Safety/Tolerability/Immunogenicity of first-in-human Aβ DNA vaccine, AV-1959D Phase 1 trials in early-stage AD subjects: based on IND18953 cleared by FDA.

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Project Summary Recent data from clinical trials with humanized or fully human mAbs targeting Aβ suggest that immunotherapy could clear/reduce brain amyloid plaques and even slow cognitive decline in vaccinated subjects when initiated as a preventive measure. However, passive immunotherapy with even the most effective anti-Aβ mAb is not practical and cost-effective as a preventive measure in healthy subjects due to the need for frequent (monthly) administrations of high concentrations (~800mg IV injections/each time) of this immunotherapeutic in a substantial patient population. At the same time, high doses of mAb frequently (~30%) induce ARIA-E and ARIA- H. In contrast, AD vaccine, similar to the vast majority of vaccines in general, could be very effective when used as a preventive/early intervention measure. Today, only limited results are available from ACC001, CAD106, and UB311 epitope vaccine clinical trials, but fortunately, comprehensive data on AN-1792 are published. These data demonstrated that the AN-1792 vaccine has induced antibodies specific to N-terminus of amyloid in ~19% immunized AD patients without causing ARIA-E and ARIA-H abnormalities. Importantly the follow-up analysis revealed that even after 14 years post-vaccination, the vaccinated subjects were plaque-free, and there was a significant inverse correlation between peripheral blood anti-Aβ antibody titers and the plaque counts. Despite the reduction of Aβ pathology, vaccination did not improve cognitive functions likely due to tau pathology buildup. These data support our long-standing proposal of starting anti-Aβ vaccination with AV-1959D as a prophylactic measure in subjects at risk for AD to inhibit/reduce oligomerization of Aβ and delay downstream pathological processes. However, based on an ethical imperative raised by the FDA during our pre-IND meeting, they recommended us to test our Aβ vaccine AV-1959D in participants with early-stage AD patients prior to initiating the preventive trials in asymptomatic people at risk of MCI/AD. Therefore, here we propose to initiate a Phase 1 safety trial with the first-in-human Aβ DNA vaccine, AV-1959D in early-stage MCI/AD patients based on FDA cleared IND18953 developed under an NIA cooperative agreement (U01 AG048310). Importantly, 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-Aβ epitopes; (ii) diminish variability of immune responses due to HLA diversity in humans; (iii) augment anti-Aβ antibody production through activation of both naïve and pre-existing memory Th cells, especially beneficial for elderly patients with immunosenescence. Therefore, in Phase 1 trials, the first-in-human MultiTEP-based DNA vaccine targeting Aβ1-11 B cell epitope should be safe and should induce therapeutically sufficient titers of anti-Aβ antibodies in an appreciable number of vaccinated early stage AD subjects. Our future program includes preventive vaccine trial in asymptomatic people at risk of MCI/AD using only the most immunogenic and safe dose of AV-1959D.