Biomarker analyses from the phase 2, randomized, placebo‐controlled ACT‐AD and open‐label extension clinical trials of fosgonimeton in patients with mild‐to‐moderate Alzheimer’s disease

Background Despite the multifactorial nature of Alzheimer’s disease (AD), research has primarily targeted amyloid‐beta and tau; other approaches are needed. Fosgonimeton, a small‐molecule positive modulator of the hepatocyte growth factor (HGF)/MET system, was evaluated in a randomized, double‐blind, placebo‐controlled, 6‐month, exploratory phase 2 trial (ACT‐AD; NCT04491006)a and an open‐label extension trial (NCT04886063)a. Method To evaluate fosgonimeton in participants with mild‐to‐moderate AD, changes from baseline (CFB) in plasma biomarkers were compared with placebo in post hoc analyses. Multifactorial correlations were assessed against the global statistical test (GST), a composite score of cognition (ADAS‐Cog11) and activities of daily living (ADCS‐ADL23) assessments. Blood samples from baseline (n = 59‐61) and week 26 were assessed for biomarkers of neurodegeneration (NfL), neuroinflammation (GFAP; YKL‐40), and proteinopathy (Aβ42/40 ratio; p‐Tau181). Result Baseline biomarker levels were similar between treatments. An ANOVA, including baseline levels, yielded a statistically significant CFB in NfL (−6.49 pg/mL; SE, 2.79; p = 0.0241) and numerical improvements in GFAP (−35.17 pg/mL; SE, 30.0; p = 0.2469), YKL‐40 (−47.37 ng/L; SE, 27.5; p = 0.0916), Aβ42/40 ratio (0.006; SE, 0.0035; p = 0.0938), and p‐Tau181 (−0.67 pg/mL; SE 0.60; p = 0.2715) were observed in fosgonimeton‐treated participants versus placebo, each without background therapy. APOE4 genotype, baseline Mini‐Mental State Examination score, sex, or age did not affect results. Additional biomarker and correlation analyses are being conducted. The potential association of biomarkers with clinical outcomes is supported by the CFB relative to GST, which significantly correlated with changes in NfL (r = 0.40; p = 0.0023) and GFAP (r = 0.35; p = 0.0408). Conclusion In this first randomized, placebo‐controlled, 6‐month trial of fosgonimeton, a statistically significant reduction in NfL and numerical improvements in GFAP, YKL‐40, Aβ42/40, and p‐Tau181 plasma concentrations were observed, suggesting a multimodal neuroprotective mechanism of action of fosgonimeton and potential to impact AD‐specific proteinopathies. The significant correlation of NfL and GFAP reduction with the composite endpoint further supports potential clinical relevance. aThe ACT‐AD trial and open‐label extension thereof are supported by a grant from the National Institute on Aging of the National Institutes of Health (award