E2086, A SELECTIVE OREXIN RECEPTOR-2 AGONIST: STUDY FOR PROMOTING WAKEFULNESS IN PATIENTS WITH NARCOLEPSY TYPE 1

Objective

To report results from the first clinical study of E2086, a novel, selective orexin receptor-2 (OX2R) agonist, in patients with narcolepsy type-1 (NT1).

Background

E2086 is hypothesized to regulate the sleep/wake cycle by supporting wakefulness through the orexin neuronal pathway; its preclinical profile showed strong dose-dependent efficacy in promoting wakefulness and mitigating cataplexy. Design/

Methods

E2086-A001-101, a multicenter, randomized, double-blind, double-dummy, single-dose, N-of-1, five-period crossover study, evaluated the efficacy, safety, and tolerability of E2086 (5 mg, 10 mg, 25 mg) compared with placebo (PBO) and modafinil 200 mg in adult participants with NT1. Male and female participants with verified diagnoses of NT1 were randomized to receive study drug within an hour of waketime following an overnight polysomnogram. Forty-minute maintenance of wakefulness tests (MWTs) were commenced 2 hours after waketime and continued every 2 hours until ~7 hours postdose (4 total). The Karolinska Sleepiness Scale (KSS) was administered at the end of each MWT. Safety data were collected.

Results

Twenty-two subjects were randomized; 19 subjects were completers (received all 5 treatments and had data from all 4 MWTs). In the safety analysis set (n=21; all randomized subjects who received ≥1 dose of study treatment), 12 (57.1%) subjects were male; mean (SD) age was 35.6 (11.8) years. At baseline, the mean (SD) of sleep latency tests was 3.0 (2.7) minutes. Mean (SD) baseline Epworth Sleepiness Scale score was 17.2 (3.5). Least squares (LS) mean sleep latencies (MSLs; 95% confidence interval [CI]) for E2086 5 mg (25.73 [21.67, 29.78] min), 10 mg (34.69 [30.64, 38.75] min), and 25 mg (37.94 [33.88, 41.99] min) were longer and statistically significant compared with PBO (6.46 [2.39, 10.52] min) and modafinil (15.92 [11.88, 19.96] min). MSL with modafinil was also significantly longer versus PBO, establishing assay sensitivity. E2086 10 mg and 25 mg sustained wakefulness for ≥30 minutes during each MWT; E2086 5 mg sustained wakefulness for greater than 19 minutes throughout each MWT trial. LS mean (95% CI) KSS scores for E2086 5 mg (4.51 [3.85, 5.18]), 10 mg (3.31 [2.65, 3.98]), and 25 mg (3.25 [2.58, 3.92]) were smaller and statistically significant versus PBO (6.61 [5.94, 7.28]); E2086 10 mg and 25 mg scores were smaller and statistically significant versus modafinil (5.35 [4.68, 6.01]). The effect of E2086 on daytime alertness was durable, with participants maintaining significantly greater alertness with E2086 (all doses) versus PBO and with E2086 (10 mg and 25 mg doses) versus modafinil for each KSS assessment. E2086 was generally well tolerated, with most treatment-emergent adverse events being mild to moderate in severity.

Conclusions

These data demonstrate that E2086 has the potential to improve daytime wakefulness in patients with NT1. The efficacy/safety profile supports continued investigation of E2086 in the narcolepsy patient population.