Effects of Oveporexton, an Orexin Receptor 2–Selective Agonist, on Cognition in Narcolepsy Type 1

Key Points

Question

What are the effects of oveporexton, an oral orexin receptor 2 (OX2R) agonist, on cognitive symptoms in narcolepsy type 1 (NT1)?

Findings

This secondary analysis of exploratory outcomes from a phase 2 randomized clinical trial reports moderate- to large-magnitude effects of oveporexton on cognitive measures in adults with NT1.

Meaning

These findings suggest that OX2R stimulation with oveporexton can improve cognitive symptoms in adults with NT1.

Abstract

Importance

Cognitive symptoms negatively impact people with narcolepsy type 1 (NT1). While the effects of orexin receptor 2 (OX2R) agonists have been explored on diagnostic features of the disorder (excessive daytime sleepiness and cataplexy), effects on cognitive symptoms are not characterized.

Objective

To explore the effects of oveporexton, an oral OX2R-selective agonist, on cognition in people with NT1.

Design, Setting, and Participants

This is a secondary analysis of the TAK-861-2001 phase 2, 8-week, parallel-group, double-blind, placebo-controlled randomized clinical trial, conducted from January 2023 to December 2023, with a 4-week follow-up period. TAK-861-2001 was a multicenter study conducted in clinical settings. Eligible participants were 18 to 70 years of age, with an International Classification of Sleep Disorders, Third Edition diagnosis of NT1. Data analysis was performed from July 2024 to July 2025.

Interventions

Participants were randomized 1:1:1:1:1 to twice-daily oral oveporexton or matching placebo, dosed 3 hours apart, in dose groups of 0.5/0.5 mg, 2/2 mg, 2/5 mg, 7 mg/placebo, or placebo/placebo, for 8 weeks.

Main Outcomes and Measures

Cognitive symptoms were assessed using the Psychomotor Vigilance Task (PVT) for attention, the Continuous Paired Associate Learning (CPAL) test for memory, and the One Back (ONB) test and International Digit Symbol Substitution Test–symbols (IDSST-s) for executive function.

Results

Of 161 eligible individuals screened, 48 did not meet study inclusion criteria, 1 withdrew, and 112 were included in the study. Of 112 participants, mean (SD) age was 34.0 (11.5) years, and 58 participants (51.8%) were female. A total of 112 participants were randomized and received 1 or more doses of oveporexton (0.5/0.5 mg, n = 23; 2/2 mg, n = 21; 2/5 mg, n = 23; 7 mg, n = 23) or placebo (n = 22). Oveporexton improved attention, memory, and executive function over 8 weeks. Least-squares (LS) mean placebo-adjusted changes from baseline were −10.77 (95% CI, −16.74 to −4.79), −9.45 (95% CI, −15.66 to −3.24), −8.60 (95% CI, −14.84 to −2.36), and −8.69 (95% CI, −14.90 to −2.47) PVT lapses with 0.5/0.5 mg, 2/2 mg, 2/5 mg, and 7 mg/placebo doses, respectively. LS mean placebo-adjusted changes were −22.52 (95% CI, −34.95 to −10.10), −16.92 (95% CI, −30.12 to −3.71), −15.51 (95% CI, −28.82 to −2.21), and −17.59 (95% CI, −30.50 to −4.68) for CPAL errors; −0.05 (95% CI, −0.10 to −0.01), −0.07 (95% CI, −0.12 to −0.02), −0.07 (95% CI, −0.12 to −0.02), and −0.05 (95% CI, −0.10 to 0.00) units for ONB log10-transformed performance speed; and 4.72 (95% CI, −1.38 to 10.83), 7.33 (95% CI, 1.06-13.61), 7.85 (95% CI, 1.75-13.95), and 11.82 (95% CI, 5.75-17.89) for IDSST-s correct responses.

Conclusions and Relevance

In this secondary analysis of the TAK-861-2001 randomized clinial trial, the OX2R agonist oveporexton improved NT1-associated cognitive symptoms in adults.

Trial Registration

ClinicalTrials.gov Identifier: NCT05687903

This secondary analysis of the TAK-861-2001 randomized clinical trial explores the effect of oveporexton, an oral orexin receptor 2–selective agonist, on cognition in people with narcolepsy type 1.

Introduction

Narcolepsy type 1 (NT1) is a central disorder of hypersomnolence characterized by excessive daytime sleepiness (EDS) and cataplexy.^1,2 People with NT1 may also have nighttime sleep disruption, sleep paralysis, and hypnopompic or hypnagogic hallucinations.^1,2 NT1 is caused by extensive loss of the orexin (hypocretin)–producing neurons in the hypothalamus, resulting in severely reduced orexin neuropeptide signaling.³ The orexin receptors 1 and 2 (OX1R and OX2R) have distinct and partially overlapping distributions within the brain. Although both receptors govern a range of physiological functions, OX2R is more important for the maintenance of wakefulness, regulation of rapid eye movement (REM) sleep, and suppression of cataplexy in animal narcolepsy models.^4,5 The significance of orexin neurotransmission in NT1 was confirmed recently by studies showing that acute treatment with selective OX2R agonists improves the major symptoms of NT1.^6,7,8

In addition to their sleep/wake symptoms, people living with NT1 report difficulties with thinking clearly, remembering, concentrating, and paying attention, even with current standard of care.^9,10 These cognitive difficulties have a major impact on daily living and social and emotional well-being and also limit educational and employment opportunities.^10,11,12 Objective assessment confirms the presence of cognitive symptoms in NT1. For example, a recent meta-analysis of neuropsychological studies of adults with NT1¹³ identified a large-magnitude impairment in attention (Cohen d approximately −0.9), with smaller-magnitude impairments in memory and executive function (Cohen d approximately −0.3). In NT1, cognitive symptoms may arise from disruption to brain regions essential for cognition that are normally excited by orexins, including the basal forebrain, ventral tegmental area, locus coeruleus, and prefrontal cortex.^14,15

A recent double-blind, placebo-controlled, phase 2 randomized clinical trial (TAK-861; NCT05687903)⁶ showed that in adults with NT1, 8 weeks of treatment with the oral OX2R-selective agonist oveporexton reduced EDS, cataplexy, and disease severity and improved quality of life. This phase 2 trial also investigated the effect of oveporexton on aspects of cognition shown to be impaired in NT1. The aim of this secondary analysis was to determine whether treatment with the OX2R-selective agonist oveporexton was associated with improvements in attention, memory, or executive function over 8 weeks of daily dosing and to investigate the nature and magnitude of these effects in adults with NT1.

Methods

Trial Design

Detailed methods of the TAK-861-2001 phase 2b, 8-week, parallel-group, double-blind, placebo-controlled, dose-finding randomized clinical trial have been reported previously. The trial protocol and statistical analysis plan are available in Supplement 1. In brief, the trial included participants aged 18 to 70 years residing in North America, Europe, Japan, and Australia with a diagnosis of NT1 using the International Classification of Sleep Disorders, Third Edition.² Participants were randomized between February 8, 2023, and October 18, 2023, using interactive response technology in a 1:1:1:1:1 ratio to receive twice-daily oral oveporexton or matching placebo, dosed 3 hours apart (at 8 am and 11 am), 0.5/0.5 mg, 2/2 mg, 2/5 mg, 7 mg/placebo, or placebo/placebo, for 8 weeks. Twice-daily dosing was selected to follow the natural variation in central nervous system orexin levels throughout the day. The 7-mg total daily dose was administered twice daily (2/5 mg) and once daily (7 mg/placebo) to determine whether once- or twice-daily regimens had similar effects throughout the day. Randomization was stratified by geographic region (US, Europe, Asia Pacific). The randomization schedule was generated with a block size of 5 by a third-party vendor using interactive response technology. Medications for the treatment of NT1 were required to be discontinued prior to study start. A screening period of up to 50 days was scheduled to allow washout of NT1 medications, if applicable. The primary end point was change from baseline to week 8 in mean sleep onset latency measured on the 40-minute Maintenance of Wakefulness test (MWT); secondary end points were change from baseline to week 8 on the Epworth Sleepiness Scale (ESS) total score and weekly cataplexy rate at week 8.⁶ The trial included a set of cognitive tests as exploratory end points, and thus expected outcomes on these tests were not used for calculations of sample size. The trial was approved by regulatory authorities in each country and the institutional review board or ethics committee at each site and was performed in accordance with the trial protocol, the Declaration of Helsinki, and the International Council for Harmonisation E6 Good Clinical Practice guidelines. All participants provided written informed consent. The Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines were followed for reporting of the primary analysis; this secondary analysis was reported in accordance with the primary report where appropriate.

Cognitive Tests

The cognitive tests used and the main outcome measure for each are described in eTable 1 in Supplement 2. Briefly, attention was measured using the Psychomotor Vigilance Task (PVT), a test of sustained attention based on a simple reaction paradigm in which participants attend to a visual display to detect predefined but rare targets presented at random interstimulus intervals over 10 minutes.¹⁶ Performance was defined as the number of lapses made during the test, with a lapse classified as reaction time to any target greater than 500 milliseconds.¹⁷ Memory was measured using the Continuous Paired Associate Learning (CPAL) test, a test of visual associate memory in which participants learned the same 8 pattern-location associations over 6 trials.¹⁸ Performance was defined as the number of errors made learning the associations.¹⁸ Executive function was measured using the One Back test (ONB) of working memory using playing card stimuli as the stimuli. Performance was defined as the mean millisecond reaction time for correct responses, with this value normalized using a logarithmic base 10 transformation (log10ms).¹⁹ Executive function was also measured using the International Digit Symbol Substitution Test–symbols version (IDSST-s), a test of processing speed for which performance was defined by the number of correct matches.²⁰ The tests were administered 1 hour after the 8 am dose in the following order: PVT, CPAL, ONB, and IDSST-s. The PVT was administered again 7 hours after dosing. Postdose assessments were time matched to baseline dose assessments. Tests were administered using a tablet computer, with the operating system and software modified to ensure ±16-millisecond timing precision for stimulus presentation and response recording. All assessments were conducted under the supervision of trained and credentialed research assistants.

Statistical Analysis

The effect of 8 weeks of treatment with oveporexton on measures of cognition was evaluated using the full analysis set, defined as randomized patients who had received at least 1 dose of oveporexton or placebo and had at least 1 postdose efficacy measurement. Data analyses were carried out with the use of SAS software version 9.4 (SAS Institute) and R version 4.4.1 (R Foundation). No imputation for missing data was performed.

For the PVT, lapses were assessed at 1- and 7-hour postdose assessments and averaged across both time points. PVT lapses and CPAL errors at baseline and week 8 were normalized using a square root transformation and each submitted to a constrained longitudinal data analysis (cLDA) model,²¹ where visit, visit by dose group interaction, and a flag indicating prior narcolepsy-specific medication use (yes/no) were defined as fixed effects, with results presented on the original scale. For the ONB log10ms and IDSST-s correct responses, changes from baseline to week 8 were each analyzed using a linear mixed-effects model for repeated measures (MMRM), with fixed effects defined as the baseline value for the end point, visit, dose group, dose group by visit interaction, and prior narcolepsy-specific medication use, with visit treated as a repeat factor.

For each measure, the magnitude of the differences in mean changes from baseline with each dose of oveporexton vs placebo was also expressed as an effect size (Cohen d), where d 0.2 to less than 0.5 was classified as small, d 0.5 to less than 0.8 as medium, and d of 0.8 or greater as large effects.²² To facilitate interpretation, signs for the effect sizes summarizing treatment group differences for PVT lapses, CPAL errors, and ONB log10-transformed performance speed, where increasing values indicated worsening performance, were reversed. Consequently, effect sizes with a positive value indicate a treatment benefit for oveporexton compared with placebo, and vice versa. No adjustment for multiplicity was conducted, and all P values presented are nominal (total α = .05, 2-sided). To reduce the potential impact of type I error on interpretation of the results, group differences with a trivial magnitude effect (ie, d <0.2) were not interpreted, irrespective of their statistical significance.

Results

Participant Characteristics

Of 161 individuals screened for inclusion in the phase 2b TAK-861-2001 randomized clinical trial, 112 participants, among whom mean (SD) age was 34.0 (11.5) years and 58 participants (51.8%) were female, were randomized and received at least 1 dose of oveporexton (0.5/0.5 mg, n = 23; 2/2 mg, n = 21; 2/5 mg, n = 23; and 7 mg/placebo, n = 23) or placebo (n = 22). A total of 109 participants (97.3%) completed the trial, and 3 (2.7%) discontinued prematurely, all due to protocol deviations. Study discontinuation was not biased by any treatment group. Sixty-one participants (54.5%) received prior NT1 medications requiring washout during the screening period. Demographic and clinical characteristics at baseline were similar between treatment groups (Table 1). After 8 weeks, the mean (SD) treatment duration was 56.0 (3.9) days with placebo and 55.3 (3.9) days with oveporexton, with comparable overall adherence (97.2% vs 99.0%, respectively).

Table 1. Demographic and Clinical Characteristics of the Study Sample.

Characteristic	Mean (SD)
	Placebo (n = 22)	Oveporexton, mg				Total (N = 112)
		0.5/0.5 mg (n = 23)	2/2 mg (n = 21)	2/5 mg (n = 23)	7 mg once daily (n = 23)
Age, y	37.5 (11.9)	32.7 (11.1)	31.7 (11.3)	34.7 (11.5)	33.3 (11.9)	34.0 (11.5)
Sex, No. (%)
Female	14 (63.6)	11 (47.8)	9 (42.9)	14 (60.9)	10 (43.5)	58 (51.8)
Male	8 (36.4)	12 (52.2)	12 (57.1)	9 (39.1)	13 (56.5)	54 (48.2)
Race, No. (%)a
Asian	1 (4.5)	2 (8.7)	0	3 (13.0)	2 (8.7)	8 (7.1)
Black or African American	2 (9.1)	1 (4.3)	2 (9.5)	0	1 (4.3)	6 (5.4)
White	19 (86.4)	19 (82.6)	19 (90.5)	19 (82.6)	20 (87.0)	96 (85.7)
Multiple	0	1 (4.3)	0	1 (4.3)	0	2 (1.8)
Age at symptom onset, y	20.6 (10.5)	19.0 (11.5)	17.9 (9.3)	19.8 (10.5)	18.9 (9.6)	19.3 (10.2)
Age at diagnosis, y	27.6 (11.0)	27.5 (12.3)	22.6 (11.4)	27.0 (10.8)	26.3 (11.5)	26.3 (11.4)
BMIb	28.3 (4.4)	26.7 (5.9)	26.0 (3.4)	28.0 (5.2)	26.3 (4.3)	27.1 (4.7)
Sleep latency on MWT, min	6.1 (8.8)	5.6 (7.9)	3.9 (6.0)	4.2 (3.6)	3.6 (4.9)	4.7 (6.5)
ESS total score	18.6 (2.7)	18.3 (3.4)	19.0 (3.1)	18.6 (3.0)	18.0 (3.0)	18.5 (3.0)

Abbreviations: BMI, body mass index; ESS, Epworth Sleepiness scale; MWT, Maintenance of Wakefulness test.

^a Collected by study sites based on patient interview.

^b Calculated as weight in kilograms divided by height in meters squared.

Effect of Oveporexton on Cognition

Of the 109 participants who remained in the study at week 8, 107 (98%) provided data for all 4 cognitive tests. Two participants (in the 0.5/0.5 mg and 2/5 mg groups) missed assessments of CPAL, ONB, and IDSST-s at week 8. Compared with baseline, 8 weeks of treatment with oveporexton improved measures of attention, memory, and executive function. For the PVT, the mean number of lapses at baseline was similar between the placebo and treatment groups. After 8 weeks, the mean (SD) number of lapses increased from baseline by 4.6 (11.76) with placebo and decreased by 9.3 (16.30), 6.4 (17.12), 6.2 (13.29), and 1.7 (18.52) with 0.5/0.5 mg, 2/2 mg, 2/5 mg, and 7 mg/placebo doses, respectively (least-squares (LS) mean changes of −10.77 [95% CI, −16.74 to −4.79] [P < .001], −9.45 [95% CI, −15.66 to −3.24] [P = .003], −8.60 [95% CI, −14.84 to −2.36] [P = .007], and −8.69 [95% CI, −14.90 to −2.47] [P = .006] with oveporexton doses vs placebo; cLDA model) (Table 2). Qualitatively similar effects were observed when the 1-hour and 7-hour postdose assessments were considered individually (eTable 2 in Supplement 2). Effect sizes indicating the magnitude of differences from placebo for mean number of PVT lapses for each treatment group were large (Figure).

Table 2. Oveporexton Performance on Each Cognitive Test.

Measure	Placebo (n = 22)	Oveporexton
		0.5/0.5 mg (n = 23)	2/2 mg (n = 21)	2/5 mg (n = 23)	7 mg once daily (n = 23)
PVT lapses (mean of 1-h and 7-h postdose assessments)
Mean (SD) at baseline	15.2 (17.38)	15.6 (17.53)	17.2 (18.41)	15.9 (21.63)	11.5 (13.70)
Mean (SD) at wk 8	17.9 (14.94)	5.5 (5.97)	10.9 (19.73)	9.6 (16.88)	9.8 (18.68)
Mean (SD) change from baseline to wk 8	4.6 (11.76)	−9.3 (16.30)	−6.4 (17.12)	−6.2 (13.29)	−1.7 (18.52)
LS mean (95% CI) difference vs placebo from baseline to wk 8a	NA	−10.77 (−16.74 to −4.79)	−9.45 (−15.66 to −3.24)	−8.60 (−14.84 to −2.36)	−8.69 (−14.90 to −2.47)
No.	21	22	21	22	23
P value vs placeboa	NA	<.001	.003	.007	.006
CPAL No. of errors
Mean (SD) at baseline	38.0 (28.17)	34.7 (34.72)	35.8 (33.27)	39.3 (33.16)	36.9 (29.87)
Mean (SD) at wk 8	42.4 (35.29)	14.7 (15.06)	19.5 (21.29)	24.0 (30.67)	21.5 (26.33)
Mean (SD) change from baseline to wk 8	3.5 (38.31)	−22.4 (25.91)	−15.9 (38.13)	−13.2 (30.81)	−19.0 (28.06)
LS mean (95% CI) difference vs placebo from baseline to wk 8a	NA	−22.52 (−34.95 to −10.10)	−16.92 (−30.12 to −3.71)	−15.51 (−28.82 to −2.21)	−17.59 (−30.50 to −4.68)
No.	21	21	21	21	23
P value vs placeboa	NA	<.001	.01	.02	.008
ONB performance speed, log10ms
Mean (SD) at baseline	2.96 (0.104)	2.94 (0.129)	2.97 (0.131)	2.92 (0.101)	2.95 (0.101)
Mean (SD) at wk 8	2.96 (0.111)	2.90 (0.124)	2.90 (0.085)	2.88 (0.077)	2.91 (0.075)
Mean (SD) change from baseline to wk 8	0.003 (0.096)	−0.036 (0.090)	−0.068 (0.116)	−0.055 (0.083)	−0.040 (0.092)
LS mean (95% CI) difference vs placebo from baseline to wk 8b	NA	−0.05 (−0.10 to 0.01)	−0.07 (−0.12 to −0.02)	−0.07 (−0.12 to −0.02)	−0.05 (−0.10 to 0.00)
No.	21	21	21	21	23
P value vs placebob	NA	.03	.006	.006	.04
IDSST-s No. of correct responses
Mean (SD) at baseline	43.1 (10.24)	47.8 (11.75)	48.1 (8.80)	45.7 (11.58)	45.2 (13.77)
Mean (SD) at wk 8	45.4 (12.06)	51.1 (15.85)	54.1 (9.52)	54.2 (8.61)	56.8 (9.72)
Mean (SD) change from baseline to wk 8	1.6 (8.81)	3.7 (14.94)	6.5 (4.97)	9.7 (12.48)	12.8 (13.76)
LS mean (95% CI) difference vs placebo from baseline to wk 8b	NA	4.72 (−1.38 to 10.83)	7.33 (1.06 to 13.61)	7.85 (1.75 to 13.95)	11.82 (5.75 to 17.89)
No.	21	21	21	21	21
P value vs placebob	NA	.13	.02	.01	<.001

Abbreviations: CPAL, Continuous Paired Associate Learning test; IDSST-s, International Digit Symbol Substitution Test–symbols; LS, least-squares; NA, not applicable; ONB, One Back test; PVT, Psychomotor Vigilance Task.

^a Constrained longitudinal data analysis model with square root transformation.

^b Linear mixed-effect model.

Figure. Oveporexton Effect Size on Cognitive Measures (Cohen d).

Effect sizes from constrained longitudinal data analysis and mixed-effects model for repeated measures models. The magnitude of the difference in mean changes from baseline with each dose of oveporexton compared to placebo was expressed as an effect size (Cohen d), where d = 0.2-<0.5 was classified as small, d = 0.5-<0.8 as medium, and d ≥0.8 as large effects. Signs for the effect sizes summarizing treatment group differences for Psychomotor Vigilance Task (PVT) lapses, Continuous Paired Associate Learning (CPAL) errors, and One Back test (ONB) logarithmic base 10 transformation (log10ms), where increasing values indicated worsening performance, were reversed so that all positive effect sizes indicated a drug-related improvement and vice versa. IDSST-s indicates International Digit Symbol Substitution Test–symbols.

For the CPAL test, the mean number of errors made in learning the 8 pattern-location associations was similar between the placebo and each oveporexton treatment group at the baseline assessment. After 8 weeks, the mean (SD) number of errors increased by 3.5 (38.31) in the placebo group and decreased by 22.4 (25.91), 15.9 (38.13), 13.2 (30.81), and 19.0 (28.06) with oveporexton doses of 0.5/0.5 mg, 2/2 mg, 2/5 mg, and 7 mg/placebo, respectively (LS mean changes of −22.52 [95% CI, −34.95 to −10.10] [P < .001], −16.92 [95% CI, −30.12 to −3.71] [P = .01], −15.51 [95% CI, −28.82 to −2.21] [P = .02], and −17.59 [95% CI, −30.50 to −4.68] [P = .008] vs placebo; cLDA model) (Table 2). Compared with placebo, effect sizes for the mean number of CPAL errors for each treatment group were medium to large in magnitude (Figure).

For the ONB, the group mean log10-transformed speed of correct responses was similar between the placebo and each oveporexton treatment group at the baseline assessment. After 8 weeks, the mean (SD) performance speed remained unchanged for the placebo group (at 2.96 [0.11] log10ms), and decreased by 0.04 (0.09), 0.07 (0.16), 0.06 (0.08), and 0.04 (0.09) log10ms for oveporexton doses of 0.5/0.5 mg, 2/2 mg, 2/5 mg, and 7 mg/placebo, respectively (LS mean log10-transformed changes of −0.05 [95% CI, −0.10 to −0.01] [P = .03], −0.07 [95% CI, −0.12 to −0.02] [P = .006], −0.07 [95% CI, −0.12 to −0.02] [P = .006], and −0.05 [95% CI, −0.10 to 0.00] [P = .04] units with oveporexton doses vs placebo; MMRM model) (Table 2). Compared with placebo, the effect sizes for mean log10-transformed performance speed for each treatment group were medium and large in magnitude (Figure).

For the IDSST-s, the mean number of correct responses was similar between the placebo and each oveporexton treatment group at the baseline assessment. After 8 weeks, the mean (SD) number of correct responses increased by 1.6 (8.81) in the placebo group vs 3.7 (14.94), 6.5 (4.97), 9.7 (12.48), and 12.8 (13.76) with oveporexton doses of 0.5/0.5 mg, 2/2 mg, 2/5 mg, and 7 mg/placebo, respectively. LS mean changes from baseline were significant with 2/2 mg, 2/5 mg, and 7 mg/placebo vs placebo (7.33 [95% CI, 1.06-13.61] [P = .02], 7.85 [95% CI, 1.75-13.95] [P = .01], and 11.82 [95% CI, 5.75-17.89] [P < .001], respectively correct responses), except for the 0.5/0.5 mg group (change of LS mean: 4.72 [95% CI, −1.38 to 10.83] responses; P = .13, MMRM model) (Table 2). Compared with placebo, effect sizes for the mean number of correct responses for each treatment group were small to large in magnitude (Figure).

Differences between observed change from baseline to week 8 and group mean change from baseline to week 8 are a consequence of a common characteristic of repeated applications of cognitive tests, where variation in performance between different participants on a single assessment, even repeated, is larger than the variation on the same outcome within the same participant over time. The change scores capture the individual or within-group trajectory of change, while a comparison of group means across the same time point reflects the overall standing of the groups relative to each other.

Discussion

Cognitive symptoms associated with NT1 are common and debilitating manifestations within the broader NT1 clinical picture, but they have only recently garnered increasing attention from the scientific community.^23,24,25 Approximately 80% to 90% of adults with NT1 report difficulties with remembering, sustaining attention, and processing information, while 30% to 60% of the same adults have difficulties in forming thoughts and learning new information, often despite treatment with currently available medications.^11,26 The results of this study showed that in adults with NT1, 8 weeks of twice-daily treatment with the OX2R agonist oveporexton, at doses of 0.5/0.5 mg, 2/2 mg, 2/5 mg, and 7 mg/placebo, resulted in moderate- to large-magnitude improvements in attention, memory, and executive function compared to placebo. In this study, these domains were measured objectively using 4 validated and standardized neuropsychological tests, chosen because they measured domains of cognition identified in meta-analyses to be most impaired in adults with NT1.^9,13 The presence of cognitive impairment in adults with NT1 suggests strongly that this may arise from loss of normal orexin neurotransmission. The finding that long-term treatment with the selective OX2R agonist oveporexton improved attention, memory, and executive function in adults with NT1 supports this hypothesis.

This study was not designed to examine differences in effects on cognition between doses of oveporexton. The treatment effect sizes summarized in the Figure show that the magnitudes of oveporexton-related improvement for each aspect of cognition assessed were similar across doses, considering the confidence intervals associated with each estimate. While the nature of any dose-response relationship between oveporexton and cognition will require a larger study designed specifically to investigate this question, the current results show that cognitive symptoms are highly responsive to treatment with an OX2R agonist.

Findings from this study confirm that cognitive symptoms are important clinical sequalae of NT1 and therefore have implications for development of clinical-pathological models of the disorder. The orexin neurons are located primarily in the lateral hypothalamus and directly innervate and excite neurons in several regions, including cholinergic and GABAergic neurons in the basal forebrain, serotonergic neurons in the dorsal raphe nucleus, dopaminergic neurons in the ventral tegmental area, histaminergic neurons in the tuberomammillary nucleus, and noradrenergic neurons in the locus coeruleus.^14,27 The orexin neurons also project directly to the medial prefrontal cortex and other parts of the cortex and hippocampus.⁴ Each of these brain regions expresses OX2R, except for the locus coeruleus, which may be indirectly activated by OX2R stimulation.^1,14 In rodents, chemical or stereotaxic lesions of these target regions impair arousal, attention, memory, motivation, and executive function.^28,29,30 Furthermore, high-dose acute treatment with dual orexin receptor antagonists worsens attention, memory, and executive function in healthy adults.^31,32,33 Thus, one hypothesis is that OX2R agonists act through midbrain and cortical regions to influence cognition in adults with NT1. However, while the specific orexigenic pathways involved in the modulation of cognition remain unknown, the methods developed here provide a strong basis for further clinical studies in humans that could localize these pathways and their influence on specific aspects of cognitive impairment in NT1.

Limitations and Strengths

The study has several limitations that warrant consideration. First, the population enrolled in this phase 2b trial consisted of predominantly White adults⁶ and must now be extended to more racially and ethnically diverse samples of adults with NT1. Although participant demographics were similar between groups, level of educational attainment was not captured; however, the use of the within-participant comparison and the provision of detailed training and familiarization for each test prior to baseline assessment was expected to minimize potential bias arising from this parameter. Second, it will be important to determine the extent to which any cognitive benefits arising from treatment with OX2R agonists extend beyond the domains of attention, memory, and executive function evaluated. As sample sizes in future clinical trials increase, it will become possible to evaluate the extent to which the effect of oveporexton on cognition is direct or whether it is an indirect consequence of the drug alleviating sleepiness.⁶ Third, although performance on the PVT at 7 hours postdose showed that the benefits of oveporexton treatment extended over the day, further study is required to determine whether drug-related benefits in memory and executive function also persist across the day.

This study does have major strengths. To our knowledge, it is the first to investigate the effect of an OX2R agonist on cognition in NT1 using double-blind, placebo-controlled methods and was conducted on the largest sample of adults with NT1 for which cognition has been studied to date.¹³ The moderate- to large-magnitude cognitive benefits observed following oveporexton treatment provide a sound basis for further development of OX2R agonists as a potential treatment for NT1-associated cognitive symptoms and inform clinical-pathological models of NT1. Future studies should examine the extent to which these improvements relate to patients’ experiences of cognitive difficulties in real-world settings and the extent to which improvements in cognitive symptoms are independent of improvements in EDS.

Conclusions

In conclusion, results from this secondary analysis of the TAK-861-2001 randomized clinial trial indicate that the OX2R agonist oveporexton improved attention, memory, and executive function in adults with NT1. These findings provide a sound basis for the development of pharmacological therapies that could ameliorate NT1-associated cognitive symptoms.

Supplement 1.

Trial Protocol and Statistical Analysis Plan

Supplement 2.

eTable 1. Cognition Assessments

eTable 2. Oveporexton on PVT at 1- and 7-Hour Post-Morning Dose

Supplement 3.

Data Sharing Statement