Oral orexin 2 receptor agonist in narcolepsy type 1
Background
Narcolepsy type 1 is caused by a severe loss or lack of orexin neuropeptides in the brain.
Methods
We conducted a phase 2 , randomized, placebo-controlled trial of TAK-994, a selective oral orexin 2 receptor agonist, in patients with narcolepsy type 1. Patients with narcolepsy type 1 confirmed by clinical criteria were randomized to receive twice daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo.
The primary endpoint was the mean change from baseline to week 8 in mean sleep latency (the time it takes to fall asleep) on the maintenance-of-wake test (range, 0 to 40 minutes; normal capacity to stay awake, ≥20 minutes).
Secondary endpoints included change in Epworth Sleepiness Scale (ESS) score (range, 0 to 24, with higher scores indicating greater daytime sleepiness; normal, <10) and weekly cataplexy rate.
Results
Of the 73 patients , 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo. The phase 2 trial and an extension trial were terminated early due to hepatic adverse events .
Primary endpoint data were available for 41 patients (56%); the main reason for missing data was early termination of the trial. The least squares mean changes at week 8 in mean sleep latency on the MWT were 23.9 minutes in the 30 mg group, 27.4 minutes in the 90 mg group, 32.6 minutes in the 180 mg and -2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30 mg group, 29.9 minutes in the 90 mg group, and 35.0 minutes in the 180 mg group mg; P<0.001 for all comparisons).
The least squares mean changes at 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).
The 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 rate versus placebo, 0.05 in the 30 mg group, 0.20 in the 90 mg group and 0.15 in the 180 mg group).
A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urgency or frequency.
Clinically important elevations in liver enzyme levels occurred in 5 patients, and drug-induced liver injury that met Hy’s law criteria occurred in 3 patients.
Conclusions In a phase 2 trial involving patients with narcolepsy type 1, an orexin 2 receptor agonist resulted in greater improvements in measures of drowsiness and cataplexy than placebo over an 8-week period, but was associated with hepatotoxic effects. |
(Funded by Takeda Development Center Americas; numbers TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov, NCT04096560. opens in new taband NCT04820842. opens in new tab.)
