Analysis finds meaningful attention gains with narcolepsy therapy

Takeda Pharmaceuticals’ Orzeyful (oveporexton) improved attention in people ages 16 to 65 with type 1 narcolepsy (NT1), with about six times the odds of achieving a clinically meaningful improvement compared with placebo, according to an analysis of Phase 3 clinical data.

“Treatment produced clinically meaningful improvements in attention,” the researchers wrote in “Defining a Clinically Meaningful Within-Person Change Threshold for the Psychomotor Vigilance Test in Narcolepsy Type 1,” published in Therapeutic Innovation & Regulatory Science. It was funded by Takeda Development Center Americas.

In narcolepsy, patients experience an overwhelming need to sleep during the day. In NT1, this is due to near-complete loss of brain cells that produce orexin, a chemical that helps regulate sleep–wake cycles. In addition to excessive daytime sleepiness, patients may also experience other symptoms, including cognitive challenges such as difficulty concentrating.

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Study defines what counts as a meaningful attention improvement

This study aimed to determine how much improvement on the Psychomotor Vigilance Test (PVT) would be considered clinically meaningful in people ages 16 to 65 with NT1. Researchers then used that threshold to determine how often Orzeyful and placebo-treated participants achieved a meaningful improvement in attention.

Orzeyful is an oral treatment approved in the U.S. for adults with NT1. It works by activating the same receptor that the body’s own orexin normally activates, helping restore orexin signaling. Taken as an oral tablet twice daily, Orzeyful helps reduce excessive daytime sleepiness and improve wakefulness.

The researchers used data from two Phase 3 clinical studies that supported the recent U.S. approval of Orzeyful: The First Light (NCT06470828), which included 166 patients, and The Radiant Light (NCT06505031), which included 105. Across the two studies, participants had a mean age of 31.2 years, ranging from 16 to 65, and 54.2% were female.

Attention was measured using the PVT, a computerized test that measures sustained attention by recording how quickly a person responds to visual signals. The researchers counted “lapses,” meaning responses that took more than 500 milliseconds. Fewer lapses indicate better sustained attention. At the start of testing, the pooled mean was 15.19 lapses, decreasing to 10.36 lapses after 84 days.

The researchers focused on a measure called meaningful within-patient change (MWPC), which identifies the smallest reliable improvement on the PVT that is meaningful to patients. To determine this threshold, they compared changes in PVT scores with patient-reported measures of cognitive and overall narcolepsy symptoms, as well as clinician-reported measures of overall narcolepsy symptoms.

Because PVT lapse scores could be unevenly distributed, the researchers also analyzed the square root of the number of lapses to account for this skewness. Changes in these transformed PVT scores were moderately related to changes in patient-reported measures of cognitive and overall narcolepsy symptoms, as well as clinician-reported measures of overall narcolepsy symptoms, at either day 56 or 84 in at least one of the two studies.

Fewer attention lapses tracked with greater symptom improvement

Across the measures used to assess meaningful change, little or no improvement in PVT scores generally accompanied no improvement or worsening in symptoms. Minimal improvement was associated with somewhat fewer lapses, while much or very much improvement was associated with even fewer. Overall, greater symptom improvement tended to track with greater improvement on the PVT.

The estimated meaningful improvement corresponded to reductions ranging from 1 to 1.9 in The First Light and 0.8 to 1.6 in The Radiant Light on the square-root-transformed PVT scores. Weighted averages across the measures were reductions of about 1.4 and 1.2, respectively. The researchers combined these findings with other statistical analyses to select a meaningful-change estimate, which they then converted back to the original number of PVT lapses.

They selected at least two fewer lapses as the main MWPC threshold, which corresponded to a “moderate” improvement. Three to four fewer lapses were associated with “much” improvement, while five fewer lapses were associated with “very much” improvement.

The proportion of patients achieving a meaningful improvement in attention was significantly higher with Orzeyful than with placebo, both in The First Light (66.9% vs. 25.7%) and The Radiant Light (57.6% vs. 17.6%). The odds of achieving meaningful improvement were 5.85 times as high with Orzeyful in The First Light and 6.33 times as high in The Radiant Light compared with placebo.

The researchers noted that the two-lapse threshold was derived from these trial populations and may not generalize to all people with NT1.

“Improvements in attention with [Orzeyful] in people with NT1 were found to be clinically meaningful,” the researchers wrote. “Future research should examine the durability of these effects, as well as their relationships with other cognition domains shown to be impaired in NT1,” they concluded.