Phase 1 clinical trial of AV-1959 amyloid-β vaccine for Alzheimer's disease (AD).

The Phase I study is a randomized, multicenter, double-blind, placebo-controlled study consisting of 3 sequential cohorts to determine the safety and tolerability of AV-1959D at three doses compared to a placebo in patients with early AD

Inclusion Criteria:

1. Male or female subjects from 60 to 85 years of age, both inclusive.

2. Mild cognitive impairment (MCI) due to Alzheimer's disease (AD), according to Albert et al., or mild AD dementia, according to McKhann et al., and must have the following:

   • Mini-Mental State Examination (MMSE) score from 22 to 30;
   • Clinical Dementia Rating (CDR) global score of 0.5 or 1.0.

3. A positive visual Aβ positron emission tomography (PET) scan. Previously obtained PET scan (within 24 months of screening) is permissible and must be submitted to the central imaging reader to confirm that study inclusion criteria are met.

4. Subjects on approved AD medications (e.g., acetylcholine esterase inhibitors, memantine) are required to be on a stable dose for a minimum 3 months before baseline and with no dosage adjustments expected during the study. Continuation of subjects with dose adjustments for approved AD medications during the study may be allowed after discussion between the Investigator and the Medical Monitor.

5. The subject has a reliable study partner who will accompany the patient to all clinic visits during the study and, in the Investigator's opinion, has frequent and sufficient contact with the subject as to be able to provide accurate information about the subject's cognitive and functional abilities.

6. The subject's sight and hearing (hearing aid permissible) are sufficient for compliance with the study procedures.

7. Signed informed consent form by the subject and study partner prior to study participation.

Exclusion criteria:

1. Participation in another investigational drug or device study or treated with an investigational drug within 30 days or 5 half-lives, whichever is longer, before dosing.

2. Prior administration of any amyloid-beta or tau immunotherapy (vaccine, antibody)

3. Magnetic resonance imaging (MRI) showing evidence of any of the following:

   • More than 1 lacunar infarct greater than 1.5 cm
   • Any territorial infarct, including acute or chronic, greater than 1.5 cm
   • Subjects who have a combined number of microbleeds and areas of leptomeningeal hemosiderosis (i.e., cumulative ARIA-H) on the MRI of > 5 (and should not include any disseminated leptomeningeal hemosiderosis)
   • Subjects who have a presence of any other significant cerebral abnormalities, including ARIA-E, as assessed in the screening MRI scan.

4. Contraindications for MRI scanning, including implanted metallic devices (e.g., non-MRI-safe cardiac pacemaker or neurostimulator; some artificial joints metal pins; surgical clips; or other implanted metal parts), or claustrophobia or discomfort in confined spaces.

5. Use of immunomodulatory or growth-stimulating factors such as systemic corticosteroids, cyclosporine, methotrexate, azathioprine, anti-CD25 antibody, GM-CSF, C-CSF, interferon (IFN), or interleukin-2 (IL-2) within 30 days prior to study entry.

6. Concurrent use of warfarin or other coumarin derivatives or a combination of acetylsalicylic acid and an anti-platelet agent (e.g., clopidogrel). Low dose of acetylsalicylic acid (≤81 mg per day) is allowed.

7. Parenteral use of immunoglobulin preparations, blood products, plasma derivatives.

8. Any serious illness requiring systemic treatment and/or hospitalization within 4 weeks prior to study entry.

9. Any major or unstable illness, including unstable ischemic cardiovascular disease, or require use of excluded medications.

10. History/evidence of clinically relevant pathology related to cardiovascular system, respiratory tract, gastrointestinal tract, endocrinology, immunology, hematology, or any other systemic disorder/major surgeries that in the opinion of the Investigator would confound the subject's participation and follow-up in the clinical study.

11. Subjects with insulin-dependent diabetes.

12. Cardiac arrhythmias or palpitations [e.g., supraventricular tachycardia, atrial fibrillation, frequent ectopy, or sinus bradycardia]. Cardiac conduction abnormalities to be specified including prolonged QT interval and bundle branch blocks.

13. Subjects with pre-existing autoimmune diseases.

14. A medical condition that in the opinion of the Investigator might be a contributing cause of cognitive impairment.

15. History/evidence of severe local or systemic reactions to vaccination or significant allergic reactions.

16. History of seizure disorder.

17. Any other medical, psychological, social condition or diagnostic test which, in the opinion of the Investigator and Medical Monitor may lead to screen failure or prevent the subject from fully participating in the study, represent a concern for study compliance, or constitute a safety concern to the subject.