Oveporexton Shows Gains in Cognition, Sleep Quality in Narcolepsy: Elena Koundourakis, PhD

At the American Academy of Sleep Medicine and Sleep Research Annual Meeting (SLEEP), Elena Koundourakis, PhD, head of orexin franchise development & neuroscience programs, Takeda, discussed phase 3 data from the FirstLight and RadiantLight studies, demonstrating that an investigational orexin agonist, oveporexin (TAK-861; Takeda) may deliver benefits in both daytime cognition and nighttime sleep quality for patients with narcolepsy.

Historically characterized by excessive daytime sleepiness and cataplexy, narcolepsy is increasingly recognized as a condition that also imposes a substantial cognitive burden. Koundourakis noted that cognition in narcolepsy spans multiple domains—attention, executive function, and memory—all critical to patients’ ability to function in daily life.

In the development program of this orexin agonist, cognition was systematically evaluated from phase 2 through phase 3. Although the phase 2 results have been extensively published, SLEEP 2026 marked the first presentation of phase 3 data on cognitive outcomes. According to Koundourakis, the treatment produced “profound” objective improvements across cognitive domains, which were mirrored by patients’ own reports of functioning.

Objective performance-based cognitive measures were correlated with subjective outcomes using a functional impact assessment, which includes a dedicated cognitive scale. Investigators observed a tight alignment between what patients reported and what was captured in formal testing, suggesting that improvements translated meaningfully into patients’ daily lives.

In addition to cognition, the phase 3 program evaluated the orexin agonist’s impact on nocturnal symptoms. Earlier data had shown subjective improvements in symptoms such as hypnagogic hallucinations and sleep paralysis, which are often highly burdensome. At SLEEP 2026, investigators presented exploratory polysomnography (PSG) data on disrupted nighttime sleep, considered the gold standard for objective sleep assessment.

Koundourakis reported that treatment was associated with normalization of REM sleep and a shift of sleep architecture toward a more typical pattern. These objective PSG findings were again linked with subjective assessments from both patients and clinicians, captured through the Narcolepsy Severity Scale – Clinical Trials version. Improvements in PSG metrics corresponded with perceived gains in overall sleep quality and symptom burden.

Together, these findings suggest that orexin agonist therapy may simultaneously address daytime cognitive impairment and nighttime sleep disruption, offering a more comprehensive approach to managing narcolepsy’s multifaceted impact on patients’ lives.