Background

This humanized IgG2 monoclonal antibody selectively binds soluble Aβ oligomers, aka Aβ-derived diffusible ligands (ADDLs). Though they constitute a minor fraction of Aβ in the brain, soluble oligomers are believed to be the most neurotoxic, and to be responsible for memory loss and neuronal death (e.g., Gong et al., 2003; Hong et al., 2018). This antibody emerged from a research and development collaboration forged in 2004 between Acumen and Merck. The partnership ended in 2011, at which point Acumen regained development rights.

Preclinical work on ACU193 has been presented at meetings. In 2013, Acumen reported that the antibody binds to soluble Aβ oligomers with low nanomolar affinity and greater than 500-fold selectivity over Aβ monomers or fibrils. ACU193 blocked oligomers from interacting with cultured hippocampal neurons at an IC50 of 17 nM, and was unaffected by addition of excess Aβ monomer. In Tg-AD mice, ACU193 bound soluble oligomers in brain tissue, lessened plaque deposition, and was claimed to reduce abnormal nighttime hyperactivity. Based on ACU193's pharmacokinetics in animals, the company expects to achieve brain levels of ACU193 more than 200 times higher than soluble oligomer concentrations measured in Alzheimer’s patient CSF (Krafft et al., 2013). In 2015, the company described the use of ACU193 in an ultrasensitive immunoassay to detect soluble Aβ oligomers in mice (Cline et al., 2015).

The mouse version of ACU193, ACU-3B3, reportedly blocks Aβ oligomer-induced calcium elevation in hippocampal neurons in culture, and reduces amyloid pathology and behavioral deficits in AD mouse models (Wang et al., 2018; Ma et al., 2019). ACU193 was also used experimentally in studies proposing a physiological signaling role for transient formation of Aβ oligomers in embryonic tissue development (Bartley et al., 2022).

ACU193 coupled to magnetic nanoparticles was used to detect Aβ oligomers in rabbit brain by MRI (Rozema et al., 2020). For a description of the treatment rationale and preclinical data, see Krafft et al., 2022.

Findings

In June 2021, Acumen began a Phase 1 trial of intravenous ACU193 in 65 people with MCI or mild AD. The study evaluated safety and tolerability, including 12-lead EEG, as well as pharmacokinetic and pharmacodynamic parameters, of up to three different single and multiple doses. Co-sponsored by the National Institute on Aging, this trial ran at 17 sites across the U.S., and finished in July 2023. The rationale and design are published (Siemers et al., 2023). The company presented top-line results at the July 2023 AAIC. The study tested single doses of 2, 10, 25, or 60 mg/kg, and three doses of 10 or 60 mg/kg monthly, or 25 mg/kg every two weeks. Three serious adverse events were deemed unrelated to drug. Four cases of ARIA-H and five of ARIA-E were detected in 48 treated participants, with one symptomatic case in the 60 mg/kg monthly cohort. All improved or resolved by the end of the study. Blood and CSF pharmacokinetics were dose-dependent, with CSF concentrations exceeding reported oligomer levels. Target engagement was assessed by measuring antibody-oligomer complexes in CSF, which were found to increase with dose. Maximum target engagement occurred after 25 mg/kg biweekly or 60 mg/kg monthly. These doses generated a small reduction in plaque load. The antibody had no clear effect on exploratory outcomes of computerized cognitive testing or cerebral blood flow.

At the 2023 CTAD, the company presented pharmacokinetic and target engagement modeling that informed dose selection for a Phase 2/3 study. That study began in February 2024. It is comparing 18-month courses of 35 mg/kg monthly, 50 mg/kg monthly with titration to mitigate ARIA, and placebo in 2,040 people with early Alzheimer’s disease. The sole primary outcome is change from baseline on the Integrated Alzheimer's Disease Rating Scale (iADRS) score. More than 30 secondary outcomes include other measures of cognition, function, quality of life, neuropsychiatric symptoms, resource utilization, caregiver burden, time saved analysis, PET, and pharmacokinetics, as well as oligomer concentrations in CSF and other biomarkers. An open-label extension is planned. The trial is currently running in the U.S., Canada, and Europe, through January 2031.

For details on ACU193 trials, see clinicaltrials.gov.