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A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of TAK-861 for the Treatment of Narcolepsy with Cataplexy (Narcolepsy Type 1)

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

168

Demographic characteristics were generally similar across the treatment groups. Approximately one-third of participants were White (35.1%) and approximately one-third (35.1%) were of unknown race (not collected due to country regulations). Of the 168 randomized participants, 25 (14.9%) were Japanese. A slightly higher proportion of female participants than male participants were enrolled: 58.3% and 58.5% of participants in the overall oveporexton and placebo groups, respectively, were female. Median age of the participants was 28 years (range: 16 to 65 years). Three participants (1.8%) aged 16 and 17 years were enrolled at 3 sites (2 in the US, 1 in Japan); 1 in the placebo group, 1 in the oveporexton 1 mg twice daily (BID) group, and 1 in the oveporexton 2 mg BID group. Baseline characteristics were generally similar across the treatment groups, including median age at narcolepsy type 1 (NT1) diagnosis and median age at symptom onset. Median sleep latency, Epworth Sleepiness Scale (ESS) total score, and weekly cataplexy rate (WCR) were also balanced across the treatment groups at baseline. Prior medication use, including use of prior medications for NT1, was generally similar across the treatment groups.

168 participants were enrolled at 41 sites in Japan, Europe, and North America. All 168 enrolled participants were randomized, and 167 received at least 1 dose of trial intervention. One participant was randomized but not treated; this participant did not complete the predose pharmacokinetic (PK) collection and was subsequently lost to follow-up. Of the 167 participants who were randomized and received at least 1 dose of trial intervention, 10 did not complete the trial. These 10 participants were discontinued from the trial for the following reasons: adverse events (4 participants); protocol deviations (3 participants); and withdrawal by participant (3 participants). Of the 157 participants who completed the trial, 150 (95.5%) entered the long-term extension (LTE) trial.

The results of the trial demonstrated that oveporexton was well tolerated with TEAEs that were manageable and generally self-limiting. - Among participants treated with oveporexton, the most commonly reported treatment-emergent adverse events (TEAEs) (>5% of participants) included pollakiuria (54.0%), insomnia (55.6%), micturition urgency (16.7%), nasopharyngitis (12.7%), headache (11.1%), and salivary hypersecretion (7.1%). Most TEAEs were mild or moderate in severity; 3 participants experienced severe TEAEs assessed as related to trial intervention by the investigator. - No deaths were reported in the trial. The rate of trial intervention discontinuation due to TEAEs was low (2.4%) and was the same in participants in the overall oveporexton group and participants in the placebo group. Two serious adverse events were reported in the trial; both were in participants treated with oveporexton, and both were considered unrelated to oveporexton treatment. - Adverse events of special interest (AESIs) of urinary events and insomnia were common in the oveporexton groups overall. Most of these events began within the first 2 days of treatment and were mild to moderate in severity. All were nonserious. The majority of the AESIs of insomnia (68.9%) resolved within 7 days. Approximately half of the AESIs of urinary events (47.0%) resolved by the end of the trial. - No markedly abnormal values (MAVs) of clinical significance that were considered related to oveporexton treatment were observed. The incidence of MAVs was comparable between the oveporexton and placebo treatment groups. - No clinically meaningful trends were observed in laboratory evaluations. The overall incidence of liver function test (LFT) elevations was low, and all LFT MAVs and AESIs were transient and considered not related to trial intervention. - Oveporexton showed low abuse potential (low incidence of TEAEs that may be related to potential abuse) and low risk of dependence in this trial. - No new trends were observed in the evaluation of vital signs. No clinically significant changes were observed in the HR data. - No notable trends in electrocardiogram (ECG) parameters were observed, and no clinically relevant ECG abnormalities were reported. - No clinically significant adverse trends were observed in vital signs, laboratory values. CONCLUSION: Oveporexton has a favorable benefit/risk profile in participants with NT1. Both the 1 and 2 mg BID dose regimens were well tolerated with no major safety concerns. No deaths occurred and the rate of TEAEs leading to discontinuation was low (2.4%) and the same in the overall oveporexton and placebo groups. The proportion of participants with AESIs (urinary events, insomnia, and increases in blood pressure and HR) was generally higher in the oveporexton treatment groups compared with the placebo treatment group and consistent with the known potential risks of oveporexton. Most insomnia and urinary AESIs were mild to moderate in intensity and self-limiting; none required significant medical intervention. No clinically meaningful trends were observed in laboratory evaluations or vital signs.

The results of the trial demonstrated a substantial clinical benefit with both oveporexton 1 and 2 mg BID for participants with NT1, compared with placebo. - Oveporexton demonstrated statistically significant and clinically meaningful improvements in excessive daytime sleepiness (EDS), including: - Statistically significant and clinically meaningful improvements compared with placebo for the change from baseline to Week 12 in mean sleep latency on the Maintenance of Wakefulness Test (MWT). - Statistically significant and clinically meaningful improvements compared with placebo for the change from baseline to Week 12 in ESS total score. - The majority of participants achieved normal ranges in MWT and ESS. - Improvements in MWT and ESS in the oveporexton groups were observed across all subgroup analyses. For the majority of these subgroups, nominal significance at the 5% level was achieved, despite the small size of the subgroups. In addition, sensitivity analyses using a Bayesian hierarchical model showed that the subgroup estimates for both oveporexton treatment groups were consistent and similar to the overall treatment effect across endpoints. - Oveporexton resulted in statistically significant and clinically meaningful incidence rate ratio (IRRs) in WCR compared with placebo, starting as early as the first assessment at Week 2 and remaining consistent through Week 12. - Oveporexton resulted in statistically significant and clinically meaningful improvements in attention at Week 12 as evidenced by decreases from baseline in the mean number of lapses from the 2 intraday sessions on the Psychomotor Vigilance Test (PVT) for both oveporexton dose groups compared with placebo. The majority of participants achieved a number of lapses on the PVT that were within normal limits. - Oveporexton resulted in clinically meaningful improvements in overall NT1 symptoms, with statistically significant odds ratios comparing the odds of reporting much or very much improved overall NT1 symptoms between oveporexton and placebo as measured by the Patient Global Impression of Change (PGI-C) scale at Week 12. - Oveporexton resulted in statistically significant and clinically relevant reductions in the overall pentad of NT1 symptoms compared with placebo as measured by improvements in the Narcolepsy Severity Scale for Clinical Trials (NSS-CT) total score at Week 12. In addition, oveporexton improved each component of the pentad of NT1 symptoms, including hallucinations, sleep paralysis, and disturbed nighttime sleep (DNS), compared with placebo as measured by improvement in the NSS-CT domain scores. - Oveporexton resulted in statistically significant and clinically relevant improvements in quality of life (QoL) as measured by the change from baseline in Mental Component Summary (MCS) and Physical Component Summary (PCS) scores (SF-36) compared with placebo at Week 12. MCS and PCS scores at Week 12 were similar to normative standards. CONCLUSION: Over 12 weeks of treatment, oveporexton at a dose of 1 or 2 mg BID demonstrated clinically meaningful and statistically significant improvements in NT1 symptoms compared to placebo. Clinically meaningful reductions in EDS and cataplexy were observed in the oveporexton treatment groups compared to placebo. Oveporexton treatment also resulted in substantial improvements in the cognitive symptoms associated with NT1 and their associated functional impacts. Substantial improvements were also observed in the severity of traditional NT1 symptoms and their functional impacts. Taken together, these results provide clear evidence of the broad efficacy of oveporexton across the spectrum of NT1 symptoms.

Results from this phase 3 trial confirm that oveporexton, an oral orexin receptor agonist, provides meaningful improvement, with the potential of transformational benefit, to people with NT1.

Yes

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

https://jrct.mhlw.go.jp/latest-detail/jRCT2051240083

Nonomura Hidenori

Takeda Pharmaceutical Company Limited

1-1, Doshomachi 4-chome, Chuo-ku, Osaka

smb.Japanclinicalstudydisclosure@takeda.com

Contact for Clinical Trial Information

Takeda Pharmaceutical Company Limited

1-1, Doshomachi 4-chome, Chuo-ku, Osaka

+81-6-6204-2111

smb.Japanclinicalstudydisclosure@takeda.com

Complete

July. 02, 2024

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

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].

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.

Both

Narcolepsy Type 1

TAK-861 Dose 1:
Participants will receive TAK-861 tablets at dose 1, orally, for 12 weeks.

TAK-861 Dose 2:
Participants will receive TAK-861 tablets at dose 2, orally, for 12 weeks.

Placebo:
Participants will receive TAK-861-matching placebo tablets, orally, for 12 weeks.

1. Change From Baseline to Week 12 in Mean Sleep Latency From the 4 Maintenance of Wakefulness Test (MWT) Wake Trials
Time Frame: 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 will be recorded. Participants will be required to stay awake in between the 4 sessions.

1. Change From Baseline to Week 12 in ESS Total Score
Time Frame: 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, and scores below 10 are considered to be within the normal range.

2. Weekly Cataplexy Rate (WCR) at Week 12
Time Frame: Week 12

3. Change From Baseline to Week 12 in Mean Number of Lapses on the 3 Psychomotor Vigilance Test (PVT)
Time Frame: Baseline, Week 12
The PVT is a simple reaction performance task that aims to measure sustained attention. The change from baseline in the mean number of lapses (delayed responses to a visual cue from intraday sessions) during the 10 minute test will be used as a measure of objective sustained attention.

4. Patient Global Impression of Change (PGI-C) Score at Week 12
Time Frame: Week 12
The PGI-C is a patient self-rated scale to assess improvement 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.

5. Change From Baseline to Week 12 in Narcolepsy Severity Scale for Clinical Trials (NSS-CT) Total Score
Time Frame: 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.

6. Change From Baseline to Week 12 in Functional Impacts of Narcolepsy Instrument (FINI) Domain Scores
Time Frame: Baseline, Week 12
The FINI measures the functional impacts of narcolepsy across 6 domains. Each domain is scored from 0 to 4, where 0 indicates the best health and 4 the worst.

7. Change From Baseline to Week 12 in Short Form-36 Survey (SF-36) Mental and Physical Component Scores
Time Frame: 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.

8. Number of Participants with At Least one Treatment-Emergent Adverse Event (TEAE)
Time Frame: 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.

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May. 22, 2024

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