Abstract Details

Title INTERCEPT-AD Biomarker Results: Early Effect of Sabirnetug Treatment on Synaptic Biomarkers in Alzheimer's Disease

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P12 - Poster Session 12 (11:45 AM-12:45 PM)

Poster/Presentation
Number 3-003

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.

Authors/Disclosures
Elizabeth A. Johnson, PhD PRESENTER	Dr. Johnson has received personal compensation for serving as an employee of Acumen Pharmaceuticals.
Erika N. Cline, PhD	Dr. Cline has received personal compensation for serving as an employee of Acumen Pharmaceuticals. Dr. Cline has stock in Acumen Pharmaceuticals.
Karen Sundell (Eli Lilly and Company)	Karen Sundell has received personal compensation for serving as an employee of Acumen Pharmaceuticals . Karen Sundell has stock in Acumen Pharmaceuticals .
Daniel Antwi-Berko, PhD	Dr. Antwi-Berko has nothing to disclose.
Marleen J. Koel-Simmelink, Dr	Dr. Koel-Simmelink has nothing to disclose.
Charlotte Teunissen, PhD	Prof. Teunissen has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer. Prof. Teunissen has received publishing royalties from a publication relating to health care.
Eric R. Siemers, MD (Siemers Integration LLC)	Dr. Siemers has received personal compensation for serving as an employee of Acumen Pharmaceuticals. The institution of Dr. Siemers has received personal compensation in the range of $500,000-$999,999 for serving as a Consultant for Vaccinex Pharmceuticals. The institution of Dr. Siemers has received personal compensation in the range of $500,000-$999,999 for serving as a Consultant for Gates Ventures LLC. Dr. Siemers has or had stock in Acumen Pharmaceuticals.Dr. Siemers has or had stock in Ell Lilly and Company.Dr. Siemers has received personal compensation in the range of $0-$499 for serving as a study section reviewer with National Institutes of Health. Dr. Siemers has a non-compensated relationship as a Volunteer with Alzheimer's Association that is relevant to AAN interests or activities.
Hao Zhang, PhD	Dr. Zhang has received personal compensation for serving as an employee of Acumen Pharmaceuticals.
Maddelyn Hyland, MPH	Miss Hyland has received personal compensation for serving as an employee of Acumen Pharmaceuticals.
Gopalan Sethuraman	Dr. Sethuraman has received personal compensation for serving as an employee of Acumen Pharmaceuticals. Dr. Sethuraman has stock in Acumen Pharmaceuticals.
Hugo M. Vanderstichele, PhD	Dr. Vanderstichele has received personal compensation in the range of $0-$499 for serving as a Consultant for Acumenpharm.
june kaplow, PhD	Dr. kaplow has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Acumen Pharmaceuticals Inc.
Robert A. Dean	Robert A. Dean has received personal compensation for serving as an employee of Acumen Pharmaceutics. Robert A. Dean has received personal compensation for serving as an employee of Gates Ventures. Robert A. Dean has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Robert A Dean Consulting, LLC. Robert A. Dean has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Acumen.
Jasna Jerecic, PhD	Dr. Jerecic has received personal compensation for serving as an employee of Acumen Pharmaceuticals Inc.

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