑related adverse events (AEs) were reported across both trials. The most frequent side effects included insomnia, urinary urgency and frequency, with most AEs being mild or moderate in severity. These safety data align with prior Phase II results, reinforcing oveporexton’s favourable tolerability profile.
What this means for NT1 treatment
These Phase III results for oveporexton are potentially transformative. For years, treatment options for NT1 have been limited to symptomatic therapies, stimulants, antidepressants, sodium oxybate, that manage some symptoms but do not address the underlying orexin deficiency that defines NT1. Oveporexton, as an oral OX2R‑selective agonist, may be the first therapy targeting this fundamental mechanism.
“Our research has shown that the loss of orexin is the cause of NT1, which results in symptoms like excessive daytime sleepiness and cataplexy,” said Dr. Emmanuel Mignot, principal investigator for the FirstLight Phase 3 study and one of the presenting authors. “Takeda’s groundbreaking efforts targeting the orexin receptor 2 in clinical studies led to positive Phase 3 results for oveporexton, bringing us a major step closer to having the first orexin therapy that addresses the underlying cause of NT1, with the potential of transforming the current treatment paradigm.”
Regulatory filings are expected globally in fiscal year 2025, according to Takeda, setting the stage for possible approval.1
Challenges and next steps
While the data are promising, several factors will determine real‑world impact:
- Long‑term efficacy and safety: The trials include ongoing long‑term extension (LTE) studies to assess durability of benefit and rare adverse effects.
- Comparative effectiveness: How oveporexton compares with existing treatments in everyday clinical practice (for example, in terms of cost, access, patient preference) will need evaluation.
- Accessibility & implementation: Oral administration is a plus for patient convenience, but health systems will need to adapt guidelines, insurers will need evidence, and clinicians will need training to use new endpoints and safety monitoring.
- Biomarkers & diagnostic accuracy: Given that NT1 diagnosis often lags, work on biomarkers of orexin level, sleep algorithm improvements, and earlier detection are essential to ensure patients benefit sooner. Takeda also shared presentations on orexin biomarkers at World Sleep Congress.
References:
- Takeda. Positive Results from Phase 3 Studies of Oveporexton (TAK-861) in Narcolepsy Type 1. 2025. Available at: https://www.takeda.com/newsroom/newsreleases/2025/positive-results-phase-3-oveporexton-narcolepsy-type-1 (accessed 15 September 2025).
- ClinicalTrials.gov. A Study to Evaluate TAK-861 in Adult Participants With Narcolepsy Type 1 (FirstLight). ClinicalTrials.gov Identifier: NCT06470828. 2025. Available at: https://www.clinicaltrials.gov/study/NCT06470828 (accessed 15 September 2025).
- Morningstar. Takeda Presents Orexin Data from Landmark Oveporexton (TAK-861) Phase 3 Program in Narcolepsy Type 1 at World Sleep 2025. 2025. Available at: https://www.morningstar.com/news/business-wire/20250908503054 (accessed 15 September 2025).
Editor: Katey Gabrysch, Editorial Director.
Disclosures: This short article was prepared by touchNEUROLOGY. The content was developed and edited by human editors. No fees or funding were associated with its publication. touchNEUROLOGY utilize AI as an editorial tool (ChatGPT (GPT-4o) [Large language model]. https://chat.openai.com/chat).
Cite: Oveporexton phase 3 data signal new hope for narcolepsy type 1 treatment. touchNEUROLOGY. 15 September 2025.
Register now to receive the touchNEUROLOGY newsletter!
Don’t miss out on hearing about our latest peer reviewed articles, expert opinions, conference news, podcasts and more.
