Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Positive Modulator of HGF/MET, Fosgonimeton, in Healthy Volunteers and Subjects with Alzheimer's Disease: Randomized, Placebo-Controlled, Double-Blind, Phase I Clinical Trial
Hua X, Church K, Walker W, L'Hostis P, Viardot G, Danjou P, Hendrix S, Moebius HJ
Journal of Alzheimer's Disease (2022) · n=88
First-in-human Phase I trial of fosgonimeton (ATH-1017), the prodrug of the active metabolite ATH-1001 that descends from the Wright/Harding dihexa program — 88 subjects across young healthy, elderly healthy, and Alzheimer's cohorts, with the drug safe and well-tolerated and signals of qEEG gamma-power induction and P300 latency normalization in the AD cohort.
This is the human-level evidence that exists for the HGF/c-Met-modulating compound class that descends from the Wright/Harding dihexa program at Washington State University, conducted by Athira Pharma. Fosgonimeton (ATH-1017, formerly NDX-1017) is a subcutaneously administered prodrug that is converted to the active metabolite ATH-1001; the program's framing positions it as a small-molecule positive modulator of HGF/MET signaling — the same mechanism Dihexa was proposed to act through in the original Wright/Harding mechanism papers, although fosgonimeton is a distinct compound from Dihexa itself. The Phase I trial enrolled 88 subjects across three cohorts: 48 healthy young males (mean age 33.4 years), 29 healthy elderly subjects (mean age 63.8 years), and 11 Alzheimer's disease subjects (mean age 69.2 years). Subjects received single ascending doses (2-90 mg subcutaneous) or multiple ascending doses (20-80 mg once daily for 9 days), with the AD cohort receiving 40 mg once daily for 9 days. Fosgonimeton was safe and well-tolerated across all doses with no serious adverse events; the primary treatment-related events were injection-site reactions (pain and pruritus). Quantitative EEG showed acute and sustained gamma-power induction, and ERP P300 latency — a measure of cognitive processing speed — showed significant normalization in the AD cohort (mean reduction of 72.8 ± 48.8 ms by day 8; P=0.027). The result is the foundational human safety and pharmacodynamic dataset for the HGF/MET-modulator mechanism in CNS indications.
This is a Phase I trial — short duration, small sample, primarily designed to establish safety and pharmacokinetic floor rather than clinical efficacy. The pharmacodynamic endpoints (qEEG gamma power, P300 latency) are surrogate biomarkers that have face-validity arguments in Alzheimer's disease but are not validated outcome measures. The trial does not address durable cognitive benefit or disease modification; that question was the subject of the subsequent Phase II ACT-AD and Phase II/III LIFT-AD trials, the LIFT-AD readout in 2025 failed to meet its primary endpoint, and Athira has paused further fosgonimeton development as of late 2025. Fosgonimeton is not Dihexa. The compounds share a mechanism framing — HGF/MET positive modulation — and they descend from the same Wright/Harding research lineage, but fosgonimeton is a distinct chemical entity developed by Athira after Dihexa itself was judged to lack optimal drug-like properties for clinical development. Inferences from this trial about Dihexa pharmacology in humans are indirect at best. Industry sponsorship is direct: Hua, Church, Walker, Hendrix, and Moebius are Athira Pharma employees; the trial is part of Athira's clinical-development dossier. The author team includes contract clinical-research personnel from European CROs as well.
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