A Study of TAK-861 for the Treatment of Narcolepsy Type 1

The drug being tested in this study is called TAK-861 (oveporexton). TAK-861 (oveporexton) is being tested to evaluate its efficacy and safety in people with narcolepsy type 1 (NT1).

The study will enroll approximately 152 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the three treatment groups:

1. TAK-861 Dose 1
2. TAK-861 Dose 2
3. Placebo

The study drug will be administered for 12 weeks. This multi-center trial will be conducted globally.

• Oveporexton (Drug), also known as TAK-861: Oral tablet.
• Placebo (Drug): OVE-matching placebo tablet.

Primary outcomes

• Change From Baseline to Week 12 in Mean Sleep Latency From the 4 Maintenance of Wakefulness Test (MWT) Wake Trials [Baseline, Week 12]: The MWT evaluates a person's ability to remain awake under soporific conditions for a defined period of time. Because there is no biological measure of wakefulness, wakefulness is measured indirectly by the inability or delayed tendency to fall asleep. This tendency to fall asleep is measured via electroencephalography-derived sleep latency in the MWT. The MWT consists of four 40-minute sessions (trials) done 2 hours apart. Sleep latency in each session was recorded. Participants were required to stay awake in between the four sessions. A positive change from baseline indicates an improvement. The linear mixed effects model for repeated measures (MMRM) was used for analysis.

Secondary outcomes

• Change From Baseline to Week 12 in Epworth Sleepiness Scale (ESS) Total Score [Baseline, Week 12]: The ESS provides individuals with 8 different situations of daily life and asks them how likely they are to fall asleep in those situations (scored 0 to 3) and to try to imagine their likelihood of dozing even if they have not actually been in the identical situation; the scores are summed to give an overall score of 0 to 24. Higher scores indicate stronger subjective daytime sleepiness. A negative change from baseline indicates an improvement. The linear MMRM was used for analysis.
• Weekly Cataplexy Rate (WCR) at Week 12 [Week 12]: Participants completed a daily participant-reported cataplexy diary to record self-reported episodes of cataplexy attacks. WCR = (total number of cataplexy attacks over a number of non-missing diary days for a given period/number of non-missing diary days in that period)*7. The generalized estimating equations (GEE) model was used for analysis. Reported here is the estimated mean of incidence rate with a 95 percent (%) confidence interval (CI).
• Change From Baseline to Week 12 in Mean Number of Lapses on the Psychomotor Vigilance Test (PVT) [Baseline, Week 12]: The PVT is a simple reaction performance task that aims to measure sustained attention. The mean number of lapses (delayed responses to a visual cue from intraday sessions) from the two 10-minute intraday sessions was used as a measure of objective sustained attention. A negative change from baseline indicates an improvement. A constrained Longitudinal Data Analysis (cLDA) model was used to analyze the mean number of lapses and to estimate change from baseline at each visit.
• Responder Rate on Patient Global Impression of Change (PGI-C) Score at Week 12 [Week 12]: The PGI-C is a participant self-rated scale to assess change in daytime sleepiness and overall narcolepsy symptoms. The PGI-C includes 7 items being scored from 1 (best outcome) to 7 (worst outcome) with 4 being no change. Responders were the participants reporting "1=very much improved" or "2=much improved" on PGI-C. Responder rate (proportion of participants who were responders) was estimated using a GEE model.
• Change From Baseline to Week 12 in Narcolepsy Severity Scale for Clinical Trials (NSS-CT) Total Score [Baseline, Week 12]: The NSS-CT is a 15-item self-administered questionnaire that assesses the severity and consequences of the 5 major narcolepsy symptoms such as daytime sleepiness, cataplexy, hallucinations, sleep paralysis, and disturbed nighttime sleep (DNS) with a total score range of 0 to 57 (sum of 6 items that assess symptoms severity are rated using a six-point Likert scale \[0-5\] and 9 items that describe the symptom effect on daily life are rated using a four-point Likert scale \[0-3\]). Higher total scores mean a worse outcome. A negative change from baseline indicates an improvement. The linear MMRM was used for analysis.
• Change From Baseline to Week 12 in Functional Impacts of Narcolepsy Instrument (FINI) Domain Scores [Baseline, Week 12]: The FINI measures the functional impacts of narcolepsy across 6 domains Tiredness (items 1-7), Cognitive Functioning (items 8-12), Cataplexy (items 13-17), Social Activities (items 18-21), Everyday Activities (items 22-25), and Everyday Responsibilities (items 26-28). Each item asks about the impact that narcolepsy has had on their daily functioning during the past 7 days, and is scored from 0 to 4, where 0 indicates the best health and 4 the worst. An average score is calculated for each domain and then standardized to a 0-100 scale, where 0 indicates the best health and 100 the worst health. Standardized score = average score/4 × 100. A negative change from baseline indicates and improvement. The linear MMRM was used for analysis.
• Change From Baseline to Week 12 in Short Form-36 Survey (SF-36) Mental and Physical Component Scores [Baseline, Week 12]: The SF-36 is participant-reported survey of participant health that assesses the quality of life and includes both physical and mental components. The scores for each component range from 0 to 100. Higher scores represent better health-related quality of life. A positive change from baseline indicates an improvement. The linear MMRM was used for analysis.
• Number of Participants With At Least One Treatment-Emergent Adverse Event (TEAE) [Up to 16 weeks]: An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product. A TEAE is defined as any event emerging or manifesting at or after the initiation of treatment with a study intervention or medicinal product or any existing event that worsens in either intensity or frequency following exposure to the study intervention or medicinal product.

Sex: All, ages: 16 Years to 70 Years

Inclusion Criteria:

1. The participant has a body mass index (BMI) within the range 18 to 40 kilograms per meter square (kg/m\^2).
2. The participant has an International Classification of Sleep Disorders, Third Edition (ICSD-3) or International Classification of Sleep Disorders, Third Edition, Text Revision (ICSD-3-TR) diagnosis of NT1.
3. The participant has greater than or equal to (≥)4 partial or complete episodes of cataplexy/week (WCR).
4. The participant is positive for the human leukocyte antigen (HLA) genotype HLA-DQB1*06:02 or results from radioimmunoassay indicate the participant's cerebrospinal fluid (CSF) orexin (OX)/hypocretin-1 concentration is less than or equal to (≤)110 picograms per milliliter (pg/mL) \[or less than one-third of the mean values obtained in normal participants within the same standardized assay\].

Exclusion Criteria:

1. The participant has a current medical disorder, other than narcolepsy with cataplexy, associated with EDS.
2. The participant: (a) has a history of myocardial infarction; (b) has a history of clinically significant hepatic disease, thyroid disease, coronary artery disease, cardiac rhythm abnormality or heart failure; or (c) has any medical condition (such as unstable cardiovascular, pulmonary, renal or gastrointestinal disease).
3. The participant has current or recent (within 6 months) gastrointestinal disease that is expected to influence the absorption of drugs.
4. The participant has a history of cancer in the past 5 years.
5. The participant has a clinically significant history of head injury or head trauma.
6. The participant has a history of epilepsy, seizure, or convulsion.
7. The participant has a history of cerebral ischemia, transient ischemic attack (<5 years from screening), intracranial aneurysm, or arteriovenous malformation.

Participant flow

Outcome results

• Change From Baseline to Week 12 in Mean Sleep Latency From the 4 Maintenance of Wakefulness Test (MWT) Wake Trials (Primary), Least squares mean, minutes: Placebo -1.32 +/- 1.502; OVE 1 mg BID 12.51 +/- 1.284; OVE 2 mg BID 15.87 +/- 1.205 (p <0.001)
• Change From Baseline to Week 12 in Epworth Sleepiness Scale (ESS) Total Score (Secondary), Least squares mean, score on a scale: Placebo -1.42 +/- 0.794; OVE 1 mg BID -9.42 +/- 0.679; OVE 2 mg BID -11.17 +/- 0.618 (p <0.001)
• Weekly Cataplexy Rate (WCR) at Week 12 (Secondary), Mean, cataplexy attacks per week: Placebo 34.04 (22.70 to 51.06); OVE 1 mg BID 11.50 (7.33 to 18.03); OVE 2 mg BID 12.80 (9.24 to 17.71) (p <0.001)
• Change From Baseline to Week 12 in Mean Number of Lapses on the Psychomotor Vigilance Test (PVT) (Secondary), Mean, number of lapses: Placebo 2.09 (-1.57 to 5.74); OVE 1 mg BID -7.60 (-9.87 to -5.32); OVE 2 mg BID -8.43 (-10.61 to -6.25) (p <0.001)
• Responder Rate on Patient Global Impression of Change (PGI-C) Score at Week 12 (Secondary), Number, proportion of participants: Placebo 0.21 (0.07 to 0.35); OVE 1 mg BID 0.69 (0.55 to 0.83); OVE 2 mg BID 0.94 (0.88 to 1.01) (p <0.001)
• Change From Baseline to Week 12 in Narcolepsy Severity Scale for Clinical Trials (NSS-CT) Total Score (Secondary), Least squares mean, score on a scale: Placebo -2.99 +/- 1.446; OVE 1 mg BID -17.36 +/- 1.224; OVE 2 mg BID -19.87 +/- 1.106 (p <0.001)
• Change From Baseline to Week 12 in Functional Impacts of Narcolepsy Instrument (FINI) Domain Scores (Secondary), Least squares mean, score on a scale: Placebo -2.13 +/- 3.664; OVE 1 mg BID -35.22 +/- 3.175; OVE 2 mg BID -48.16 +/- 2.858 (p <0.001)
• Change From Baseline to Week 12 in Short Form-36 Survey (SF-36) Mental and Physical Component Scores (Secondary), Least squares mean, score on a scale: Placebo -1.74 +/- 1.548; OVE 1 mg BID 5.04 +/- 1.292; OVE 2 mg BID 8.36 +/- 1.162 (p <0.001)
• Number of Participants With At Least One Treatment-Emergent Adverse Event (TEAE) (Secondary), Count of participants, Participants: Placebo 22; OVE 1 mg BID 52; OVE 2 mg BID 59

Adverse events

Time frame: Up to 16 weeks

Serious adverse events by term

Other adverse events by term

• Results publication: Dauvilliers Y, Mignot E, Antczak J, Arnulf I, Barateau L, Buntinx E, Corser B, Iranzo A, Khatami R, Lammers GJ, Lederer K, Nilsen KB, Pizza F, Schmidt MH, Sivam S, Sum-Ping O, Taniguchi M, Zhan S, Abraham A, Cai A, Du Y, Etherton MR, Faessel H, Hsiao S, Kadali H, Koundourakis E, Naylor M, Neuwirth R, Olsson T, Rogers R, Sheikh S, Tanaka S, von Rosenstiel P, von Hehn C, Hang Y, Yao B, Del Rio Villegas R, Plazzi G. Oveporexton for Narcolepsy Type 1 - Results from Two Phase 3 Trials. N Engl J Med. 2026 Sep 9. doi: 10.1056/NEJMoa2601598. Online ahead of print. PMID 42714024

• Study Protocol (PDF, 2024-10-23)
• Statistical Analysis Plan (PDF, 2025-05-26)

• Medical Director, Study director, Takeda

NIH grants: 2023