Overview
This is a Phase 1, multicenter, randomized, double-blind, placebo-controlled, multiple dose-escalating trial to evaluate the safety, tolerability, and immune response of AV-1980R, an investigational vaccine targeting tau protein, in participants with preclinical Alzheimer's disease. Up to 48 cognitively unimpaired adults aged 65-80 with biomarker evidence of early Alzheimer's disease will be enrolled into three ascending dose cohorts. The study is designed as a secondary prevention trial to test whether therapeutic immunization at the preclinical stage is safe, induces an immune response, and, exploratorily, may favorably affect biomarkers associated with disease progression.
Description
This first-in-human study investigates AV-1980R, a MultiTEP-based active immunotherapy formulated with the adjuvant, as a secondary prevention approach for Alzheimer's disease. The study will randomize up to 48 participants aged 65-80 years in a 3:1 ratio to AV-1980R or placebo across three ascending dose cohorts (20 μg, 60 μg, 180 μg). Participants will receive four intramuscular doses at Weeks 0, 4, 12, and 36, with follow-up through Week 56.
Primary objectives are to evaluate safety and tolerability, monitored by adverse events, labs, ECGs, MRI, and neurological assessments. Secondary objectives include immunogenicity measured by anti-tau antibody titers. Exploratory endpoints include plasma biomarker and tau-PET changes.
Eligibility
Inclusion Criteria:
Male or post-menopausal/surgically sterile female, 65-80 years of age.
Cognitively unimpaired with preclinical Alzheimer's disease:
CDR global score = 0. MMSE ≥ 26. WMS-R LM II ≥ 6. Amyloid Probability Score 2 (APS2) \> 54 (PrecivityAD2™). Adequate vision/hearing to comply with study procedures. Stable concomitant medications if applicable. Signed informed consent.
Exclusion Criteria:
MRI abnormalities: \>1 large lacunar infarct, territorial infarct, \>5 microbleeds, ARIA-E, or other significant pathology.
Contraindications to MRI (e.g., pacemaker, metallic implants, severe claustrophobia).
Serious illness or hospitalization within 4 weeks prior to enrollment. Clinically significant cardiovascular, endocrine, hematologic, autoimmune, or neurological disease.
Insulin-dependent diabetes, significant arrhythmias, or seizure disorder. Positive C-SSRS (score ≥ 3). Prior tau or amyloid-beta immunotherapy within 1 year. Immunosuppressive or anticoagulant use that could interfere with study safety. Clinically significant lab abnormalities or positive HIV, HBV, or HCV screening.
