Vafidemstat in mild to moderate Alzheimer’s disease: The ETHERAL study European cohort interim analysis

Background ETHERAL is a global, multicentre, 12‐month, randomized, Phase IIa safety study of vafidemstat in mild to moderate AD. The study includes a 6‐month, placebo‐controlled, 3‐arm period followed by a 6‐month, 2‐arm active treatment period where participants remain blinded to dose. Vafidemstat is the first epigenetic compound to be studied in clinical trials in CNS disorders. The primary endpoint is safety though data on cognition, behaviour and function and extensive CSF biomarker data was collected at 0, 6 and 12 months. The CSF biomarkers include amyloid and tau and the pro‐inflammatory biomarker S100A9, which is one of the top ten upregulated genes in late onset AD. This paper presents the first unblinded analysis of the data at the end of the first 6‐month period for the EU cohort. Method 117 participants comprise the EU cohort recruited from sites in Spain, France and the UK. They were randomised to two doses of vafidemstat and placebo; with the placebo participants subsequently randomised to one of the two doses for the second half of the study. Unblinding will occur in February 2020 and randomised results will be presented on safety, cognition, behaviour and function, along with biomarker changes and correlations with clinical efficacy. Result Baseline data has shown that all participants meet the amyloid and tau requirements for a diagnosis of AD and S100A9 levels were elevated across groups, as expected. Safety data to‐date supports that vafidemstat has been safe and well‐tolerated, and there has been a low drop‐out rate. Conclusion This first analysis presentation will provide data analyses from the EU cohort of randomized, double‐blind 6‐month period of ETHERAL, examine safety data, and correlate clinical data with biomarker changes in CSF. While we may assume the sample size is likely not powered for the clinical efficacy outcomes, the study will demonstrate: a) that an epigenetic compound (vafidemstat, an LSD1 inhibitor) can be developed for CNS disorders, b) that vafidemstat is generally safe and well tolerated, especially in this frail population, and c) that initial efficacy of vafidemstat will provide further knowledge on how to design the confirmatory studies.