Fosgonimeton Being Evaluated for Alzheimer Disease Without Acetylcholinesterase Inhibitors
There has been an update for the ongoing LIFT-AD clinical trial (NCT04488419) of fosgonimeton (ATH-1017; Athira Pharma, Bothell, WA) as treatment for individuals with mild-to-moderate Alzheimer disease (AD). The LIFT-AD trial will enroll 300 participants who are not taking concomitant AChEIs who will be randomly assigned 1:1:1 to 1 of 2 fosgonimeton doses or placebo. The update is based on results of the ACT-AD study (NCT04491006) that suggest a positive effect in people who were not taking concomitant acetylcholinesterase inhibitors (NCT).
The ACT-AD study was originally designed to better understand the effect fosgonimeton has on biomarkers, psychometric measures, and safety over 6 months. In prespecified subgroup analysis of the 41% of participants in ACT-AD who stopped or never took cholinergic treatments, those treated with fosgonimeton vs placebo had a significant reduction in neurofilament light (NfL; -6.89 pg/mL; P=.018), a biomarker of axonal degeneration. In this subgroup, post-hoc analysis showed those treated with fosgonimeton vs placebo also had improved Alzheimer Disease Assessment Scale-Cognitive 11 (ADAS-Cog-11) scores and shorter event related potential (ERP) P300 latencies at 26 weeks, although these did not reach statistical significance. The ERP P300 latency is a functional measure of working memory and processing speed, thought to reflect increased functional brain connectivity.
In a prespecified modified intention to treat (mITT) analysis of all participants (with or without concomitant cholinergics), however, no difference seen on ADAS-Cog-11. Post-hoc analysis with a mixed measures repeated analysis did suggest a trend toward improvement in ERP 300 with fosgonimeton (P<.06). Prespecified subgroup analysis showed no differences between apolipoprotein E (ApoE) ε4 carriers vs noncarriers or those with mild vs moderate AD.
“We look forward to advancing the clinical evaluation of fosgonimeton in a way that will best determine its potential for Alzheimer disease patients while preserving the integrity of the LIFT-AD study and optimizing its chances for success,” said Hans Moebius, MD, PhD, chief medical officer of Athira. “Our decision to focus LIFT-AD on fosgonimeton treatment without background cholinergics was guided by results from the ACT-AD trial and a blinded analysis of the ongoing LIFT-AD study. Importantly, fosgonimeton remains well tolerated, with a favorable safety profile in the full study population.”