Oral Orexin Receptor 2 Agonist improves cataplexy and sleepiness in patients with Narcolepsy Type 1: Phase 2 trial

The findings from the phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2–selective agonist, in narcolepsy type 1 patients, were published in the New England Journal of Medicine. Owing to hepatic adverse events, the phase 2 trial and an extension trial were terminated early.

Christian von Hehn, Takeda Development Center Americas, Lexington, MA, and colleagues included patients with confirmed narcolepsy type 1 according to clinical criteria. 73 patients were randomly assigned to receive twice-daily oral TAK-994 (30 mg; n=17, 90 mg; n=20, or 180 mg' n=19) or placebo (n=17). Primary end-point data were available for 41 patients; the main reason for missing data was early trial termination.

The study's primary endpoint was determined as the mean change in average sleep latency (the time it takes to fall asleep) from baseline to week 8; measured through the Maintenance of Wakefulness Test (range, 0 to 40 minutes; normal ability to stay awake, ≥20 minutes). Secondary endpoints were Epworth Sleepiness Scale (ESS) score (ranging from 0 to 24, higher scores indicated greater daytime sleepiness; normal, <10) and the weekly cataplexy rate.

Owing to hepatic adverse events, the phase 2 trial and an extension trial were terminated early. Primary end-point data were available for 41 patients; the main reason for missing data was early trial termination.

The study led to the following findings:

• Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes (30-mg group), 27.4 minutes (90-mg group), 32.6 minutes (180-mg group), and −2.5 minutes in the placebo group.
• The difference versus placebo was 26.4 minutes (30-mg group), 29.9 minutes (90-mg group), and 35.0 minutes in the 180-mg group.
• Least-squares mean changes to week 8 in the ESS score were −12.2 in the 30-mg group, −13.5 in the 90-mg group, −15.1 in the 180-mg group, and −2.1 in the placebo group (difference vs. placebo, −10.1 in the 30-mg group, −11.4 in the 90-mg group, and −13.0 in the 180-mg group).
• Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group).
• 79% of the patients receiving TAK-994 had adverse events, most commonly urinary urgency or frequency.
• Clinically important elevations in liver enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy’s law criteria occurred in 3 patients.

"The orexin receptor 2 agonist resulted in greater improvements in measures of cataplexy and sleepiness than placebo in patients with narcolepsy type 1 but was associated with hepatotoxic effects," the researchers concluded.

Reference:

Yves Dauvilliers et al, Oral Orexin Receptor 2 Agonist in Narcolepsy Type 1, New England Journal of Medicine (2023). DOI: 10.1056/NEJMoa2301940