Topline results of INTERCEPT‐AD: A phase I trial of Aβ oligomer‐targeting ACU193 in early Alzheimer’s disease

Abstract

AbstractBackgroundACU193 is a humanized IgG2 subclass monoclonal antibody targeting soluble amyloid‐beta oligomers (sAβOs). Growing evidence supports the view that sAβOs may be the most toxic and pathogenic form of Aβ relative to Aβ monomers and amyloid plaques and are one of the primary drivers of Alzheimer’s disease (AD) neurodegeneration. Thus, blocking the toxicity of sAβOs with ACU193 is a promising approach for treating AD.MethodINTERCEPT‐AD is a phase 1 randomized, placebo‐controlled, single‐ and multiple‐ ascending dose (SAD/MAD) study of the safety, tolerability, and pharmacokinetics (PK) of intravenous ACU193 in participants with early AD, i.e., mild cognitive impairment or mild dementia due to AD. Key inclusion criteria are 55‐90 years of age, confirmation of amyloid pathology with a PET scan, MMSE score of 18‐30, and CDR‐Global score (CDR‐GS) of 0.5 or 1.0. The MAD portion of the study includes three administrations of ACU193 at doses of 10, 25, or 60 mg/kg. In addition to standard safety measures, MRI is assessed periodically. Cerebrospinal fluid is collected to assess PK and evidence of target engagement. The study also includes exploratory measures such as standard cognitive and functional assessments, a computerized cognitive test battery, measures of cerebral blood flow via arterial spin labeling on MRI, and various plasma biomarkers.ResultSixty‐five participants from 17 U.S. study sites were randomized to INTERCEPT‐AD, with 53% female and baseline age of 72.1 ± 7.8 years (mean ± SD). The baseline MMSE was 24.2 ± 3.6, CDR‐GS was 0.64 ± 0.27, and CDR‐Sum of Boxes was 3.5 ± 1.8. In addition to baseline characteristics, the presentation will provide topline safety results, frequency of amyloid‐related imaging abnormalities (ARIA), PK assessments, and evidence of target engagement. Some exploratory measures including cognitive and functional assessments, computerized cognitive testing, and endpoint florbetapir PET results will also be presented.ConclusionWe will present topline results, along with key baseline demographic, clinical, and cognitive characteristics of participants in the INTERCEPT‐AD trial. The data generated from this trial will guide further development of ACU193 in a subsequent trial to test the novel mechanism of action of ACU193 in the treatment of early AD.