Biofluid biomarker changes following treatment with sabirnetug (ACU193) in INTERCEPT-AD, a phase 1 trial in early Alzheimer's disease.

Objective: Sabirnetug (ACU193) is a humanized monoclonal antibody selective for soluble amyloid beta oligomers (AβOs), synaptotoxins that are early and persistent triggers of Alzheimer's disease (AD). Sabirnetug pharmacodynamics were examined in the INTERCEPT-AD phase 1 study in mild cognitive impairment and mild dementia due to AD (NCT04931459) using biofluid biomarkers associated with Aβ and tau pathology, synaptic dysfunction, neuroinflammation, and neurodegeneration.
Methods: INTERCEPT-AD was a randomized, first-in-human study of sabirnetug versus placebo administered as a single (SAD; 2, 10, 25, 60 mg/kg) or multiple (MAD; three doses of 10 or 60 mg/kg every 4 weeks [Q4W] or 25 mg/kg Q2W) ascending doses. Biomarkers were measured pre-/post-dose in CSF and EDTA-plasma. Correlations of biomarker changes versus dose, exposure duration, and target engagement were determined.
Results: In MAD cohorts, CSF pTau181 decreased significantly (60 mg/kg Q4W, p = 0.049). VAMP2 decreased significantly at all doses (p ≤ 0.041); neurogranin decreased significantly at 60 mg/kg Q4W (p = 0.037). Aβ _1-42 /Aβ _1-40 trended upward with sabirnetug dose. Aβ _1-42 /Aβ _1-40 and neurogranin changes correlated with sabirnetug-AβO target engagement (p ≤ 0.01). Decreases in tTau, VAMP2, and neurogranin correlated with exposure duration (p ≤ 0.007). Plasma pTau181, pTau217, GFAP, and NfL trended lower.
Discussion: Following three sabirnetug doses, changes in CSF and plasma biomarkers were observed. The CSF biomarker response increased with increasing dose and exposure duration, consistent with previous reports that sabirnetug reaches the central compartment and engages its AβO target. The ongoing phase 2 ALTITUDE-AD study (NCT06335173) will test whether sabirnetug's pharmacodynamic effects can be substantiated with a larger sample size and longer treatment duration.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Erika N. Cline, Karen Sundell, Elizabeth Johnson, Maddelyn Hyland, Hao Zhang, Gopalan Sethuraman, Todd Feaster, Eric Siemers, and Jasna Jerecic are employees of, and minor stockholders in, Acumen Pharmaceuticals, Inc. Hugo Vanderstichele, June Kaplow, and Robert A. Dean are paid consultants of Acumen Pharmaceuticals, Inc Eugeen Vanmechelen and Erik Stoops are employees of ADx NeuroSciences, which provided services under contract to Acumen Pharmaceuticals, Inc. Charlotte E. Teunissen received grants of research funding from the European Commission, the European Partnership on Metrology, The Duch Research Council, The Alzheimer's Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, Topsector Life Sciences & Health, Acumen Pharmaceuticals, ADX Neurosciences, AC Immune, Alamar, Aribio, Axon-Neurosciences, Beckman-Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapy, EIP Pharma, Eisai, Eli Lilly and Company, Fijirebio, Instant Nano Biosciences, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Toyama, and Vivoryon. She received consulting and or speaking fees from Aribio, Biogen, Beckman-Coulter, Cognition Therapy, Eli Lilly and Company, Merck, Novo Nordisk, Olink, Roche, and Veravas. Daniel Antwi-Berko and Marleen J.A. Koel-Simmelink declare no conflict of interests.
(Copyright © 2025. Published by Elsevier Masson SAS.)