Safety Assessment of Leronlimab and Its Effect on Brain Inflammation in Alzheimer's Disease

Safety Assessment of Leronlimab and Its Effect on Neuroinflammation Targets in Alzheimer's Disease

The present study will administer the drug leronlimab to 20 participants who are above 50 years old with Alzheimer's disease (AD) or mild cognitive impairment (MCI) due to AD. While leronlimab is considered safe in other diseases like Human Immunodeficiency Virus (HIV) and certain types of cancer, its safety and tolerability in AD will be tested for the first time. The main purpose of this study is to learn:

1. Is this drug safe for participants with AD and MCI due to AD?
2. Does leronlimab change levels of brain inflammation?

The results of this study could lead to future studies with more participants that will test whether leronlimab may slow or prevent the decline in thinking abilities and brain function in this group of participants. Using leronlimab for Alzheimer's disease is experimental, which means that the Food and Drug Administration (FDA) has not approved leronlimab for this purpose.

Participants will be asked to take leronlimab once a week for 12 weeks in our clinic or in their own home. Participants will also be asked to complete the below procedures before and after taking leronlimab for 12 weeks:

1. Undergo 2 types of brain scans, Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI).
2. Visit our clinic for routine lab work, an electrocardiogram (ECG), and a physical exam.
3. Donate blood so the researchers can better understand how leronlimab affects levels of inflammation and proteins related to AD in the blood.
4. Undergo a series of tests and questionnaires that test thinking abilities.
5. Have weekly phone calls with researchers to let them know if there are side effects while taking this drug.

Inclusion Criteria:

Potential participants are required to meet all the following criteria for enrollment into the study:

1. Adult males or females, 50 years of age and older
2. Biomarker confirmed mild-to-moderate i.e., mild cognitive impairment/AD (MCI/AD) based on standard criteria (CDR 0.5 to 1.5).
3. Cognition intact enough to participate in study procedures including cognitive testing (MoCA>11)
4. Clinically normal resting 12-lead ECG at screening or, if abnormal, considered not clinically significant by the investigator
5. Participant (or legally authorized representative) provides written informed consent prior to initiation of any study procedures
6. Understands and agrees to comply with planned study procedures
7. If receiving an FDA approved drug that treat the symptoms of AD (e.g., cholinesterase inhibitors and/or memantine) must be on a stable dose for at least 12 weeks prior to baseline
8. If receiving an FDA approved drug that targets brain amyloid must be on a stable dose for at least 12 weeks prior to baseline
9. If the participant is taking any supplement or medical food that may affect brain function must be on a stable dose or regimen for at least 12 weeks prior to baseline
10. Participants on permitted concomitant medications should be on a stable dose of the permitted concomitant medication for at least 4 weeks unless a shorter duration is deemed acceptable by the investigator
11. In the opinion of the investigator, have adequate cognition, literacy, vision, and hearing for neuropsychological testing
12. The participant should have a study partner who can support the study participant and provide collateral information.

Exclusion Criteria:

Potential participants meeting any of the following criteria will be excluded from enrolment into the study:

1. Participant with a gene variation that would inhibit binding to the PET radiotracer (11C-DPA-713) and/or clinical factors that could affect PET signal, such as chronic use of benzodiazepines or NSAIDS
2. Women who are pregnant or breastfeeding at screening or baseline
3. Females of childbearing potential who within 28 days before study entry, did not use a highly effective method of contraception, which includes any of the following: (1) total abstinence, if it is their preferred and usual lifestyle; (2) an intrauterine device or intrauterine hormone-releasing system; (3) a contraceptive implant; (4) an oral contraceptive (with additional barrier method) with the participant being on a stable dose of the same oral contraceptive product for at least 28 days before dosing and throughout the study and for 28 days after study drug discontinuation; (5) have a vasectomized partner with confirmed azoospermia. Women who do not agree to use a highly effective method of contraception (as described above) throughout the entire study period and for 28 days after study drug discontinuation shall be excluded. However, at the discretion of the investigator it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the subject, then the subject must agree to use a medically acceptable method of contraception, i.e., double-barrier methods of contraception such as latex or synthetic condom plus diaphragm or cervical/vault cap with spermicide. NOTE: All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).
4. Male participants with female partners of childbearing potential are not eligible to participate if they do not agree to ONE of the following from the time prior to first dosing until 90 days after the last dose of study treatment: (1) are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; (2) Agree to use a male condom plus partner use of a contraceptive method with a failure rate of <1% per year when having penile-vaginal intercourse with a partner of childbearing potential who is not currently pregnant. Men with a pregnant or breastfeeding partner are not eligible to participate if they do not agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile penetration from the time prior to first dosing until 90 days after the last dose of study treatment
5. Participants who are HIV positive at screening
6. Participants with a past history (suspected or confirmed) of Hepatitis B should have HBsAg testing at screening and are excluded if HBsAg is positive
7. Participants with a past history (suspected or confirmed) of Hepatitis C should have HCV RNA PCR testing at screening and are excluded if the HCV RNA PCR test is positive
8. Presence based on exam, history or MRI of significant brain disease other than AD such as schizophrenia, epilepsy, Parkinson's disease or large territory stroke
9. Current substance abuse in accord with Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) criteria
10. Significantly depressed (Geriatric Depression Scale > 10)
11. Contraindications to MRI scanning, including claustrophobia, cardiac pacemaker/defibrillator, ferromagnetic metal implants (e.g., in skull and cardiac devices other than those approved as safe for use in MRI scanners)
12. Contraindications to PET
13. Any other clinically significant abnormalities in physical examination, vital signs, laboratory tests, or ECG at screening or baseline which in the opinion of the investigator require further investigation or treatment or which may interfere with study procedures or safety
14. Any other medical conditions (e.g., cardiac, respiratory, gastrointestinal, or renal) which are not stable and/or adequately controlled, or which in the opinion of the investigator(s) could affect the participant's safety or interfere with the study assessments
15. Participants with malignant neoplasms within 3 years of screening (except for basal or squamous cell carcinoma in situ of the skin or localized prostate cancer in male participants). Participants who had malignant neoplasms but who have had at least 3 years of documented uninterrupted remission before screening need not be excluded
16. Participants who are participating in other interventional clinical trials that in the opinion of the investigator is likely to interfere with participation in or completion of the study or to affect study results or interpretation.
17. Participants who were dosed in a clinical trial involving any new investigational drug for AD within 12 months prior to screening unless it can be documented that they received placebo
18. Participants are not eligible if they have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to leronlimab
19. Participants who have previously received leronlimab
20. Participants who are taking prohibited medications
21. Inability for patient or proxy to provide informed consent or to comply with test requirements
22. Visual or hearing impairment that, in the opinion of the investigator, would prevent the participant from performing psychometric tests accurately