Fosgonimeton Well Tolerated With Possible Benefits for Alzheimer Disease in the Absence of Cholinergic Treatment
In the phase 2 ACT-AD trial (NCT04491006), fosgonimeton (Athira Pharma, Bothell, WA) was well-tolerated, and no serious adverse events (AEs ) occurred. Mild-to-moderate AEs occurred in 89% (24/27) and 100% (26/26), respectively, with 40 or 70 mg/day fosgonimeton and 70% with placebo (17/24). The overall discontinuation rate was 14.3% (11/77). AEs that were more frequent with fosgonimeton included injection site reactions, transient eosinophilia, and dizziness.
In prespecified subgroup analysis of the 41% of participants 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.
Hans Moebius, MD, PhD, chief medical officer of Athira Pharma commented, "We are pleased with continued safety and encouraging clinical and electrophysiologic signals of potential benefit of fosgonimeton for treating AD, especially in concert with a significant reduction of NfL in participants not using cholinergic medications. These results point toward the unique mechanism of action of fosgonimeton, which is especially important because it suggests potential for concomitant treatment with other therapies could be possible. At Athira, we recognize research and development does not proceed in a straight line, and we remain resolutely committed to continuing development of fosgonimeton."
Fosgonimeton is a positive modulator of the hepatocyte growth factor (HGF)/MET proto-oncogene, receptor tyrosine kinase (MET) neurotrophic factor system, which activates neuroprotective and neurotrophic properties. In vitro studies have shown that the active metabolite of fosgonimeton is neuroprotective against the effect of several neurotoxins.
Participants in this study were mostly white and age 55-85; to participate, they had to have Mini-Mental State Examination (MMSE) scores of 14 to 24, Clinical Dementia Rating (CDR) global scores of 1 or 2, and a clinical diagnosis of dementia probably due to AD. Fosgonimeton or placebo were administered subcutaneously daily. Prior or concomitant use of cholinergics was allowed, provided the dose was stable those being treated concomitantly.