INTERCEPT-AD Biomarker Results: Early Effect of Sabirnetug Treatment on Synaptic Biomarkers in Alzheimer's Disease
Elizabeth Johnson1, Erika N Cline1, Karen Sundell1, Daniel Antwi-Berko2, Marleen JA Koel-Simmelink2, Charlotte Teunissen2, Eric Siemers1, Hao Zhang1, Maddelyn Hyland1, Gopalan Sethuraman1, Hugo Vanderstichele1, June Kaplow1, Robert A Dean1, Jasna Jerecic1
1Acumen Pharmaceuticals, Inc, 2Amsterdam UMC
Objective:
To examine early effects of sabirnetug (ACU193) on cerebrospinal fluid (CSF) levels of synaptic biomarkers in study participants with early symptomatic Alzheimer's disease (AD).
Background:
Sabirnetug is a humanized monoclonal antibody selective for soluble amyloid β oligomers (AβOs). AβOs accumulate early in AD and trigger synaptic dysfunction. Sabirnetug pharmacodynamics were assessed in the INTERCEPT-AD phase 1 study of mild cognitive impairment and mild dementia due to AD (NCT04931459).
Design/Methods:
INTERCEPT-AD was a randomized, double-blind, placebo-controlled study with single ascending dose and multiple ascending dose (MAD) parts. MAD participants were randomized 8:2 to sabirnetug (three administrations at 10 or 60 mg/kg every 4 weeks [Q4W] or 25 mg/kg Q2W) or placebo. The synaptic biomarkers vesicle-associated membrane protein 2 (VAMP2), neurogranin, and neuronal pentraxin 2 (NPTX2) were measured in CSF before and after drug administration.
Results:
CSF concentrations of VAMP2 decreased with nominal statistical significance in sabirnetug-treated participants relative to placebo in all three MAD cohorts. The post-synaptic protein neurogranin also showed reductions in concentration, reaching nominal statistical significance after treatment with 60 mg/kg sabirnetug Q4W. The decreases in CSF VAMP2 and neurogranin correlated with time of drug exposure but not with plaque reduction. The pre-synaptic protein NPTX2 did not change with sabirnetug treatment, in contrast to numeric increases in NPTX2 in the placebo group.
Conclusions:
In INTERCEPT-AD, three administrations of sabirnetug were associated with lower CSF concentrations of pre- and post-synaptic AD-related proteins, consistent with sabirnetug nonclinical data demonstrating interruption of AβO synaptic binding. VAMP2 concentrations in the CSF appeared most sensitive to sabirnetug, lowering in all three MAD cohorts. Numeric decreases in neurogranin were also consistently observed. Longer term changes in biomarkers and their relationship with clinical efficacy will be evaluated in the ongoing ALTITUDE-AD phase 2 study (NCT06335173) over 18 months.
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