Drug Update · Neurology

Oveporexton: Increases Wakefulness (MWT) 25.4 min in Narcolepsy Type 1

July 23, 2026

MWT mean changes at week 8

12.5, 23.5, 25.4, and 15.0 minutes for the four oveporexton dosing groups versus −1.2 minutes with placebo [1]

ESS mean changes at week 8

−8.9, −13.8, −12.8, and −11.3 for the four dosing groups versus −2.5 with placebo [1]

Weekly cataplexy rate at week 8

4.24, 3.14, 2.48, and 5.89 for dosing groups versus 8.76 for placebo; adjusted P<0.05 for two dosing groups vs placebo [1]

Trial enrollment

90 participants received oveporexton; 22 received placebo [1]

Common adverse events

Insomnia 48%; urinary urgency 33%; urinary frequency 32%; no hepatotoxic effects reported [1]

ClinicalTrials.gov identifier

TAK-861-2001 / NCT05687903 [1]

Clinical Perspective

Clinician type was not reported in the provided source excerpts; the trial enrolled participants with narcolepsy type 1. The phase 2 data support that oral orexin receptor 2–selective agonism with oveporexton produced clinically measurable increases in objective wakefulness (MWT), large reductions in ESS scores, and dose-dependent reductions in weekly cataplexy incidence at week 8 for selected dosing regimens ^[1]. Will these 8‑week efficacy and tolerability findings be confirmed in larger, longer-duration trials and establish optimal dosing for long-term use in narcolepsy type 1?

Dr. Aditi Kulkarni · Neurology

Oveporexton (TAK-861), an oral orexin receptor 2–selective agonist, increased average sleep latency on the Maintenance of Wakefulness Test (MWT) at week 8 versus placebo in a phase 2 randomized, placebo-controlled trial in participants with narcolepsy type 1. The trial reported mean MWT changes of 12.5, 23.5, 25.4, and 15.0 minutes across four dosing groups versus −1.2 minutes with placebo at week 8 ^[1].

Clinical Context

Oveporexton is described in the primary publication as an oral orexin receptor 2–selective agonist developed by Takeda Development Center Americas. The phase 2 trial enrolled participants with narcolepsy type 1 and assessed wakefulness, subjective sleepiness, and weekly cataplexy rate over an 8‑week treatment period ^[1]. The trial’s outcome measures included the Maintenance of Wakefulness Test (MWT) (range, 0 to 40 minutes; normal, ≥20) and the Epworth Sleepiness Scale (ESS) (range, 0 to 24; normal, ≤10) ^[1]. The study was funded by Takeda Development Center Americas ^[1].

Key Findings

In the phase 2 randomized, placebo-controlled trial, oveporexton increased mean average sleep latency on the MWT at week 8 to 12.5 minutes (0.5 mg twice daily), 23.5 minutes (2 mg twice daily), 25.4 minutes (2 mg followed by 5 mg daily), and 15.0 minutes (7 mg once daily) versus −1.2 minutes with placebo (adjusted P≤0.001 for all comparisons vs. placebo) ^[1].
Clinicians should consult current prescribing information for full dosing guidance.
The trial also reported mean changes in the ESS total score at week 8 of −8.9, −13.8, −12.8, and −11.3 for the four oveporexton dosing groups versus −2.5 for placebo (adjusted P≤0.004 for all comparisons vs. placebo) ^[1].
Weekly incidence of cataplexy at week 8 was 4.24, 3.14, 2.48, and 5.89 for the four dosing groups versus 8.76 for placebo; the reductions were statistically significant (adjusted P<0.05) for the 2 mg twice daily and the 2 mg then 5 mg daily groups versus placebo ^[1].

Safety & Tolerability

The most common adverse event reported was insomnia (in 48% of participants; most cases resolved within 1 week) ^[1].
Urinary urgency was reported in 33% of participants ^[1].
Urinary frequency was reported in 32% of participants ^[1].
The authors reported no hepatotoxic effects observed in the trial population ^[1].

Study Design

The report describes a phase 2, randomized, placebo-controlled trial in participants with narcolepsy type 1. A total of 90 participants received oveporexton across four dosing regimens (0.5 mg twice daily, 2 mg twice daily, 2 mg followed by 5 mg daily, and 7 mg once daily) and 22 received placebo; outcomes were assessed to week 8 ^[1]. Clinicians should consult current prescribing information for full dosing guidance. The primary end point was the mean change from baseline to week 8 in average sleep latency on the Maintenance of Wakefulness Test (MWT) (range, 0 to 40 minutes) ^[1]. Secondary end points included change in ESS total score, weekly cataplexy rate at week 8, and adverse events ^[1]. The trial was funded by Takeda Development Center Americas and is identified as TAK-861-2001 (ClinicalTrials.gov number NCT05687903) ^[1].

FAQ

Q1 What did the trial show?

The phase 2 randomized, placebo-controlled trial of oveporexton in participants with narcolepsy type 1 showed mean increases in average sleep latency on the MWT at week 8 of 12.5, 23.5, 25.4, and 15.0 minutes across four oveporexton dosing groups versus −1.2 minutes with placebo, with adjusted P≤0.001 for all comparisons versus placebo. The trial also reported reductions in ESS score and decreases in weekly cataplexy rate for some dosing regimens.

Q2 Who was enrolled in the trial?

The trial enrolled participants with narcolepsy type 1. A total of 90 participants received oveporexton distributed among four dosing regimens (0.5 mg twice daily, 2 mg twice daily, 2 mg followed by 5 mg daily, and 7 mg once daily) and 22 participants received placebo, with efficacy and safety assessed through week 8.

Q3 What were the side effects in the trial?

The most commonly reported adverse events in participants receiving oveporexton were insomnia (48% of participants; most cases resolved within 1 week), urinary urgency (33%), and urinary frequency (32%). The authors reported no hepatotoxic effects in the trial population.

Q4 What does the trial mean for clinical practice?

At 8 weeks, oveporexton showed objective and subjective improvements in wakefulness and sleepiness and reduced weekly cataplexy incidence for selected doses. These data are from a phase 2 trial and indicate proof of concept for oral orexin receptor 2–selective agonism in narcolepsy type 1, but larger and longer trials will be needed to define durability, optimal dosing, safety in broader populations, and comparative effectiveness versus existing treatments.

Clinicians should consult current prescribing information for complete dosing guidance.

References

PubMed — Primary trial publication (PMID 40367374)

Oveporexton: Increases Wakefulness (MWT) 25.4 min in Narcolepsy Type 1

Oveporexton: Increases Wakefulness (MWT) 25.4 min in Narcolepsy Type 1

Clinical Perspective

Clinical Context

Key Findings

Safety & Tolerability

Study Design

FAQ

References

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