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A 3-Part, Randomized, Double-Blind, Placebo-Controlled, Multiple Rising Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of TAK-925 in Healthy Volunteers and Patients with Narcolepsy

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of TAK-925 in Healthy Volunteers and Participants with Narcolepsy

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The demographics between placebo and active treatment groups were generally similar in each part. In Part A, healthy participants were all male. In narcolepsy patients, the BMI was slightly higher in NT1 patients than in NT2 patients. Except for TAK-925 44 mg group in NT1 patients, the mean sleep latency was lower in NT1 patients than in NT2 patients, consistent with previous reports.

At 3 sites in Japan, 83 participants in Part A, 17 participants in Part A', 18 participants in Part B, and 15 participants in Part C signed the informed consent form. Among them, 59 participants in Part A, 11 participants in Part A', 5 participants in Part B, and 1 participant in Part C were not randomized. In Part A, a total of 24 healthy adults were treated with the study drug (6 participants each in the placebo, IV TAK-925 44 mg, TAK 925 112 mg, and TAK-925 180 mg groups). In Part A', a total of 6 healthy adults were treated with an oral solution of TAK-925 112 mg. In Part B, a total of 13 patients with NT1 were treated with the study drug (4, 4, and 5 participants in the placebo, IV TAK-925 11 mg, and TAK 925 44 mg groups, respectively). In Part C, a total of 14 patients with NT2 were treated with the study drug (5, 4, and 5 participants in the placebo, IV TAK-925 44 mg, and TAK 925 112 mg groups, respectively). All participants completed all planned study visits.

No severe TEAEs, deaths, SAEs, or TEAEs leading to study drug discontinuation were reported in any treatment group of any part throughout the study. In Part A (healthy adults), treatment-emergent adverse events (TEAEs) were reported in 1 participant (16.7%) in the placebo group, 2 participants (33.3%) in the TAK-925 112 mg group, and 4 participants (66.7%) in the TAK-925 180 mg group; no TEAEs were reported in the TAK-925 44 mg group. No TEAEs were reported in more than 1 participant in any treatment group. In Part A' (oral administration, healthy adults), no TEAEs were reported. In Part B (patients with NT1), TEAEs were reported in 1 participant (25.0%) in the placebo group, 1 participant (25.0%) in the TAK-925 11 mg group, and 5 participants (100.0%) in the TAK-925 44 mg group. The most common TEAE was pollakiuria that occurred in 4 participants (80.0%) in the TAK-925 44 mg group; no other TEAEs were reported in more than 1 participant in any treatment group. In Part C (patients with NT2), TEAEs were reported in 1 participant (25.0%) in the TAK-925 44 mg group and 3 participants (60.0%) in the TAK-925 112 mg group; no TEAEs were reported in the placebo group. The most common TEAE was pollakiuria that occurred in 2 participants (40.0%) in the TAK-925 112 mg group; no other TEAEs were reported in more than 1 participant in any treatment group.

Refer to "Adverse Events".

Pharmacokinetic Results: Part A (Intravenous dose in healthy adults) and Part A' (Oral dose in healthy adults): The mean plasma systemic exposures of TAK-925 on Day 1 and Day 7 both increased generally in dose- proportional manner, as evidenced by the lack of apparent difference in AUCtau/Dose and Cmax/Dose of TAK-925 across doses of 44 to 180 mg. Since the time concentration profiles on Day 1 and Day 7 were similar and Rac(AUC) and Rac(Cmax) were approximately 1, no drug accumulation with once daily (QD) dosing of 9-hours IV infusion was observed. After switching off the IV infusion, TAK-925 plasma concentrations declined rapidly and in a biphasic manner with a mean terminal disposition phase t1/2z ranging from approximately 3.3 to 4.0 hours across all doses, which were also similar between Day 1 and Day 7. Part B (Intravenous dose in patients with NT1): The mean plasma systemic exposures of TAK-925 on Day 1 and Day 7 in NT1 patients were similar to that observed in healthy participants in Part A. Since the time concentration profile on Day 1 and Day 7 were similar and Rac(AUC) and Rac(Cmax) were approximately 1, no drug accumulation with QD dosing of 9-hours IV infusion was observed, which was similar to healthy participants. Part C (Intravenous dose in patients with NT2): The mean plasma systemic exposures of TAK-925 on Day 1 and Day 7 in NT2 patients were also similar to that observed in healthy participants in Part A. Since the time concentration profile on Day 1 and Day 7 were similar and Rac(AUC) and Rac(Cmax) were approximately 1, no drug accumulation with QD dosing of 9-hours IV infusion was observed, which was similar to healthy participants. Pharmacodynamic Results: MWT In Part B (patients with NT1), the average sleep latency in MWT was improved in the TAK-925 11 mg group and TAK-925 44 mg group compared with the placebo group. The mean changes from baseline in average sleep latency in MWT (min) were -0.66, 35.13, and 34.19 on Day 1 and -0.38, 21.00, and 34.78 on Day 7 for placebo, TAK-925 11 mg, and TAK-925 44 mg, respectively. In Part C (patients with NT2), the average sleep latency in MWT was improved in the TAK-925 44 mg and TAK 925 112 mg groups compared with the placebo group. The mean changes from baseline in average sleep latency in MWT (min) were 2.58, 23.88, and 31.15 on Day 1 and 2.35, 25.79, and 28.28 on Day 7 in the placebo, TAK-925 44 mg, and TAK-925 112 mg groups, respectively.

TAK-925 was safe and well tolerated in the multiple intravenous administrations of up to 180 mg for healthy participants, up to 44 mg for patients with NT1, and up to 112 mg for patients with NT2; and also in single oral administration of 112 mg for healthy participants.

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.

Takeda Pharmaceutical Company Limited

https://www.takeda.com/jp/who-we-are/contact-us/

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Takeda Pharmaceutical Company Limited

https://www.takeda.com/jp/who-we-are/contact-us/

+81-6-6204-2111

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completed

Nov. 21, 2018

Interventional

Randomized, Double-Blind, Placebo-Controlled, Multiple Rising Dose Study

treatment purpose

1

Healthy adult participants and Healthy elderly participants:
- Participant weighs at least 50 kg (Healthy adults participants) / 40 kg (Healthy elderly participants) and has a body mass index (BMI) from 18.5 to 30 kg/m^2, inclusive at Screening.
Narcolepsy patients:
- Patient weighs at least 40 kg inclusive at Screening (>=50 kg is required for Cohort B4).
- A diagnosis of narcolepsy, as defined by the International Classification of Sleep Disorders, Third Edition (ICSD-3).
- At Day -1, Epworth sleepiness scale (ESS) score >=10

All Participants:
- Participants consume excessive amounts, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated beverages per day.
- Participants have a moderate to severe substance use disorder.
- Participants have a risk of suicide according to endorsement of item 4 or 5 with Screening/Baseline visit C-SSRS or has made a suicide attempt in the previous 6 months.
- Participants have a lifetime history of major psychiatric disorder, such as bipolar disorder or schizophrenia.
- Participants experienced sleep wake cycle disturbance with external factors such as irregular work hours.

Both

Healthy Participants and Patients with Narcolepsy

investigational material(s)
Generic name etc : TAK-925
INN of investigational material : -
Therapeutic category code : 117 Psychotropic agents
Dosage and Administration for Investigational material : Cohorts A1-A6: TAK-925 (Dose Levels A1-A6); TAK-925, once daily for up to 7 days in healthy participants (or healthy elderly participants). Cohorts A3-A6 are additional optional cohorts and dose levels will be determined based on the data of safety, tolerability and PK data from previous cohorts.
Generic name etc : TAK-925
INN of investigational material : --
Therapeutic category code : 117 Psychotropic agents
Dosage and Administration for Investigational material : Cohorts B1-B4: TAK-925 (Dose Levels B1-B4); TAK-925, once daily for up to 7 days in patients with narcolepsy. Cohorts B3-B4 are additional optional cohorts and dose levels will be determined based on the data of safety, tolerability and PK data from previous cohorts.
Generic name etc : TAK-925
INN of investigational material : -
Therapeutic category code : 117 Psychotropic agents
Dosage and Administration for Investigational material : Cohort C1-C2: TAK-925 (Dose Levels C1-C2); TAK-925, once daily for up to 7 days in patients with narcolepsy. Cohort C2 is an additional optional cohort and dose level will be determined based on the data of safety, tolerability and PK data from previous cohorts.
Generic name etc : TAK-925
INN of investigational material : -
Therapeutic category code : 117 Psychotropic agents
Dosage and Administration for Investigational material : Cohort A'1-A'2: TAK-925 (Dose Levels A'1- A'2); TAK-925, single dose in healthy participants. Cohort A'2 is an additional optional cohort and dose level will be determined based on the data of safety, tolerability and PK data from previous cohorts.

control material(s)
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : Part A (Cohorts A1-A6): TAK-925 Placebo; TAK-925 Placebo, once daily for up to 7 days in healthy participants (or healthy elderly participants).
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : Part B (Cohorts B1-B4): TAK-925 Placebo; TAK-925 Placebo, once daily for up to 7 days in patients with narcolepsy.
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : Part C (Cohorts C1-C2): TAK-925 Placebo, once daily for up to 7 days in patients with narcolepsy.

safety
Number of Participants who Experience at Least One Treatment-Emergent Adverse Events (TEAE)
Timeframe; From the first dose of study drug up to 7 days after the last dose of study drug (up to Day 15)

pharmacokinetics
Parts A, B and C; Ceoi:Observed Plasma Concentration at the End of Infusion for TAK-925
Timeframe; Part A,Days 1,7:pre-infusion(inf),0.5,1, 1.5, 2, 4, 6, 8, 9 hours(h)post start of inf;0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 6, 10, 15 h post end of inf;Part B,C:Days 1,7:Pre-inf, 1, 2, 4, 6, 9 h post start of inf; 0.17, 0.5, 2, 6, 10, 15 h post end of inf

pharmacokinetics
Parts A, B and C; AUCtau: Area Under the Plasma Concentration-Time Curve during a Dosing Interval for TAK-925
Timeframe; Part A,Days 1,7:pre-infusion(inf),0.5,1, 1.5, 2, 4, 6, 8, 9 hours(h)post start of inf;0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 6, 10, 15 h post end of inf;Part B,C:Days 1,7:Pre-inf, 1, 2, 4, 6, 9 h post start of inf; 0.17, 0.5, 2, 6, 10, 15 h post end of inf

pharmacokinetics
Parts A, B and C; Rac (AUC): Accumulation Ratio Based on AUCtau for TAK-925
Timeframe; Part A,Days 1,7:pre-infusion(inf),0.5,1, 1.5, 2, 4, 6, 8, 9 hours(h)post start of inf;0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 6, 10, 15 h post end of inf;Part B,C:Days 1,7:Pre-inf, 1, 2, 4, 6, 9 h post start of inf; 0.17, 0.5, 2, 6, 10, 15 h post end of inf
Accumulation Ratio of AUC was calculated as AUCtau on Day 7 divided by AUCtau on Day 1.

efficacy
Parts B and C: Change from Baseline in Sleep Latency in the Maintenance of Wakefulness Test (MWT) at Days 1 and 7
Timeframe; Baseline,Day 1 and to Day 7
The MWT is a validated objective measure that is used to measure excessive daytime sleepiness in clinical studies. It has been used as a secondary outcome measure for excessive daytime sleepiness. The MWT evaluates a person's ability to remain awake under soporific conditions for a defined period of time. Wakefulness in this study was measured indirectly by time to fall asleep using MWT. In this study, four 40-minute (1 session) MWT assessments per day was administered on Baseline, Day 1 and Day 7. MWT sleep latency ranges from 0 to 40 minutes, with longer sleep latency indicating greater ability to stay awake.

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Nov. 16, 2018