Phase 1 Study to Evaluate the Safety and Tolerability of 8M2D in Healthy People and Alzheimer's Patients

A Phase Ia (SAD/MAD), Randomized, Double-Blind, Placebo-Controlled Trial and Phase Ib Open-Label Trial to Evaluate Safety, Tolerability, PK, and Exploratory Immunogenicity of Single and Multiple Doses of 8M2D in Healthy Participants and Early AD Participants.

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.

Inclusion Criteria:

Part I (Single Ascending Dose) and Part II (Multiple Ascending Dose):

1. Voluntarily consents to participate in this trial and provides written informed consent before the start of any trial assessments.

2. Healthy male and female adults, 18 and 55 years of age (inclusive).

3. Participants with a body mass index (BMI) ≥ 18 and ≤ 32 kg/m2 (inclusive) and weigh a minimum of 50 kg.

4. Participants with a normal 12-lead ECG at Screening.

5. Participant has normal renal function.

6. Females participants must meet one of the following criteria:

   a. Females must either be of non-childbearing potential, or if of childbearing potential, must agree to use contraceptives throughout the study period and have a negative pregnancy test at both Screening and Check-in (Day -1).

7. Males with a sexual partner who is a female of childbearing potential must be surgically sterile, or agree to use condoms with spermicide or abstain from sexual intercourse, starting from Screening until 90 days after the last dose of the trial medication.

8. Participant is willing and able to complete all trial assessments in compliance with the protocol and is able to remain in the inpatient treatment unit for the entire duration of the confinement period and return for outpatient visits.

Part III Alzheimer's Disease:

1. Participant is able to provide written informed consent prior to the performance of any trial -specific procedures.

2. Male or female participants with early Alzheimer's disease between 55 and 80 years of age (inclusive) in good health as determined by the Investigator.

3. Participants with a BMI of ≥ 18.0 and ≤ 32.0 kg/m2 (inclusive) and weigh a minimum of 50 kg.

4. Participants with a 12-lead ECG at screening which, in the opinion of the Investigator, has no abnormalities that compromise participant's safety in this study.

5. Females participants must meet one of the following criteria:

   a. Females must either be of non-childbearing potential, or if of childbearing potential, must agree to use contraceptives throughout the study period and have a negative pregnancy test at both Screening and Check-in (Day -1).

6. Males with a sexual partner who is a female of childbearing potential must be surgically sterile, or agree to use condoms with spermicide or abstain from sexual intercourse, starting from Screening until 90 days after the last dose of the trial medication.

7. Participant is willing and able to complete all trial assessments in compliance with the protocol and is able to remain in the inpatient treatment unit for the entire duration of the confinement period and return for outpatient visits.

8. Participant meets the diagnostic criteria of mild cognitive impairment (MCI) of probable Alzheimer's disease consistent with National Institute On Aging - Alzheimer's Association (NIA-AA) research framework.

9. Participant with a qualifying amyloid score.

10. Participant with a Mini-Mental State Examination (MMSE) score between 20 and 28 inclusive at screening and baseline.

Exclusion Criteria:

Part I (Single Ascending Dose) and Part II (Multiple Ascending Dose):

1. History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, or psychiatric disease or any other condition that, in the opinion of the Investigator, would jeopardize the safety of the participant or the validity of the trial results.
2. Participant has abnormal laboratory values detected at Screening or on clinic admission (Day -1) that suggest a clinically significant underlying disease.
3. Participant who shows evidence of suicidal ideation as assessed by the C-SSRS at screening and at Day -1 or history of suicide attempt (lifetime).
4. Participant with positive serology for Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (HBcAb), Hepatitis C Virus (HCV), or Human Immunodeficiency Virus (HIV) at Screening.
5. Participant smokes cigarettes or uses other nicotine-containing products in the past 3 months prior to Screening.
6. Participant with regular alcohol consumption within 6 months prior to the trial defined as an average weekly intake of > 20 units for males or > 16 units for females (8g ethanol = 1 unit).
7. Participant tests positive in the urine test for alcohol, cotinine, and/or screen for drugs of abuse at the time of screening or Day -1.
8. Participant with a history of drug abuse according to Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM V criteria or later) within the 2 years prior to study entry.
9. Participation in any clinical trial and/or recipient of investigational trial medication within 90 days prior to the first dose of 8M2D.
10. Participant with a loss of ≥ 500 mL (1 unit) of blood within 90 days prior to receiving the first dose of 8M2D.
11. In addition to the above criteria, those judged by the Investigator as not suitable for participating in this clinical trial

Part III Alzheimer's Disease:

1. Participant with history or presence of any uncontrolled systemic disease (e.g., hypertension (systolic BP ≥ 150 mmHg/diastolic BP ≥ 100 mmHg), diabetes mellitus (HbA1c ≥ 8% at the time of screening) etc.).
2. Participant with history or presence of unstable or clinically significant cardiovascular (e.g., myocardial infarction), kidney, or liver disease.
3. Participant with any active or unstable clinically significant medical or psychiatric condition as judged by the Investigator.
4. Participant who has current serious or unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic (other than AD), psychiatric, immunologic, or hematologic disease and other conditions that, in the Investigator's opinion, could interfere with the analyses of safety and efficacy in this trial.
5. Participant with any evidence of a condition other than AD that may affect cognition such as other dementias, stroke, brain damage, autoimmune disorders (e.g. multiple sclerosis) or infections with neurological sequelae.
6. Participant with history within the past 5 years of a primary or recurrent malignant disease with the exception of resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with a normal prostate specific antigen post-resection.
7. Participant with history of intracranial hemorrhage, cerebrovascular aneurysm, or arteriovenous malformation, carotid artery occlusion, stroke, or epilepsy.
8. Participant who shows evidence of suicidal ideation as assessed by the C-SSRS at screening and at Day -1 or history of suicide attempt (lifetime).
9. Participant with positive serology for HBsAg, HBcAb, HCV, or HIV at Screening.