To evaluate changes from baseline in plasma biomarkers in subjects with mild-to-moderate Alzheimer’s disease (AD) treated with fosgonimeton, a small-molecule positive modulator of the hepatocyte growth factor (HGF)/MET system, compared with placebo and to assess multifactorial correlations with the global statistical test (GST), a composite score informed by both ADAS-Cog11 and activities of daily living (ADCS-ADL23).

Despite the multifactorial nature of AD, research has primarily targeted proteotoxicity; approaches addressing other contributory factors are needed. Fosgonimeton was evaluated in the randomized, double-blind, placebo-controlled, phase 2 ACT-AD study (NCT04491006); biomarker results are reported here.

Blood samples were collected at baseline (N=77) and week 26 of treatment. Biomarkers assessed include neurofilament light chain (NfL; indicates ongoing neurodegeneration), GFAP (indicates microglial activation), YKL-40 (indicates neuroinflammation), and amyloid beta 40 and 42 (Aβ40, Aβ42). Results are represented for pooled active arms versus placebo, without background therapy.

Baseline biomarker levels were similar between treatments. A statistically significant change from baseline versus placebo in NfL (−7.9 pg/mL; SE, 2.7; P=0.0059) and directionally favorable improvements in GFAP (−29.3 pg/mL; SE, 28.6; P=0.312), YKL-40 (−34.9 ng/mL; SE, 26.5; P=0.195), and Aβ42/40 ratio (0.0066; SE, 0.0035; P=0.064) were observed in fosgonimeton-treated subjects. ApoE4 genotype, baseline Mini-Mental State Examination score, sex, or age did not affect these results.

In an analysis to confirm correlation of biomarkers and clinical outcomes, the composite endpoint GST proved to be highly correlated with changes in NfL (r=0.46; P=0.0011) and GFAP (r=0.30; P=0.0394).

In this first-ever, randomized, placebo-controlled trial of fosgonimeton, a statistically significant reduction in NfL and descriptive, congruent GFAP and YKL-40 plasma concentration improvements were observed, which would be consistent with a neuroprotective effect and multimodal mechanism of action of fosgonimeton. The significant correlation of NfL and GFAP reduction with the composite clinical endpoint further supports clinical relevance.