An investigational drug previously shown to improve wakefulness and reduce sleepiness in patients with narcolepsy type 1 (NT1) has now been linked to improved cognition.

After 8 weeks of treatment, oveporexton (Takeda), which is a first-in-class OX2R-selective agonist, improved measures of attention, memory, and executive function in adults with NT1.

In 2024, the drug was designated as a breakthrough therapy by the FDA, although it hasn’t yet been approved.

“These findings provide a sound basis for the development of pharmacological therapies that could ameliorate NT1-associated cognitive symptoms,” the investigators, led by Brian Harel, PhD, JD, Takeda Development Center Americas in Cambridge, Massachusetts, wrote.

The study was published online on December 8 in JAMA Neurology.

Cognitive Difficulties

NT1 affects an estimated 1 in 3000 people. The disorder is caused by the loss of orexin neurons, which are involved in sleep regulation.

As previously reported by Medscape Medical News, the results of a randomized placebo-controlled 2b trial showed that treatment with oveporexton, which acts on the brain’s orexin receptors to restore signaling, led to improved sleep latency and reduced daytime sleepiness in this patient population.

However, the investigators note that beyond sleep-wake symptoms, cognitive difficulties — such as problems with clear thinking, memory, concentration, and attention — are core features of the disorder. 

These symptoms, they note, have a major impact on daily functioning, as well as social and emotional well-being, and can limit educational and employment opportunities, which are not responsive to current treatments. 

In a secondary analysis of the trial results, the investigators explored whether, in addition to the primary symptoms of the disorder, the drug improved memory, attention, and executive function. 

The analysis included 112 participants with NT1 (mean age, 34; 51.8% women). Participants were randomized in a 1:1:1:1:1 ratio. They received oral oveporexton or placebo in dose groups of 0.5/0.5 mg, 2/2 mg, 2/5 mg, 7 mg/placebo or placebo/placebo, for 8 weeks.

Doses were administered twice daily “to follow the natural variation in central nervous system orexin levels throughout the day.”

Participants’ attention was assessed using the Psychomotor Vigilance Task (PVT), which gauges lapses in alertness and reaction times. Memory was evaluated by the Continuous Paired Associate Learning (CPAL) test, which assesses the number of mistakes made on recall of pattern-location associations.

Lastly, the investigators measured executive function using both the One Back (ONB) test and International Digit Symbol Substitution Test-symbols version (IDSST-s), which look at the speed of identifying correct answers and the total count of correct number-symbol matches, respectively.

Participants were tested on PVT, CPAL, ONB, and IDSST-s, in this order, 1 hour after their first dose. The PVT was repeated 7 hours later.

Improvements Across All Measures

Differences in mean changes from baseline with each dose of oveporexton or placebo were expressed as Cohen’s d, with values of 0.2 equaling a small effect size and 0.8 or above indicating a large effect.

After 8 weeks of treatment, oveporexton was associated with improved attention across all dose levels, while attention worsened in the placebo group. Least-square mean placebo-adjusted reductions in attention lapses ranged from -10.77 (95% CI, -16.74 to -4.79) with the 0.5/0.5-mg dose to -8.60 (95% CI, -14.84 to -2.36) with the 2/5-mg dose.

At baseline, the mean number of errors on memory testing was similar for placebo and oveporexton groups. After 8 weeks, errors decreased across all oveporexton groups, with mean changes of -22.52 (95% CI, -34.95 to -10.10) and -15.51 (95% CI, -28.82 to -2.21) for the 0.5/0.5-mg and 2/5-mg doses, respectively. In the placebo group, memory performance worsened slightly over the study period.

The initial mean speed and number of correct responses on executive-function tests were similar across the placebo and oveporexton groups. After 8 weeks, performance speed remained unchanged in the placebo group, while the number of correct responses increased slightly.

In contrast, oveporexton was associated with faster reaction times across all dose levels, with medium to large effect sizes compared with placebo. The mean number of correct responses also increased across all oveporexton doses, with statistically significant mean improvements observed for all dose groups except the 0.5/0.5-mg group.

Although the study did not account for effect differences between drug doses, the investigators noted that the magnitude of oveporexton-related cognitive improvements was similar across doses.

Limitations of the study included its predominantly White population and the assessment of only select cognitive domains — attention, memory, and executive function — rather than a broader range of cognitive functions.

This research was funded by Takeda Development Center Americas, Inc. The company also provided open-access funding and was involved in the design and conduct of the study. See study for author disclosures.