Trial Results Show Oral Orexin Receptor 2 -Selective Agonist Is Effective Over Placebo in Improving Wakefulness, Cataplexy in Patients With Narcolepsy Type 1

Narcolepsy type 1 is distinguished by symptoms of cataplexy and a loss of orexin-producing neurons in the lateral hypothalamus with low to absent orexin levels in the cerebrospinal fluid. Orexins act through 2 G-protein-coupled receptors, orexin receptor 1 and orexin receptor 2 (OX2R), the latter of which plays an important role in the maintenance of wakefulness and rapid eye movement sleep. Previously, danavorexton (TAK-925; Takeda Pharmaceutical), an intravenous (IV) form of an OX2R selective agonist, was proven to be effective in promoting wakefulness in heathy, sleep-deprived patients.

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In this study, which was a phase 2, 8-week, parallel-group, double-blind, randomized placebo-controlled dose-finding trial, patients with type 1 narcolepsy were enrolled. Each participant would receive either TAK-994, an oral OX2R-selective agonist, at a dose of 30 mg, 90 mg, or 180 mg, or a placebo at a matching dose twice daily for 8 weeks. All patients were eligible for inclusion in a TAK-994-1504 extension trial—an 8-week, dose-blind, active treatment period followed by a 4-week double-blind, randomized withdrawal period—where patients who had received TAK-994 continued treatment with the same dose, and those who had received placebo were randomly assigned to receive 1 of 3 doses of TAK-994.

The 74 total participants included in the trial were adults aged 18 to 65 years who were diagnosed with narcolepsy type 1, with each being randomly assigned to a different dose group (17 were in the 30-mg dose group, 20 were in the 90-mg dose group, 19 were in the 180-mg dose group, and 17 were in the placebo group). A total of 43 participants (59%) completed the phase 2 trial, whereas 30 participants (41%) dropped out of the trial prematurely due to trial termination, adverse effects (AEs), or protocol deviation. Of those who completed the phase 2 trial, 26 patients (60%) continued to the treatment period of the extension trial (8 in the 30-mg dose group, 9 in the 90-mg dose group, 9 in the 180-mg dose group), and 8 of those participants completed the phase.

Each participant involved in the study had a score of 10 or more (range, 0 to 24 with higher scores indicating greater daytime sleepiness; normal <10) on the Epworth Sleepiness Scale (ESS) and had at least 4 partial or complete patient-reported episodes of cataplexy per week during the screening process. If applicable, patients did not take any medication for their narcolepsy.

The results from both the phase 2 and extension trials showed that participants’ measures of wakefulness and cataplexy had improved more with the 3 doses of TAK-994 compared to placebo. Maintenance of the Wakefulness Test (6.1±5.9 to 30.8±10.1 minutes in the 30-mg dose group; 6.1±5.9 to 35.5±10.4 in the 90-mg dose group; 4.9±6.4 to 39.6±1.2 in the 180-mg dose group; and 6.0±8.3 to 4.1±3.9 in the placebo group), ESS values (18.5±3.0 to 5.5±5.2 in the 30-mg dose group; 17.5±3.7 to 3.6±3.9 in the 90-mg dose group; 17.4±3.3 to 1.2±2.1 in the 180-mg dose group; and 16.6±3.8 to 13.9±5 in the placebo group), and cataplexy rates (15.0±16.5 to 1.2±1.6 episodes in the 30-mg dose group; 11.7±7.7 to 1.3±2.2 in the 90-mg dose group; 15.4±10.9 to 1.2±2.2 in the 180-mg dose group; and 15.9±13.2 to 10.6±13.5 in the placebo group) reached levels consistent with those in healthy control groups.

A greater number and severity of AEs with TAK-994 were reported over placebo, the most common being urinary urgency or liver-related effects in higher dose TAK-994 groups. As a result of hepatotoxic effects observed in several patients, the trials were terminated early, and recruitment was incomplete.

Limitations of the study include the small number of participants, a substantial dropout rate, and missing patient data. Further, trials were terminated due to several patients presenting hepatotoxic effects. TAK-994 will not go forward as a treatment for type 1 narcolepsy, however, it may potentially indicate a biologic target for future drug development.

Reference

Dauvilliers Y, Mignot E, del Río Villegas R, et al. Oral orexin receptor 2 agonist in narcolepsy type 1. N Engl J Med. 2023; 389(4):309-321. doi: 10.1056/NEJMoa2301940.