Impact of the Oral Orexin Receptor 2 Agonist TAK-994 on Sustained Attention in Patients with Narcolepsy Type 1: Exploratory Results from a Phase 2 Study
Yves Dauvilliers1, Giuseppe Plazzi2, Elena Koundourakis3, Yeting Du3, Christian von Hehn3, Dmitri Volfson3, Robert D. Latzman3, Brian Harel3
1Sleep and Wake Disorders Centre, Department of Neurology, Gui de Chauliac Hospital, 2IRCCS, Istituto delle Scienze Neurologiche Di Bologna, 3Takeda Development Center Americas, Inc
Objective:
To evaluate the effect of TAK-994 on sustained attention and vigilance in patients with narcolepsy type 1 (NT1).
Background:
NT1 is a rare, chronic, neurologic disorder characterized by sleep-wake instability. The oral orexin receptor 2 (OX2R)-selective agonist TAK-994 was developed for the potential treatment of narcolepsy; clinical development was discontinued owing to associated hepatotoxicity.
Design/Methods:
A multi-part, phase 2, randomized, double-blind, placebo-controlled study evaluated the safety (Part A) and efficacy (Part B) of twice-daily oral TAK-994 in patients with narcolepsy type 1 (NCT04096560). Exploratory endpoints included Psychomotor Vigilance Task (PVT; Part A), and Sustained Attention to Response Test (SART; Part B).
Results:
In Part A, 22 patients were randomized (placebo, n=7; 120mg TAK-994, n=7; 180mg TAK-994, n=8) and 21 completed. In Part B, 73 patients were randomized (placebo, n=17; 30mg TAK-994, n=17; 90mg TAK-994, n=20; 180mg TAK-994, n=19); 43 completed owing to study termination. Change from baseline to week 4 in PVT lapses were greater with TAK-994 (Cohen’s d: 0.78 [120mg], 2.22 [180mg]) than placebo (-0.23); corresponding baseline adjusted changes in LSMEANS were significant: p=0.009 (120mg TAK-994), p<0.001 (180mg TAK-994). In Part B, Cohen’s d for change from baseline to week 8 for SART scores were greater with TAK-994 (0.84 [30mg], 1.22 [90mg], 1.11 [180mg]) than placebo (-0.48); corresponding baseline adjusted changes in LSMEANS were significant with TAK-994 for the two highest doses: p=0.089 (30mg), p=0.022 (90mg), p=0.026 (180mg). Treatment-emergent adverse events were reported by 2 (28.6%), 6 (85.7%) and 7 (87.5%) patients with placebo, 120mg and 180mg TAK-994 in part A.
Conclusions:
Significant improvements on the PVT and SART were achieved with TAK-994 versus placebo, suggesting potential use for OX2R agonists to address attention deficits in patients with narcolepsy.