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

Phase 1

Terminated

• Conditions: Healthy Volunteers
• Interventions: Drug: TAK-418; Drug: [18F]MNI-1054 (radiotracer)

• Registration Number: NCT04202497
• Lead Sponsor: Takeda

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.

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 Timeline

• Study First Submitted: 2019-12-12
• Study First Submitted QC: 2019-12-16
• Study First Posted: 2019-12-17
• Study Start: 2019-12-18
• Primary Completion: 2020-03-05
• Study Completion: 2020-03-19
• Results First Submitted: 2021-03-16
• Status Verified: 2021-07
• Results First Submitted QC: 2021-07-09
• Last Update Submitted: 2021-07-09
• Results First Posted: 2021-07-30
• Last Update Posted: 2021-07-30

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 7

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).

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
TAK-418 1.5 mg	TAK-418	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.
TAK-418 1.5 mg	[18F]MNI-1054 (radiotracer)	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.

Primary Outcome Measures

Name	Time	Method
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.
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
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'.
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'.
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'.
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.
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
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

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

Trial Locations

Locations (1)

Invicro, A Konica Minolta Company; 🇺🇸 New Haven, Connecticut, United States