The Alzheimer's Disease Tau Platform Clinical Trial

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PROJECT SUMMARY / ABSTRACT Tau protein is an attractive AD therapeutic target because the amount and anatomical distribution of insoluble tau at autopsy is strongly correlated with the symptoms and severity of disease during life. Multiple tau therapies are now in clinical trials for AD, with many new agents entering the clinic. New approaches to accelerating their clinical development are urgently needed. A variety of AD biomarkers now exist, including CSF and plasma beta amyloid ratios and phosphorylated tau (P-tau) levels, and amyloid and tau PET tracers, providing tools to measure pharmacodynamic effects of amyloid and tau therapies on the core biology of AD. The goal of the Alzheimer’s Tau Platform (ATP) trial is to conduct a randomized, placebo controlled, Phase 2 platform trial in preclinical-prodromal AD that will simultaneously test at least two different tau-directed therapies, alone or in combination with an anti-amyloid therapy, to determine safety, tolerability, and biological based proof of concept based on the tau PET tracer 18F MK6240 and other tau biomarkers. Platform trials create efficiencies through generation of a common clinical trial protocol and shared placebo groups to allow a greater number of therapies to be tested in less time with less expense than by conducting multiple independent trials. This trial will test 5 therapeutic hypotheses involving combinations of 3 drugs versus placebo: Two tau therapies will be studied in a 2 x 3 factorial design (placebo vs. anti-amyloid [n=2] x two tau therapies or placebo [n=3]) for 24 months, in six parallel arms. The key inclusion criteria for ATP will be >20 centiloids of amyloid PET uptake, 18F MK6240 temporal ROI SUVr >1.25, with a global Clinical Dementia Rating (CDR) of 0 or 0.5 and MMSE >23. Using these criteria, we estimate that 150 participants per arm will be necessary to have 80% power to detect a 30% slowing in the accumulation 18F MK6240 signal over 24 months of blinded therapy. Key secondary endpoints will be changes in plasma P-tau species (-217, etc.) and neurofilament light chain (NfL), clinical rating scales and volumetric MRI. Leveraging the experience and resources of the NIH AD Clinical Trial Consortium (ACTC), we propose to enroll 900 participants at ~100 ACTC sites over 24 months, randomize them 5:1 drug:placebo for 24 months of blinded treatment, followed by a 24 month open label extension. We aim to: 1) test the ability of two tau-directed therapies, either alone or in combination with an anti-amyloid therapy, to slow the accumulation of tau PET signal over 24 months as compared to placebo or anti-amyloid therapy alone; 2) test the safety and tolerability of 24 months of blinded therapy followed by an optional 24 month open label extension of combination tau/anti-amyloid therapy; and 3) explore the ability of each of two tau directed therapies to slow disease progression as measured by CSF and plasma biomarkers (plasma P-tau, NfL), volumetric MRI and clinical assessments (Preclinical Alzheimer’s Composite [PACC], etc.). If successful, the ATP will provide data for decision-making about which tau therapies or combinations to pursue in larger efficacy studies, an ongoing resource to test new therapeutic approaches beyond tau, and will improve understanding of AD biology.