This study is testing a new investigational drug called 8M2D to learn whether it is safe and well-tolerated in humans. 8M2D has not previously been given to people. Hypothesis: Researchers believe that 8M2D can be administered safely to healthy adults and to people with early Alzheimer's disease, and that it may reduce levels of amyloid beta. Amyloid beta is a protein that builds up in the brains of people with Alzheimer's disease and is thought to contribute to its progression. The study will be conducted in three parts. In the first two parts, healthy volunteers will receive either a single dose or multiple doses of 8M2D so researchers can understand how the drug moves through the body and whether it causes any side effects. In the third part, a small group of people with early Alzheimer's disease will receive multiple doses so researchers can also begin to assess whether the drug has any effect on amyloid beta levels. Doses will be increased gradually and carefully. An independent safety board will review safety information before any dose increase is allowed. The information gathered in this study will be used to identify the appropriate dose of 8M2D and to help design future studies in people with Alzheimer's disease.
Trial Rationale: This is a three-part Phase 1a/b clinical trial. Phase Ia is a first-in-human (FIH), 2-part (Part I \[SAD\] and Part II \[MAD\]) clinical trial designed to evaluate the safety, tolerability, pharmacokinetics (PK), and exploratory immunogenicity of single and multiple doses of 8M2D in healthy participants. Phase Ib will consist of Part III (Alzheimer's Disease \[AD\]), designed to evaluate the safety, tolerability, PK, exploratory immunogenicity, and pharmacodynamics (PD) of multiple doses of 8M2D in participants with early AD. Data from this trial will be used to identify doses of 8M2D that show safety and tolerability and PD effects on amyloid beta (Aβ), to aid in the design of future trials in patients with AD. Prior to this trial, 8M2D has not been administered to humans. Safety and tolerability evaluations will be conducted over a range of single and multiple doses of 8M2D and dose escalation will not proceed until safety and tolerability data and PK parameters from previous doses have been reviewed by an independent Data and Safety Monitoring Board (DSMB). This trial will aim to assess a maximum-tolerated dose (MTD), or a maximum feasible dose (based on tolerability of the subcutaneous \[SC\] injections), or a maximum pharmacologically active dose, based on safety, tolerability and PK data as well as on model-based prediction of the anticipated Aβ lowering. The data generated in this trial will be used to help design subsequent clinical trials in participants with early AD.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
54
8M2D administered by subcutaneous injection. Evaluated across single ascending doses (Part I) and multiple ascending doses (Part II) in healthy participants, and as multiple doses in participants with early Alzheimer's disease (Part III).
Matching placebo administered by subcutaneous injection in healthy participants across the single ascending dose (Part I) and multiple ascending dose (Part II) parts of the study.
Number of participants reporting treatment-emergent adverse events
A treatment-emergent adverse event is defined as any adverse event that has an onset on or after the first dose of the trial medication, or any pre-existing condition that has worsened on or after the first dose of the trial intervention.
Time frame: Baseline to Day 44
Number of participants reporting treatment-emergent adverse events that require discontinuation of therapy due to intolerable side effects
Evaluation of the number of participants withdrawn from study medication due to treatment-emergent adverse events.
Time frame: Baseline to Day 14
Number of participants reporting injection site reactions
Evaluation of skin reactions at the injection site, including pain, itching, and swelling or redness around the injection site.
Time frame: Baseline to Day 22
Number of participants demonstrating abnormal laboratory findings
Evaluation of laboratory results outside the documented normal range as defined by the clinical laboratory.
Time frame: Baseline to Day 14
Number of participants demonstrating abnormal vital signs
Evaluation of absolute vital sign value and the changes from baseline that are outside the normal range.
Time frame: Baseline to Day 22
Number of participants demonstrating abnormal vital electrocardiogram (ECG) parameters
Evaluation of 12-lead ECG parameters.
Time frame: Baseline to Day 15
Number of participants demonstrating adverse changes in physical and/or neurologic examinations
Evaluation of the physical and/or neurological examinations conducted by site clinicians during the study period.
Time frame: Baseline to Day 22
Number of participants reporting changes in Columbia-Suicide Severity Rating Scale (C-SSRS) from baseline
The C-SSRS is a suicidal ideation and behavior rating scale to evaluate suicide risk. The total score ranges from 0 (no ideation is present) to 5 (active suicidal ideation with specific plan and intent).
Time frame: Baseline to Day 22
Maximum observed concentration (Cmax) of 8M2D
Maximum concentration of 8M2D, determined directly from individual concentration-time data determined through plasma and CSF analysis.
Time frame: Baseline to Day 14
Time to maximum observed concentration (tmax) of 8M2D
Time of the maximum concentration of 8M2D determined through plasma and CSF analysis.
Time frame: Baseline to Day 14
Area under the concentration-time curve from time 0 to the last quantifiable concentration (AUC-last) of 8M2D
Evaluated from time-zero to the time of the last quantifiable concentration of 8M2D determined through plasma and CSF analysis.
Time frame: Baseline to Day 14
Terminal phase half-life (t1/2)
The observed terminal half-life of 8M2D determined through plasma and CSF analysis.
Time frame: Baseline to Day 14
Area under the concentration-time curve from time 0 to infinity (AUC-inf)
Area under the concentration-time curve from time-zero extrapolated to infinity.
Time frame: Baseline to Day 14
Assessment of changes from baseline after 14 days of dosing in plasma and CSF biomarkers of AD [such as Aβ42, Aβ40, p-tau217, and np-tau217
Evaluation of biomarkers of AD through plasma and CSF collected from all participants in Part III (AD) of the study.
Time frame: Baseline to Day 14
Assessment of the presence of anti-8M2D antibody in participants of all cohorts.
Evaluation of anti-8M2D antibody presence in blood samples collected from all participants.
Time frame: Baseline to Day 22
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