FDA approved IND 29644: Multicenter Phase 1 Trial to Evaluate Safety and Immunogenicity of Preventive Tau Vaccine, AV-1980R/A, in cognitively unimpaired preclinical AD participants. - Project Summary Alzheimer's disease (AD) is the most common type of dementia characterized by memory impairment and alteration of diverse cognitive abilities. It is a complex and multifactorial disease involving various genetic and environmental risk factors that lead to the development of two hallmark pathologies: β-amyloid (Aβ) oligomers/fibrils/plaques and tau aggregates/tangles followed by inflammation and severe neurodegeneration. The modern version of the amyloid cascade hypothesis suggests that Aβ oligomer formation is critical for initiating tau pathology and downstream pathological processes, including inflammation, oxidative stress, and synaptic and neuronal loss, while the accumulation of pathological tau is directly correlated with the disease progression and severity. Therefore, the development of potential therapies for AD has been mainly focused on reducing pathological Aβ or Tau and, more recently, on inflammation associated with accumulating these pathological molecules in the brain. Although results from active and passive immunotherapy in AD patients and MCI subjects are promising, thus far collectively, they showed only little benefit of the cognitive or functional outcomes, likely because the treatment was initiated too late. Therefore, currently, AD research shifts from the treatment to the prevention of disease, and it coincides with our long-standing tenet that a safe and immunogenic preventive Aβ and/or tau vaccines should be initiated in cognitively unimpaired people at risk of MCI due to AD (preclinical stage). Passive mAb-based immunotherapy initiated in cognitively unimpaired people at risk of AD, however, is impractical due to the complexity, cost, and need for frequent (weekly/monthly) administrations of very high doses of antibodies. By comparison, safe and immunogenic active vaccines are suitable candidates for preventing the accumulation of Aβ and/or tau pathologies and delaying the onset of symptoms in people at risk. Here we propose to evaluate the safety and immunogenicity of the first-in-human MultiTEP-based Tau vaccine, AV-1980R/A, targeting the Phosphatase Activating Domain (PAD) exposed in pathological tau in volunteers with preclinical AD selected by a novel plasma test, PrecivityAD2™ Amyloid Probability Score 2 (APS2) ≥ 47.5 and absent cognitive impairment as evidenced by CDR = 0, MMSE > 26, and WMS LM II > 6. Notably, our vaccine strategy differs from all previous or current vaccines tested in clinical trials, as our approach is based on the very immunogenic and proprietary MultiTEP platform designed for human use and aimed to (i) overcome self-tolerance by inducing Th cell responses to MultiTEP, but not to self-tau epitopes; (ii) diminish variability of immune responses due to HLA diversity in humans; (iii) augment pathological tau-specific antibody production through activation of both naïve and pre-existing memory Th cells, especially beneficial for the elderly with immunosenescence. This clinical trial will enable us to develop an effective preventive vaccination strategy for future Phase 2/3 trials.
