Project Summary We are developing ALZ-801 (also known as valiltramiprosate), an oral brain-penetrant small molecule that inhibits the formation of toxic amyloid oligomers. With support from NIA through R01-AG065253, we are conducting a Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Safety and Biomarker Effects of ALZ-801 in Subjects with Early Alzheimer’s Disease and APOE4/4 Genotype (NCT04770220). This study (ALZ-801-AD301, APOLLOE4) evaluates the efficacy, safety, fluid biomarkers, and MRI effects of ALZ-801 265 mg bid or placebo in 300 patients over 78 weeks (150/arm). The study is being conducted in the US, Canada, Iceland, United Kingdom, Czech Republic, Netherlands, Germany, France, and Spain. A major clinical research organization (CRO), ICON plc, is contracted to manage the study. Study start-up commenced in July 2020, in the middle of the first year of the COVID-19 pandemic and the first subject was randomized in June 2021. The original goal for the study was to complete randomization within 18 months (i.e., by October 2022) with a goal of completing the study by May 2024. Due to the complications of the pandemic, the study has faced many complications that have increased both the cost and duration of the study: • many sites initially chosen for the study were unable to participate or were severely delayed in participation due to COVID as many sites were unable to conduct on-site visits or were unable to see potential new subjects for evaluation and recruitment – as a result an additional 14 sites are being brought to site initiation and a new country (Czech Republic) was added to the study • especially at some of the larger institutions, administrative support was focused on COVID studies and contracting was for other studies was severely delayed • enhancement or initiation of alternate strategies for recruitment were employed to address the very limitation application of traditional, local outreach strategies • supply chain issues have lately had a significant impact, especially on the provision of laboratory supplies, particularly kits to support screening activities causing some sites to pause screening activities The sum of these challenges has resulted in a delay of approximately two months in recruitment with subsequent increases in project management. This delay would likely have been significantly longer without the increase in investment already applied to the study by the sponsor.