A Study With [18F]MNI-1054 to Determine Lysine -Specific Demethylase 1A (LSD1) Brain Enzyme Occupancy of TAK-418 After Single-Dose Oral Administration in Healthy Participants

• Sponsor: Takeda (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT04202497
• Collaborator: (none)
• Enrollment: 7
• Location: 1
• Arm: 1
• Actual Duration (Months): 3
• Patients Per Site Per Month: 2.3

Study Details

Study Description

Brief Summary

The purpose of this study is to determine brain LSD1 enzyme occupancy and the relationship of occupancy to TAK-418 dose and plasma exposure after single oral dosing of TAK-418 in healthy participants using [18F]MNI-1054 positron emission tomography (PET) imaging.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: TAK-418; Drug: [18F]MNI-1054 (radiotracer)	Phase 1

Detailed Description

The drug being tested in this study is called TAK-418. TAK-418 is being tested to determine the relationship between brain LSD1 enzyme occupancy and TAK-418 plasma concentration. This study will utilize the PET radiotracer [18F]MNI-1054 to evaluate the brain LSD1 enzyme occupancy of TAK-418 after single dose oral administration in healthy adult participants.

The study will enroll approximately 16 participants. The TAK-418 starting dose is 1.5 mg, given on Day 1. Each participant will receive one dose of TAK-418 and up to 3 dynamic [18F]MNI-1054 PET scans to assess enzyme occupancy on baseline, Day 1 and Day 2 or 3 post-TAK-418 dosing.

This single center trial will be conducted in the United States. The overall time to participate in this study is 62 days. Participants will be followed up on Day 14 for follow-up safety assessments.

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Phase 1, Open-label, Positron Emission Tomography Study With [18F]MNI-1054 to Determine Lysine-Specific Demethylase 1A Brain Enzyme Occupancy of TAK-418 After Single-Dose Oral Administration in Healthy Subjects
• Actual Study Start Date: Dec 18, 2019
• Actual Primary Completion Date: Mar 5, 2020
• Actual Study Completion Date: Mar 19, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TAK-418 1.5 mg TAK-418 1.5 milligram (mg), orally, once on Day 1. Participants will also receive 10 millicurie (mCi) of [18F]MNI-1054 injection intravenously, prior to each PET scans on Day -1, Day 1, and either on Day 2 or 3. Dose levels for subsequent participants may vary based on available review of imaging and pharmacokinetics (PK) data.	Drug: TAK-418; TAK-418 orally.; Drug: [18F]MNI-1054 (radiotracer); [18F]MNI-1054 injection.

Outcome Measures

Primary Outcome Measures

1. Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 [Day -1]

   Enzyme binding parameter [Ki] was obtained from irreversible 2-tissue compartment model (mL/cm^3/min). Data is reported for the following brain regions: cerebellum, frontal lobe, hippocampus, occipital Lobe, pons, and striatum. Here, mL/cm^3/min signifies 'milliliter per cubic centimeter per minute'.

2. Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 [Day 1]

   Enzyme binding parameter [Ki] was obtained from irreversible 2-tissue compartment model (mL/cm^3/min). Data is reported for the following brain regions: cerebellum, frontal lobe, hippocampus, occipital Lobe, pons, and striatum. Here, mL/cm^3/min signifies 'milliliter per cubic centimeter per minute'.

3. Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 [Day 2]

   Enzyme binding parameter [Ki] was obtained from irreversible 2-tissue compartment model (mL/cm^3/min). Data is reported for the following brain regions: cerebellum, frontal lobe, hippocampus, occipital Lobe, pons, and striatum. Here, mL/cm^3/min signifies 'milliliter per cubic centimeter per minute'.

4. Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 [Day 1]

   Lysine-Specific Demethylase 1A (LSD1) enzyme occupancy (%) in region of interest (ROI) after a single dose of TAK-418 was obtained from the baseline and postdose Ki values as follows: occupancy (1st postdose) = 100*(Ki [baseline] - Ki [1st postdose]) / Ki (baseline). Data is reported for following brain regions: cerebellum, frontal lobe, hippocampus, occipital Lobe, pons, and striatum.

5. Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 [Day 2]

   LSD1 enzyme occupancy (%) in ROI after a single dose of TAK-418 was obtained from the baseline and postdose Ki values as follows: occupancy (2nd postdose) = 100*(Ki [baseline] - Ki [2nd postdose]) / Ki (baseline). Data is reported for following brain regions: cerebellum, frontal lobe, hippocampus, occipital Lobe, pons, and striatum.

6. Cmax: Maximum Observed Plasma Concentration for TAK-418 [Day 1: pre-dose and at multiple time points (up to 3 hours) post-dose, immediately before and after the Day 1 PET scan, and within 30 minutes before and 30 minutes after Day 2 or 3 PET scan]

7. AUClast: Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration for TAK-418 [Day 1: pre-dose and at multiple time points (up to 3 hours) post-dose, immediately before and after the Day 1 PET scan, and within 30 minutes before and 30 minutes after Day 2 or 3 PET scan]

8. AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-418 [Day 1: pre-dose and at multiple time points (up to 3 hours) post-dose, immediately before and after the Day 1 PET scan, and within 30 minutes before and 30 minutes after Day 2 or 3 PET scan]

Secondary Outcome Measures

1. ED50 PET Enzyme Occupancy [Days 1 to 2]

   The relationship between PET enzyme occupancy and TAK-418 dose level was investigated using an Emax model containing the regression parameters maximal target occupancy (Emax) and dose that gives 50 percent (%) of Emax (ED50). ED50 values are reported for following brain regions: cerebellum, frontal lobe, hippocampus, occipital Lobe, pons, and striatum. The data tabulated are the estimated value and confidence intervals of the ED50 value derived from an Emax model fit across all data points from all arms. ED50 is the dose at which 50% enzyme occupancy is expected.

2. Number of Participants Reporting One or More Adverse Events (AEs) and Serious Adverse Events (SAEs) [From first dose of [18F]MNI-1054 radiotracer injection up to Day 14]

3. Number of Participants With Clinically Significant Abnormal Laboratory Values [From first dose of [18F]MNI-1054 radiotracer injection up to Day 14]

4. Number of Participants With Clinically Significant Abnormal Vital Signs [From first dose of [18F]MNI-1054 radiotracer injection up to Day 14]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. The participant must have a body mass index (BMI) greater than or equal to (>=) 18.5 and less than or equal to (<=) 30.0 kilogram per square meter (kg/m^2) at the screening visit.

2. The participant must be a current nonsmoker at screening as demonstrated by negative cotinine test.

3. The participant has adequate circulation to both hands for safe placement of arterial lines (as determined by Allen's test).

Exclusion Criteria:

1. Has a known hypersensitivity to any component of the formulation of TAK-418 or related compounds, including [18F]MNI-1054.

2. The participant has a positive alcohol or drug screen.

3. The participant has a history of alcohol consumption exceeding 2 standard drinks per day on average (1 glass is approximately equivalent to the following: beer [354 milliliter (mL)/12 ounce (oz)], wine [118 mL/4 oz], or distilled spirits [29.5 mL/1 oz] per day).

4. The participant consumes 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.

5. The participant has a substance abuse disorder.

6. The participant cannot tolerate venipuncture or has poor venous access that would cause difficulty in collecting blood samples.

7. The participant has contraindications to undergoing magnetic resonance imaging (MRI) examination including but not limited to implants, such as implanted cardiac pacemakers or defibrillators, insulin pumps, cochlear implants, metallic ocular foreign body, implanted neural stimulators, central nervous system aneurysm clips, and other medical implants that have not been certified for MRI, or history of claustrophobia in MRI.

8. The participant has clinically significant abnormal findings on brain MRI scan that in the opinion of the investigator may interfere with the interpretation of the PET imaging.

9. The participant has experienced an acute illness within 10 days before the screening visit.

10. The participant has a risk of suicide according to the investigator's clinical judgement per the Columbia-Suicide Severity Rating Scale at screening or has made a suicide attempt in the 12 months before screening.

11. The participant has luteinizing hormone, follicle stimulating hormone (FSH), or estradiol levels that are clinically abnormal.

12. The participant has existing skin rashes that can be diagnosed as dermatitis.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Invicro, A Konica Minolta Company	New Haven	Connecticut	United States	06510

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director, Takeda

Study Documents (Full-Text)

• Study Protocol - Mar 5, 2020
• Statistical Analysis Plan - Feb 19, 2020

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT04202497
• Other Study ID Numbers: TAK-418-0004; U1111-1242-8485
• First Posted: Dec 17, 2019
• Last Update Posted: Jul 30, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Takeda: Drug Therapy

Study Results

Participant Flow

Recruitment Details

Participants took part in the study at 1 investigative site in the United States from 18 December 2019 to 19 March 2020.

Pre-assignment Detail

Healthy participants were enrolled in this study to receive up to 10 millicurie [mCi]) of [18F]MNI-1054 for 1 positron emission tomography (PET) Scan on Day -1 (Baseline Scan), and then eligible participants entered into 1 of 3 treatment groups in the Treatment Period to receive 10 mCi of [18F]MNI-1054 for 2 PET scans after single dose of TAK-418 1.5 milligram (mg), 10 mg, or 30 mg on Day 1 and either Day 2 or 3. Study was prematurely terminated because of administrative reasons.

Arm/Group Title	Baseline [18F]MNI-1054	TAK-418 1.5 mg	TAK-418 10 mg	TAK-418 30 mg
Arm/Group Description	[18F]MNI-1054 up to 10 mCi, PET radiotracer injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 1.5 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 10 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 30 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).
Period Title: Baseline Scan (Day-1)
STARTED	7	0	0	0
COMPLETED	6	0	0	0
NOT COMPLETED	1	0	0	0
Period Title: Baseline Scan (Day-1)
STARTED	0	2	2	2
COMPLETED	0	2	2	2
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Baseline [18F]MNI-1054
Arm/Group Description	[18F]MNI-1054 up to 10 mCi, PET radiotracer injection, intravenously, prior to PET scan on Day -1 (Baseline scan).
Overall Participants	7
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.7 (8.04)
Sex: Female, Male (Count of Participants)
Female	2 28.6%
Male	5 71.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 28.6%
Not Hispanic or Latino	5 71.4%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 42.9%
White	3 42.9%
More than one race	1 14.3%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	7 100%
Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	26.81 (2.594)

Outcome Measures

1. Primary Outcome

Title	Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1
Description	Enzyme binding parameter [Ki] was obtained from irreversible 2-tissue compartment model (mL/cm^3/min). Data is reported for the following brain regions: cerebellum, frontal lobe, hippocampus, occipital Lobe, pons, and striatum. Here, mL/cm^3/min signifies 'milliliter per cubic centimeter per minute'.
Time Frame	Day -1

Outcome Measure Data

Analysis Population Description

The pharmacodynamics (PD) set included all participants who received TAK-418 and have at least 1 analyzable PET Scan following TAK-418.

Arm/Group Title	TAK-418 1.5 mg	TAK-418 10 mg	TAK-418 30 mg
Arm/Group Description	TAK-418 1.5 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 10 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 30 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).
Measure Participants	2	2	2
Cerebellum	0.03405 (0.002192)	0.03515 (0.005869)	0.03560 (0.003394)
Frontal Lobe	0.01930 (0.004525)	0.02070 (0.004384)	0.02140 (0.002263)
Hippocampus	0.01900 (0.000141)	0.01935 (0.005303)	0.01960 (0.001414)
Occipital Lobe	0.02140 (0.002404)	0.02225 (0.003606)	0.02365 (0.002616)
Pons	0.01685 (0.000071)	0.01855 (0.004313)	0.01870 (0.004667)
Striatum	0.01575 (0.004031)	0.01930 (0.004950)	0.01995 (0.003323)

2. Primary Outcome

Title	Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1
Description	Enzyme binding parameter [Ki] was obtained from irreversible 2-tissue compartment model (mL/cm^3/min). Data is reported for the following brain regions: cerebellum, frontal lobe, hippocampus, occipital Lobe, pons, and striatum. Here, mL/cm^3/min signifies 'milliliter per cubic centimeter per minute'.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

The PD set included all participants who received TAK-418 and have at least 1 analyzable PET Scan following TAK-418.

Arm/Group Title	TAK-418 1.5 mg	TAK-418 10 mg	TAK-418 30 mg
Arm/Group Description	TAK-418 1.5 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 10 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 30 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).
Measure Participants	2	2	2
Cerebellum	0.01020 (0.003536)	0.00405 (0.000495)	0.00760 (0.000849)
Frontal Lobe	0.01295 (0.001768)	0.00980 (0.001697)	0.01435 (0.002333)
Hippocampus	0.01260 (0.000990)	0.00635 (0.004031)	0.01240 (0.000000)
Occipital Lobe	0.01245 (0.002758)	0.00910 (0.000990)	0.01430 (0.001556)
Pons	0.01265 (0.006718)	0.00970 (0.000707)	0.01515 (0.000212)
Striatum	0.01185 (0.002192)	0.00785 (0.000495)	0.01365 (0.000071)

3. Primary Outcome

Title	Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2
Description	Enzyme binding parameter [Ki] was obtained from irreversible 2-tissue compartment model (mL/cm^3/min). Data is reported for the following brain regions: cerebellum, frontal lobe, hippocampus, occipital Lobe, pons, and striatum. Here, mL/cm^3/min signifies 'milliliter per cubic centimeter per minute'.
Time Frame	Day 2

Outcome Measure Data

Analysis Population Description

The PD set included all participants who received TAK-418 and have at least 1 analyzable PET Scan following TAK-418.

Arm/Group Title	TAK-418 1.5 mg	TAK-418 10 mg	TAK-418 30 mg
Arm/Group Description	TAK-418 1.5 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 10 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 30 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).
Measure Participants	2	2	2
Cerebellum	0.01865 (0.004455)	0.00875 (0.001485)	0.00690 (0.000566)
Frontal Lobe	0.01610 (0.003111)	0.01020 (0.001838)	0.01130 (0.002404)
Hippocampus	0.01650 (0.003960)	0.00865 (0.001061)	0.01015 (0.000919)
Occipital Lobe	0.01665 (0.003889)	0.01045 (0.002192)	0.01180 (0.001980)
Pons	0.01265 (0.004738)	0.01045 (0.002475)	0.00985 (0.000636)
Striatum	0.01410 (0.004667)	0.00915 (0.003182)	0.00965 (0.001344)

4. Primary Outcome

Title	Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1
Description	Lysine-Specific Demethylase 1A (LSD1) enzyme occupancy (%) in region of interest (ROI) after a single dose of TAK-418 was obtained from the baseline and postdose Ki values as follows: occupancy (1st postdose) = 100*(Ki [baseline] - Ki [1st postdose]) / Ki (baseline). Data is reported for following brain regions: cerebellum, frontal lobe, hippocampus, occipital Lobe, pons, and striatum.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

The PD set included all participants who received TAK-418 and have at least 1 analyzable PET Scan following TAK-418.

Arm/Group Title	TAK-418 1.5 mg	TAK-418 10 mg	TAK-418 30 mg
Arm/Group Description	TAK-418 1.5 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 10 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 30 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).
Measure Participants	2	2	2
Cerebellum	68.5 (10.61)	87.0 (1.41)	79.5 (2.12)
Frontal Lobe	19.5 (10.61)	44.0 (9.90)	38.0 (9.90)
Hippocampus	33.0 (5.66)	59.5 (26.16)	40.0 (0.00)
Occipital Lobe	37.0 (14.14)	54.5 (4.95)	43.5 (6.36)
Pons	25.0 (39.60)	37.5 (4.95)	31.0 (1.41)
Striatum	8.0 (16.97)	50.5 (3.54)	39.0 (0.00)

5. Primary Outcome

Title	Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2
Description	LSD1 enzyme occupancy (%) in ROI after a single dose of TAK-418 was obtained from the baseline and postdose Ki values as follows: occupancy (2nd postdose) = 100*(Ki [baseline] - Ki [2nd postdose]) / Ki (baseline). Data is reported for following brain regions: cerebellum, frontal lobe, hippocampus, occipital Lobe, pons, and striatum.
Time Frame	Day 2

Outcome Measure Data

Analysis Population Description

The PD set included all participants who received TAK-418 and have at least 1 analyzable PET Scan following TAK-418.

Arm/Group Title	TAK-418 1.5 mg	TAK-418 10 mg	TAK-418 30 mg
Arm/Group Description	TAK-418 1.5 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 10 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 30 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).
Measure Participants	2	2	2
Cerebellum	42.5 (13.44)	71.5 (4.95)	82.0 (1.41)
Frontal Lobe	0.5 (19.09)	42.0 (9.90)	51.0 (9.90)
Hippocampus	13.0 (21.21)	44.5 (6.36)	50.5 (4.95)
Occipital Lobe	16.0 (19.80)	47.0 (11.31)	53.5 (7.78)
Pons	25.0 (28.28)	32.5 (16.26)	55.0 (2.83)
Striatum	-9.0 (35.36)	42.0 (19.80)	56.5 (6.36)

6. Primary Outcome

Title	Cmax: Maximum Observed Plasma Concentration for TAK-418
Time Frame	Day 1: pre-dose and at multiple time points (up to 3 hours) post-dose, immediately before and after the Day 1 PET scan, and within 30 minutes before and 30 minutes after Day 2 or 3 PET scan

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) set included all participants from the safety set who received TAK-418 and had at least 1 measurable plasma concentration for TAK-418.

Arm/Group Title	TAK-418 1.5 mg	TAK-418 10 mg	TAK-418 30 mg
Arm/Group Description	TAK-418 1.5 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 10 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 30 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).
Measure Participants	2	2	2
Median (Full Range) [nanogram per milliliter (ng/mL)]	4.420	43.80	130.5

7. Primary Outcome

Title	AUClast: Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration for TAK-418
Time Frame	Day 1: pre-dose and at multiple time points (up to 3 hours) post-dose, immediately before and after the Day 1 PET scan, and within 30 minutes before and 30 minutes after Day 2 or 3 PET scan

Outcome Measure Data

Analysis Population Description

The PK set included all participants from the safety set who received TAK-418 and had at least 1 measurable plasma concentration for TAK-418.

Arm/Group Title	TAK-418 1.5 mg	TAK-418 10 mg	TAK-418 30 mg
Arm/Group Description	TAK-418 1.5 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 10 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 30 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).
Measure Participants	2	2	2
Median (Full Range) [hour*nanogram per milliliter(h*ng/mL)]	22.40	227.5	812.0

8. Primary Outcome

Title	AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-418
Time Frame	Day 1: pre-dose and at multiple time points (up to 3 hours) post-dose, immediately before and after the Day 1 PET scan, and within 30 minutes before and 30 minutes after Day 2 or 3 PET scan

Outcome Measure Data

Analysis Population Description

The PK set included all participants from the safety set who received TAK-418 and had at least 1 measurable plasma concentration for TAK-418. Here "overall number of participants" analyzed are those who were evaluable for this outcome measure.

Arm/Group Title	TAK-418 1.5 mg	TAK-418 10 mg	TAK-418 30 mg
Arm/Group Description	TAK-418 1.5 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 10 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 30 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).
Measure Participants	1	2	2
Median (Full Range) [h*ng/mL]	25.60	230.0	817.0

9. Secondary Outcome

Title	ED50 PET Enzyme Occupancy
Description	The relationship between PET enzyme occupancy and TAK-418 dose level was investigated using an Emax model containing the regression parameters maximal target occupancy (Emax) and dose that gives 50 percent (%) of Emax (ED50). ED50 values are reported for following brain regions: cerebellum, frontal lobe, hippocampus, occipital Lobe, pons, and striatum. The data tabulated are the estimated value and confidence intervals of the ED50 value derived from an Emax model fit across all data points from all arms. ED50 is the dose at which 50% enzyme occupancy is expected.
Time Frame	Days 1 to 2

Outcome Measure Data

Analysis Population Description

The PD set included all participants who received TAK-418 and have at least 1 analyzable PET Scan following TAK-418

Arm/Group Title	TAK-418
Arm/Group Description	TAK-418 1.5 mg, 10 mg, or 30 mg capsules, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).
Measure Participants	6
Cerebellum	0.756
Frontal Lobe	4.328
Hippocampus	1.639
Occipital Lobe	1.416
Pons	1.112
Striatum	7.496

10. Secondary Outcome

Title	Number of Participants Reporting One or More Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame	From first dose of [18F]MNI-1054 radiotracer injection up to Day 14

Outcome Measure Data

Analysis Population Description

The safety set included all enrolled participants who received at least 1 dose of [18F]MNI-1054 or TAK-418

Arm/Group Title	Baseline [18F]MNI-1054	TAK-418 1.5 mg	TAK-418 10 mg	TAK-418 30 mg
Arm/Group Description	[18F]MNI-1054 up to 10 mCi, PET radiotracer injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 1.5 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 10 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 30 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).
Measure Participants	7	2	2	2
AEs	1 14.3%	0 NaN	1 NaN	2 NaN
SAEs	0 0%	0 NaN	0 NaN	0 NaN

11. Secondary Outcome

Title	Number of Participants With Clinically Significant Abnormal Laboratory Values
Time Frame	From first dose of [18F]MNI-1054 radiotracer injection up to Day 14

Outcome Measure Data

Analysis Population Description

The safety set included all enrolled participants who received at least 1 dose of [18F]MNI-1054 or TAK-418

Arm/Group Title	Baseline [18F]MNI-1054	TAK-418 1.5 mg	TAK-418 10 mg	TAK-418 30 mg
Arm/Group Description	[18F]MNI-1054 up to 10 mCi, PET radiotracer injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 1.5 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 10 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 30 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).
Measure Participants	7	2	2	2
Count of Participants [Participants]	0 0%	0 NaN	0 NaN	0 NaN

12. Secondary Outcome

Title	Number of Participants With Clinically Significant Abnormal Vital Signs
Time Frame	From first dose of [18F]MNI-1054 radiotracer injection up to Day 14

Outcome Measure Data

Analysis Population Description

The safety set included all enrolled participants who received at least 1 dose of [18F]MNI-1054 or TAK-418.

Arm/Group Title	Baseline [18F]MNI-1054	TAK-418 1.5 mg	TAK-418 10 mg	TAK-418 30 mg
Arm/Group Description	[18F]MNI-1054 up to 10 mCi, PET radiotracer injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 1.5 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 10 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).	TAK-418 30 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).
Measure Participants	7	2	2	2
Count of Participants [Participants]	0 0%	0 NaN	0 NaN	0 NaN

Adverse Events

Time Frame	Treatment-emergent adverse events are adverse events that started after the first administration of [18F]MNI-1054 radiotracer injection until the Day 14
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Baseline [18F]MNI-1054		TAK-418 1.5 mg		TAK-418 10 mg		TAK-418 30 mg
Arm/Group Description	[18F]MNI-1054 up to 10 mCi, PET radiotracer injection, intravenously, prior to PET scan on Day -1 (Baseline scan).		TAK-418 1.5 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).		TAK-418 10 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).		TAK-418 30 mg, capsule, orally, once on Day 1 and up to 10 mCi of [18F]MNI-1054 PET radiotracer injection, intravenously, prior to each PET scans on Day 1, and either on Day 2 or 3 post-TAK-418 dose in the Treatment Period. All participants received [18F]MNI-1054 up to 10 mCi, injection, intravenously, prior to PET scan on Day -1 (Baseline scan).
All Cause Mortality
	Baseline [18F]MNI-1054		TAK-418 1.5 mg		TAK-418 10 mg		TAK-418 30 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/2 (0%)		0/2 (0%)		0/2 (0%)
Serious Adverse Events
	Baseline [18F]MNI-1054		TAK-418 1.5 mg		TAK-418 10 mg		TAK-418 30 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/2 (0%)		0/2 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	Baseline [18F]MNI-1054		TAK-418 1.5 mg		TAK-418 10 mg		TAK-418 30 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/7 (14.3%)		0/2 (0%)		1/2 (50%)		2/2 (100%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/7 (0%)		0/2 (0%)		0/2 (0%)		2/2 (100%)
Nervous system disorders
Somnolence	0/7 (0%)		0/2 (0%)		1/2 (50%)		0/2 (0%)
Skin and subcutaneous tissue disorders
Ecchymosis	0/7 (0%)		0/2 (0%)		0/2 (0%)		2/2 (100%)
Dermatitis contact	1/7 (14.3%)		0/2 (0%)		0/2 (0%)		0/2 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.