Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Open-Label Extension Study

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SUMMARY: This is an application for NIH support to enable an Open Label Extension (OLE) of the Anti- Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) Study. The A4 Study was launched in 2014 as the first of its kind secondary prevention trial in clinically normal (CN) older individuals with evidence of elevated amyloid-beta (Aβ) accumulation on screening PET scan. A4 eligible participants are in the preclinical (asymptomatic) stages of AD and at high risk for cognitive decline. The overall goal of the A4 study is to test the hypothesis that immunotherapy targeting Aβ (solanezumab) can prevent the cognitive decline associated with early AD pathology, if initiated early enough. The A4 Study screened over 6700 participants (age 65-85, 14% minority) and exceeded our enrollment target with 1169 participants randomized. Our initial prediction of 30% “amyloid positivity” was proven correct with 29.5% of the participants with screening PET meeting “elevated amyloid” criteria. We also launched the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) observational study in “amyloid negative” CN (n=541) in 2015. Based on the sola trial results in AD dementia, we quadrupled the dose and extended the double-blind (DB) protocol to 4.5 years. The first A4 participant will complete the DB protocol in early 2019, with the last participant completing in mid- 2022. Maintaining the blind of the initial treatment assignment, the A4 OLE will enable us to continue to assess these participants after they complete the DB, and to investigate the long-term effects of sola exposure on cognitive and functional decline in preclinical AD. In addition, we will explore the “critical window” for optimal response to anti-Aβ therapy utilizing amyloid PET, MRI, and tau PET (in a subset) acquired at start of OLE. The A4 Study is a public-private-philanthropic partnership with funding from NIA, Lilly, Alzheimer’s Association, Fidelity Biosciences, GHR Foundation, and the Accelerating Medicines Partnership (AMP). Here we seek partial funding from the NIH for the A4 OLE with Lilly providing the remainder of funding and in-kind support. This funding will allow us to offer all of the very dedicated A4 participants access to study drug in the OLE, and continue to collect extremely valuable longitudinal data on the largest available cohort of CN characterized by amyloid status, until the primary efficacy analyses are completed in late 2022. We have already begun to share the data and biosamples from the A4 screening data, and the A4/LEARN longitudinal data will be made publicly available within one year of completion of the primary efficacy analyses of the A4 Study. The A4 Study is well positioned to rigorously test the amyloid hypothesis with a higher dose of solanezumab and at the appropriate stage of disease, in a population estimated to be up to 15 years earlier in the Aβ accumulation process than the previous AD dementia trials. The additional longitudinal data from the A4 Study, in combination with similar data acquired in LEARN, has the potential to fundamentally alter the detection and treatment of AD, and move us closer to the NAPA goal of finding a successful prevention therapy by 2025.