Fosgonimeton Provides Congruent Improvements on Neurodegeneration Biomarkers, Significantly Correlating With Composite Clinical Score of Cognition and Function in Alzheimer’s Disease (S26.008)

Abstract

<h3>Objective:</h3> 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). <h3>Background:</h3> 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. <h3>Design/Methods:</h3> 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. <h3>Results:</h3> Baseline biomarker levels were similar between treatments. A statistically significant change from baseline versus placebo in NfL (−7.9 pg/mL; SE, 2.7; <i>P</i>=0.0059) and directionally favorable improvements in GFAP (−29.3 pg/mL; SE, 28.6; <i>P</i>=0.312), YKL-40 (−34.9 ng/mL; SE, 26.5; <i>P</i>=0.195), and Aβ42/40 ratio (0.0066; SE, 0.0035; <i>P</i>=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; <i>P</i>=0.0011) and GFAP (r=0.30; <i>P</i>=0.0394). <h3>Conclusions:</h3> 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. <b>Disclosure:</b> Dr. Moebius has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for Athira Pharma, Inc.. Dr. Moebius has stock in Athira Pharma, Inc.. Ms. Ooi has received personal compensation for serving as an employee of Athira Pharma Inc. Ms. Ooi has stock in Athira Pharma Inc. Dr. Hale has received personal compensation for serving as an employee of Athira Pharma. Dr. Hale has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Takeda. Dr. Hale has stock in Amgen. Dr. Setti has received personal compensation for serving as an employee of Athira Pharma. Dr. Setti has stock in Athira Pharma. Mrs. Kleist has received personal compensation for serving as an employee of Athira Pharma. Mrs. Kleist has received personal compensation for serving as an employee of Alpine Immune Sciences. Mrs. Kleist has stock in Athira Pharma. Mrs. Kleist has stock in Alpine Immune Sciences. Dr. Bernick has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lilly. Dr. Bernick has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Optina. Dr. Bernick has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai. Dr. Bernick has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Corium. Dr. Bernick has stock in Aurora. The institution of Dr. Bernick has received research support from UFC. The institution of Dr. Bernick has received research support from Top Rank Promotions. The institution of Dr. Bernick has received research support from Haymon Boxing.