A Study to Investigate Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of JNJ-63733657 in Healthy Subjects and Subjects With Alzheimer's Disease

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and tolerability of JNJ-63733657 following single ascending intravenous (IV) dose administration in healthy subjects (Part 1) and multiple ascending IV dose administrations in subjects with prodromal or mild Alzheimer's disease (AD) (Part 2).

Official Title
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A 2-Part Randomized, Placebo-Controlled, Double-Blind, Single and Multiple Ascending Dose Study to Investigate Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of JNJ-63733657 in Healthy Subjects and Subjects With Alzheimer's Disease

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: JNJ-63733657
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: General Inclusion Criteria: Body mass index (BMI) between 18 and 35 kilogram per meter square (kg/m^2), inclusive (BMI = weight/height^2) and body weight greater than 40 kilogram (kg) but less than 110 kg at screening Women must not be of childbearing potential Specific Inclusion Criteria Part 2: Each potential subject enrolled in Part 2 must satisfy all of the following specific criteria in addition to the general criteria to be enrolled in the study: Clinical Dementia Rating Scale (CDR) global rating score of 0.5 or 1.0 at screening Must have a reliable informant (example, relative, partner, friend) Must have cerebrospinal fluid (CSF) finding consistent with Alzheimer's disease (AD) pathology Exclusion Criteria: General Exclusion Criteria Any potential subject who meets any of the following criteria will be excluded from participating in the study: History of or current liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic (including but not limited to neurodegenerative disease (excluding AD for Part 2) [example, Parkinson's disease], seizure disorders, transient ischemic attacks, etc.), hematologic (including coagulation disorders), rheumatologic, psychiatric, or metabolic disturbances, any inflammatory illness or any other illness that the Investigator considers should exclude the subject Relevant history of or current neurological disease (other than prodromal AD or mild AD for Part 2), which in the opinion of the investigator may make interpretation of possible new neurological signs or symptoms difficult History of human immunodeficiency virus (HIV) antibody positive, or tests positive for HIV at Screening (per screening evaluations) History of hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-Hepatitis C virus [HCV]) positive, or other clinically active liver disease, or tests positive for HBsAg or anti-HCV at screening (per screening evaluations) Specific Exclusion Criteria Part 1 - Mini-Mental State Examination (MMSE) score less than or equal to (<=) 27 at screening Specific Exclusion Criteria Part 2 - Evidence of brain disease, other than AD, that could explain the cognitive deficit (including, but not limited to, vascular encephalopathy or strokes, as imaged by cerebral Magnetic resonance imaging (MRI)

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAD (Part 1): Healthy Subjects<br>In Part 1, single ascending intravenous (IV) doses of JNJ-63733657 or placebo will be administered to sequential cohorts (Cohorts 1 to 5) of healthy subjects on Day 1. The progression to the next (higher) dose level is dependent on acceptable safety and tolerability profile of JNJ-63733657 obtained after dose administration of the current dose level. Here, SAD indicates single ascending dose. | Drug: JNJ-63733657<br>* Subjects will receive single (Part 1) or multiple (Part 2) ascending dose levels of JNJ-63733657 intravenously.<br>Drug: Placebo<br>* Subjects will receive matching placebo intravenously.<br>|
| Experimental: MAD (Part 2): Subjects With Alzheimer's Disease (AD)<br>In Part 2, multiple ascending IV doses of JNJ-63733657 or placebo will be evaluated at three dose levels in sequential cohorts in subjects with prodromal or mild AD; 3 doses will be administered over a period of 8 weeks (Day 1, Day 29, Day 57). The starting dose will be decided based on the data from Part 1. Escalations will be done based on safety and tolerability similar to Part 1. Doses will not exceed those tested in Part 1. Here, MAD indicates multiple ascending dose. | Drug: JNJ-63733657<br>* Subjects will receive single (Part 1) or multiple (Part 2) ascending dose levels of JNJ-63733657 intravenously.<br>Drug: Placebo<br>* Subjects will receive matching placebo intravenously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Single Ascending Dose (SAD) (Part 1): Number of Subjects With Adverse Events as a Measure of Safety and Tolerability of JNJ-63733657 | An adverse event is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. | Up to Day 106 | 
| Multiple Ascending Dose (MAD) (Part 2): Number of Subjects With Adverse Events as a Measure of Safety and Tolerability of JNJ-63733657 | An adverse event is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. | Up to Day 162 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SAD (Part 1) and MAD (Part 2): Maximum Observed Serum Concentration (Cmax) of JNJ-63733657 | The Cmax is the maximum observed serum concentration of drug JNJ-63733657. | Up to Day 106 (SAD) and up to Day 162 (MAD) | 
| SAD (Part 1) and MAD (Part 2): Time to Reach Maximum Observed Serum Concentration (Tmax) of JNJ-63733657 | Tmax is defined as time to reach the maximum observed serum JNJ-63733657 concentration. | Up to Day 106 (SAD) and up to Day 162 (MAD) | 
| SAD (Part 1) and MAD (Part 2): Area Under the Serum Concentration-time Curve From Time Zero to Time of the Last Observed Quantifiable Concentration (AUC [0-Last]) of JNJ-63733657 | AUC (0-last) is defined as area under the serum JNJ-63733657 concentration-time curve from time 0 to time of the last observed quantifiable concentration. | Up to Day 106 (SAD) and up to Day 162 (MAD) | 
| SAD (Part 1) and MAD (Part 2): Area Under the Serum Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity]) of JNJ-63733657 | AUC (0-infinity) is defined as area under the serum JNJ-63733657 concentration-time curve from time 0 to infinite time. | Up to Day 106 (SAD) and up to Day 162 (MAD) | 
| MAD (Part 2): Area Under the Serum JNJ-63733657 Concentration-time Curve During a Dosing Interval (t) (AUC tau) | AUC tau is defined as area under the serum JNJ-63733657 concentration-time curve during a dosing interval (tau). | Up to Day 85 (MAD) | 
| MAD (Part 2): Accumulation Ratio (R) | R is obtained by dividing AUC of JNJ-63733657 at two different time points. | Up to Day 162 (MAD) | 
| SAD (Part 1) and MAD (Part 2): Total Systemic Clearance (CL) of JNJ-63733657 | CL is a quantitative measure of the rate at which JNJ-63733657 is removed from the body. The total systemic clearance after intravenous dose is estimated by dividing the total administered dose by the plasma Area Under the Serum Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]). | Up to Day 106 (SAD) and up to Day 162 (MAD) | 
| SAD (Part 1) and MAD (Part 2): Volume of Distribution at Steady-State (Vss) of JNJ-63733657 | Vss is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state Vss is the apparent volume of distribution at steady-state which is estimated by (D/AUC[0-infinity])*(AUMC[0-infinity])/AUC[0-infinity]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the serum concentration-time curve from time zero to infinite time. | Up to Day 106 (SAD) and up to Day 162 (MAD) | 
| SAD (Part 1) and MAD (Part 2): Terminal Half-Life(t[1/2]) of JNJ-63733657 | t(1/2) is associated with the terminal slope (lambda [z]) of the semi-logarithmic drug concentration-time curve, calculated as 0.693/lambda(z). | Up to Day 106 (SAD) and up to Day 162 (MAD) | 
| SAD (Part 1) and MAD (Part 2): JNJ-63733657 Concentration in Cerebrospinal Fluid (CSF) | CSF concentration assessment will be done to characterize the pharmacokinetics (PK) to estimate CSF concentration of JNJ-63733657. | Up to Day 57 (SAD) and up to Day 148 (MAD) | 
| SAD (Part 1) and MAD (Part 2): Number of Subjects With Anti-JNJ-6373365 Antibodies as a Measure of Immunogenicity | Number of subjects with Anti-JNJ-63733657 antibodies will be evaluated in serum samples and potential CSF samples. | Up to Day 106 (SAD) and up to Day 162 (MAD) | 
| SAD (Part 1) and MAD (Part 2): Percent Change From Baseline in Total, Free, and Bound tau Biomarker Fragments in CSF | Percent change from baseline in total, free, and bound tau (phosphorylation site) biomarker fragments in CSF will be evaluated to assess the effect of JNJ-63733657. | Up to Day 106 (SAD) and up to Day 162 (MAD) |