On August 5, the US Food and Drug Administration (FDA) announced the approval of oveporexton for the treatment of narcolepsy type 1 (NT1) in adults, making it the first drug approved to treat NT1 as a complete disorder rather than targeting individual symptoms such as excessive daytime sleepiness or cataplexy.1 The approval was supported by two randomized, double-blind, placebo-controlled phase 3 studies, FirstLight (NCT06470828) and RadiantLight (NCT06505031), which together enrolled a combined 273 individuals with NT1.2
“For too long, people with narcolepsy type 1 have had to manage a complex, lifelong neuropsychiatric condition with treatments that only address pieces of it,” Tiffany R. Farchione, MD, Director of the FDA Division of Psychiatry, said in a statement accompanying the approval.
NT1 affects an estimated 1 in 2,000 people and is characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic or hypnopompic hallucinations, and disrupted nighttime sleep. The disorder results from the loss of hypothalamic neurons that produce orexin, also known as hypocretin. Oveporexton is administered twice daily and acts as a selective orexin receptor 2 (OX2R) agonist, restoring signaling normally mediated by the orexin-producing neurons lost in patients with NT1.
NT1 treatment strategies have generally focused on individual symptoms. Wake-promoting agents and stimulants are used to improve daytime alertness, while sodium oxybate and antidepressants may be used to reduce cataplexy and other rapid eye movement sleep-related symptoms. As noted in a recent CHEST Physician article, these therapies do not address the underlying orexin deficiency that drives the disease.
Development of orexin agonists has been a longstanding goal in narcolepsy research.
The findings from FirstLight and RadiantLight represent a potentially transformative advance for patients with NT1, according to study investigator Gert Jan Lammers, MD, neurologist and head of the Sleep-Wake Center SEIN in Heemstede, the Netherlands, which is affiliated with Leiden University Medical Center. Dr. Lammers, who has spent more than three decades studying narcolepsy, is a cofounder and past president of the European Narcolepsy Network.
“The improvement—and for a significant proportion of patients, the normalization—of excessive sleepiness and cognitive symptoms and impairments was the most clinically meaningful outcome of the phase 3 program,” Dr. Lammers said.
Results from a pooled analysis presented at SLEEP 2026 showed participants had substantial disease burden at baseline, with a mean Epworth Sleepiness Scale (ESS) score of 18.1, mean Maintenance of Wakefulness Test (MWT) sleep latency of 4.8 minutes, and a median weekly cataplexy rate of 26 attacks.
At 12 weeks, patients receiving 2 mg of oveporexton twice daily experienced a placebo-adjusted increase in MWT sleep latency of 19.16 minutes (95% CI, 16.65-21.68; P < .001). ESS scores improved by 9.71 points vs placebo (95% CI, -10.92 to -8.50; P < .001).
Dr. Lammers said improvements in measures such as the MWT and ESS can sometimes be difficult to translate into meaningful changes in everyday functioning when the magnitude of effect is modest. In contrast, he characterized the benefits observed with oveporexton as both substantial and clinically convincing.
“With oveporexton, the improvement is so significant, and such a high percentage of patients achieve results that fall within the normal range, that it represents a telling and convincing improvement,” he said.
Treatment was also associated with significant reductions in cataplexy frequency. The incidence rate ratio for weekly cataplexy rate vs placebo was 0.32 (95% CI, 0.23-0.45; P < .001) in patients receiving the 2-mg twice-daily regimen.
According to the FDA, patients taking oveporexton also reported improvements across the broader symptom spectrum of NT1, including sleep paralysis, hypnagogic hallucinations, and disrupted nighttime sleep.
Still, Dr. Lammers urged caution in interpreting these findings as evidence that all manifestations of NT1 improve to the same degree.
“The improvement in nighttime sleep appears to be relatively limited,” he said.
Although patients experienced benefits across multiple symptom domains, Dr. Lammers noted that some patients who had previously received sodium oxybate and discontinued it to qualify for the trials reported stronger effects on certain nocturnal symptoms with that therapy.
He added that this impression emerged from conversations with patients who had tapered off sodium oxybate before entering the oveporexton studies.
Safety findings in the pooled phase 3 analysis were consistent with previous studies. The most common treatment-emergent adverse events were pollakiuria and insomnia. Six participants discontinued study medication because of adverse events, including two in the 2-mg oveporexton group, three in the 1-mg group, and one in the placebo group.
The FDA similarly identified insomnia, increased urinary frequency, urinary urgency, and increased salivation as the most common adverse events.
Dr. Lammers said early observations from an ongoing long-term extension study have been encouraging.
“In principle, virtually all patients, provided the diagnosis has been correctly made, are likely to benefit from this therapy,” he said.
References
1. US Food and Drug Administration. US Food and Drug Administration. Published August 5, 2026.
2. Emmanuel Mignot, Yves Dauvilliers, Rafael Del Rio Villegas, et al. 0737 Efficacy and safety of oveporexton (TAK-861), an oral orexin receptor 2 agonist, for narcolepsy type 1 treatment: a pooled analysis of phase 3 studies. Sleep. 2026;49(suppl 1):A328-A329. doi:10.1093/sleep/zsag091.0737
