Positive Modulator of MET Tyrosine Kinase Clinical Trials Update
In an update presented at the Clinical Trials in Alzheimer Disease meeting in Boston, MA November 9-12, 2021, baseline characteristics from the ACT-AD (NCT04491006) and LIFT-AD (NCT04488419) clinical trials were presented. These trials are evaluating a novel small molecule (ATH-1017; Athira, Bothell, WA) that positively modulates the hepatocyte growth factor (HGF)-MET receptor neurotrophic system for potential treatment of mild-to-moderate Alzheimer disease (AD).
The ACT-AD trial is a phase 2 26-week study that has reached full enrollment of 77 participants with results expected in the first half of 2022. In this trial, participants have been randomly assigned 1:1:1 to receive daily subcutaneous injections of 40 mg or 70 mg of ATH-1017 or placebo for 26 weeks. Outcome measures in this trial include change in event-related potential (ERP) P300 latency, as the primary outcome, and secondary outcomes include the Global Statistical Test (GST), Alzheimer Disease Assessment Scale-Cognitive 11 (ADAS-Cog11), Alzheimer Disease Cooperative Study (ADCS)-Clinical Global Impression of Change (CGIC) and ADCS-Activities of Daily Living 23 (ADL23).
The LIFT-AD trial has a target enrollment of 300 and is currently enrolling individuals with mild-to-moderate AD. The primary outcome measure of LIFT-AD is the GST, an unweighted mathematical algorithm that combines the outcomes of 2 separate measures, in this case ADAS-cog and CGIC. Because the GST is component agnostic, this will allow independent statistical analyses of ADAS-Cog11 and ADCS-CGIC, if needed, to detect any clinical result for this potentially pivotal trial.
The daily doses of 40 mg and 70 mg being used in these trials are, in part, based on earlier clinical trials in a small cohort of people with AD treated with 40 mg ATH-1017 daily who had substantial positive effects as measured by quantitative EEG (qEEG) and shortened latency of the ERP P300.
ATH-1017 is a positive modulator of HGF/MET, and neuronal MET expression is reduced by 25% to 75% in brains from people with AD. In vitro, ATH-1017 binds to HGF/MET and results in increased activation of MET receptors. In addition, activation of HGF/MET has been shown to induce translocation of glutamatergic N-methyl D aspartate receptors (NMDARs) to the synaptic cleft. Such translocation of NMDARs to the synaptic cleft increases long-term potentiation and may also reduce glutamatergic excitotoxicity.
Hans Moebius, MD, PhD, chief medical officer of Athira Pharma explained, “Our approach with ATH-1017 is to use a single small molecule in a multipronged approach addressing the many biologic processes in the pathophysiology of AD. Neurotrophic support at the MET receptor results in activity-dependent stabilization of the synapse, decreasing neuroinflammation and neurodegeneration, and improving neuronal support by microglia and blood perfusion. We see this directly in patients by measuring changes in the ERP P300 latency, a proven quantitative measure of executive function”
Dr. Moebius noted, "better information about ongoing trials, especially at certain severity stages is also very important for people living with AD and their care partners. We hope that sharing information about ongoing trials will increase participation.”