Treatment with the oral orexin receptor 2 (OX2R) agonist oveporexton improves symptom control, daily function, and cognitive outcomes in patients with narcolepsy type 1, according to pooled data from two phase III studies, The First Light and The Radiant Light.
“Narcolepsy type 1 is a neurologic disorder of hypersomnolence caused by loss of orexin-producing neurons, [and] currently available therapies do not address orexin deficiency,” noted Dr Markus Schmidt from the University Hospital of Bern, Bern, Switzerland.
“Oveporexton is a highly potent, oral OX2R-selective agonist that activates the OX2E to restore signalling, addressing the underlying orexin deficiency in narcolepsy type 1,” Schmidt added.
Symptomatic benefit
Twice-daily oral doses of oveporexton at 1 and 2 mg, administered 3 h apart, were already found to be superior to placebo in improving wakefulness, sleepiness, and cataplexy frequency over 12 weeks of treatment, while having a tolerable safety profile, in both The First Light and The Radiant Light studies. [Mignot E, et al, World Sleep 2025; Dauvilliers Y, et al, World Sleep 2025]
Pooled analysis of the two studies yielded consistent results. At week 12, the primary endpoint of sleep latency on the Maintenance of Wakefulness Test (MWT) significantly improved with oveporexton at either the 1- or 2-mg dose, with mean differences of 15.90 and 19.16 min, respectively, relative to placebo (p<0.0001 for both), Schmidt reported. [EAN 2026, abstract EPO-0796]
Oveporexton was also associated with greater improvements in subjective sleepiness, with mean total scores on the Epworth Sleepiness Scale (ESS) decreasing by 8.27 points with the 1-mg dose vs placebo and by 9.71 points with the 2-mg dose vs placebo at week 12 (p<0.0001 for both).
“Most participants receiving oveporexton reached normative levels of objective wakefulness and subjective sleepiness,” Schmidt said.
The proportions of participants achieving mean MWT sleep latency of ≥20 min were 48 percent with oveporexton 1 mg, 63 percent with 2 mg, and 3 percent with placebo. The proportions of participants achieving ESS total score of ≤10 at week 12 were 67 percent, 83 percent, and 14 percent, respectively.
Weekly cataplexy rate decreased by 82.6 percent with oveporexton 1 mg and by 82.1 percent with 2 mg but remained unchanged with placebo (incidence rate ratios, 0.28 and 0.32, respectively; p<0.0001 for both).
“Participants had improvements in the severity of narcolepsy symptoms over 12 weeks with twice-daily 1 and 2 mg doses of oral oveporexton vs placebo as assessed by the Narcolepsy Severity Scale for Clinical Trials (NSS-CT) and Patient Global Impression of Change,” Schmidt said.
At week 12, 73.7 percent of participants who received oveporexton 1 mg and 93.9 percent of those who received the 2-mg dose reported much or very much improved symptoms as opposed to only 18.6 percent of placebo-treated participants.
Functional benefit
In a separate analysis, pooled data from The First Light and The Radiant Light also showed clinically meaningful improvements in narcolepsy-specific functioning with oveporexton vs placebo.
“Improvements were observed across all six Functional Impacts of Narcolepsy Instrument (FINI) domains and for both oveporexton doses at week 12,” reported Prof Ramin Khatami from the Center of Sleep Medicine and Sleep Research, Klinik Barmelweid, Barmelweid, Switzerland.
Mean differences in scores between the 1- and 2-mg doses vs placebo were –33.3 and –43.7 points for tiredness, –30.4 and –34.1 points for cognitive functioning, –18.1 and –20.8 points for cataplexy, –28.4 and –33.4 points for social activities, –34.1 and –43 points for everyday activities, and –30.4 and –36.9 points for everyday responsibilities, respectively. [EAN 2026, abstract EPO-0798]
“More than 64 percent of participants reached or exceeded the normative threshold for all FINI domains, except the Everyday Activities domain for which 40 percent and 60 percent of participants who received oveporexton 1 or 2 mg met the normative threshold,” Khatami noted.
These findings demonstrate that oveporexton “may holistically treat narcolepsy type 1 by impacting outcomes that allow people with [the condition] to manage their everyday life by normalizing function,” he concluded.
Cognitive benefit
Finally, oveporexton was associated with improvements in both objective and subjective measures of cognition in narcolepsy type 1, as shown in another pooled analysis of data from The First Light and The Radiant Light studies. [EAN 2026, abstract EPO-0940]
Compared with those who received placebo, oveporexton-treated participants performed better on the following assessments:
“The benefit to memory was less, although still classified as moderate to large. This effect could be due to memory being the least impaired cognitive domain at baseline,” Lammers noted.
Study details
The First Light and The Radiant Light included a total of 273 participants ages 16–70 years who had an established diagnosis of narcolepsy type 1. These participants were required to have an ESS score of ≥11 and at least four partial/complete episodes of cataplexy per week.
The participants were randomly assigned to receive twice daily oral oveporexton 1 mg (n=61; mean age 33.5 years, 45.9 percent female) or 2 mg (n=136; mean age 29.4 years, 61 percent female) or placebo (n=76; mean age 32.3 years, 48.7 percent female), given ≥3 h apart for 12 weeks.
Oveporexton was generally well tolerated, with most treatment-emergent adverse events being mild to moderate in severity and primarily on-target (urinary and insomnia) effects, Schmidt said.