ACT‐AD: Fosgonimeton in mild‐to‐moderate Alzheimer's disease – first results of a randomized, placebo‐controlled, 26‐week Phase 2 proof‐of‐concept trial. (20th December 2022) - Moebius, Hans J.
Abstract: Background: Fosgonimeton (ATH‐1017) is a positive modulator of HGF/MET, a key neurotrophic pathway impaired in Alzheimer's disease (AD). Neuronal MET expression is decreased in the cortex and hippocampus, which may contribute to synaptic loss, neurodegeneration, and functional decline. ACT‐AD seeks to replicate and extend the previously shown improvement of event‐related potential (ERP) P300 latency in AD patients demonstrated in an 8‐day randomized, placebo‐controlled, double‐blind Phase 1 trial. ERP P300 latency is a noninvasive, objective, quantitative biomarker of cognitive performance without learning effects. Method: ACT‐AD is a Phase 2, 26‐week, randomized, double‐blind, placebo‐controlled, parallel group trial in patients with a clinical diagnosis of mild to moderate AD. Patients enrolled were aged 55‐85 years, had a mini‐mental state examination (MMSE) score of 14‐24, a Clinical Dementia Rating global score of 1 or 2 at screening, a syndromal clinical diagnosis of probable AD according to McKhann et al. ( Alzheimers Dement . 2011), and were treatment‐naïve or receiving stable acetylcholinesterase inhibitor therapy. Patients were randomized (1:1:1) to placebo or fosgonimeton at doses of 40 or 70 mg, administered subcutaneously once daily. The trial is powered for the primary endpoint, change in ERP P300 latency. Secondary endpoints include ADAS‐Cog11, ADCS‐CGIC and ADCS‐ADL23 . The relationship of ERP P300 latency with cognition, memory and executive function, as well as pharmacokinetics, and safety will also be analyzed. Result: In total, 77 patients with mild to moderate AD were randomized, with a mean (SD) age of 71.4 (7.3) years, 50.6% female, and mean (SD) baseline MMSE score of 19.5 (3.1). ApoE4 carriers made up 56% of the population, with 42% as noncarriers and 2% unknown. Conclusion: The double‐blind period of ACT‐AD is ongoing and estimated to complete in May 2022, with results available in June 2022. First analyses will be presented at the annual 2022 AAIC congress. This study is sponsored by Athira Pharma, registered at Clinicaltrials.gov: NCT04491006, and supported by a grant from the National Institute on Aging of the National Institutes of Health under Award Number R01AG06268.