Phase 3 Data for Oral Orexin Agonist in Narcolepsy Type 1 Published in NEJM

Key takeaways:

• Oveporexton improved mean sleep latency on the Maintenance of Wakefulness Test by 14.3 to 19.8 minutes compared to placebo.
• Participants experienced median percent reductions in weekly cataplexy rates ranging from 79.0% to 88.8% with the treatment.
• The most common adverse events reported in the studies were increased urinary frequency and transient insomnia.

The New England Journal of Medicine recently published results from two phase 3 studies evaluating oveporexton (ORZEYFUL), an oral orexin receptor 2 (OX2R) agonist, in people with narcolepsy type 1. The medication recently secured global approvals, including from the US Food and Drug Administration (FDA).

Narcolepsy type 1 is a chronic neurological disease driven by orexin deficiency, leading to symptoms such as excessive daytime sleepiness, cataplexy, disrupted nighttime sleep, and sleep paralysis. Oveporexton is designed to selectively stimulate the OX2R to restore signaling and address this underlying deficiency, representing a major development in the race toward orexin agonists targeting the root cause of the disorder.

“People living with narcolepsy type 1 face persistent symptoms across the day and night, which can impact many aspects of daily life,” says Emmanuel Mignot, MD, PhD, principal investigator for the FirstLight phase 3 study, in a release.

The published data includes findings from the FirstLight and RadiantLight trials, which evaluated the medication’s efficacy over 12 weeks. In the trials, mean changes from baseline to week 12 in mean sleep latency on the Maintenance of Wakefulness Test ranged from 14.3 to 19.8 minutes with oveporexton, compared with -0.4 to -0.8 minutes with placebo.

Additionally, mean changes in the Epworth Sleepiness Scale total score ranged from -9.7 to -11.8 with the treatment, compared with -1.5 to -1.7 with placebo. The studies also showed median percent reductions in the weekly cataplexy rate ranging from 79.0% to 88.8% with oveporexton, compared with 27.7% to 39.1% with placebo.

“The magnitude of effect seen across the full range of symptoms evaluated reinforces the potential of oveporexton to redefine how people feel on treatment,” says Sarah Sheikh, MSc, BM, BCh, MRCP, head of the neuroscience therapeutic area unit and global development at Takeda, in a release.

Regarding safety, adverse events occurred in 86% to 89% of the participants taking oveporexton, compared with 43% to 54% of those on placebo. The most common adverse events were increased urinary frequency and transient insomnia. More than 95% of the participants who completed the initial studies enrolled in the ongoing long-term extension study.

More in Narcolepsy Treatments: