Acumen presents Phase 1 updates on ACU193 in early AD

Acumen Pharmaceuticals presented further analyses of the Phase 1 INTERCEPT-AD trial evaluating ACU193, the first clinical-stage AbetaO-targeting antibody, at the 16th Annual Clinical Trials on Alzheimer’s Disease conference in Boston and online. The additional analyses reveal robust target engagement data modeling informing dose selection for Acumen’s upcoming Phase 2/3 trial, as well as further details and characteristics around the observed plaque reduction and relatively low overall levels of ARIA-E during a late breaking symposium. Acumen additionally presented new target engagement and pharmacokinetic analyses from clinical trial recruitment in four posters at the conference. Acumen plans to progress to a Phase 2/3 clinical study, with the Phase 2 portion planned to begin in the first half of 2024.: Positive topline results from the Phase 1 INTERCEPT-AD, announced in July 2023, demonstrated that ACU193 was well-tolerated with a compelling overall safety profile, meeting the primary objective of this Phase 1 study in both single- and multiple-dose regimens in 62 participants with early AD. Results also demonstrated dose related plaque reduction, low overall ARIA-E and PK results supporting dosing of ACU193 every four weeks, ultimately confirming proof-of-mechanism for the first clinical-stage monoclonal antibody designed to selectively bind AbetaOs while potentially offering improved safety and clinical benefit over existing amyloid-directed therapies. Further analyses and data modeling of the robust Phase 1 dataset, presented at CTAD, shed deeper insights into the broad therapeutic potential of ACU193 and the clinical validity of targeting AbetaOs, while helping to inform the subsequent Phase 2/3 study that will assess clinical efficacy. In a late-breaking symposium, titled “INTERCEPT-AD phase 1 insights and findings from the investigation of ACU193, a monoclonal antibody targeting soluble Abeta oligomers,” detailed results were discussed during the following presentations: Determination of Target Engagement at Various Doses of ACU193 in INTERCEPT-AD: ACU193 demonstrated direct target engagement of toxic AbetaOs in a dose-proportional manner, using a novel assay to measure cerebral spinal fluid concentrations of ACU193 bound to AbetaOs, which approached maximal target engagement with higher doses of ACU193. Further analysis of this novel endpoint, based on robust pharmacokinetic/pharmacodynamic data modeling conducted in collaboration with Certara, demonstrated the pharmacokinetics of ACU193 in CSF and its correlation with dose and dose regimen and serum PK. Modeling the target engagement Emax curve offered the opportunity to select doses of 35 and 50 mg/kg with substantial target engagement of AbetaOs for the Phase 2/3 study. Amyloid plaque reduction results from the Phase 1 trial were also considered in the selection of 35 and 50 mg/kg doses, which will be evaluated versus placebo in the Phase 2/3 study. Reduction in Amyloid Plaque Load at Higher Doses of ACU193 in INTERCEPT-AD: In INTERCEPT-AD, dose-related, statistically significant amyloid plaque reduction that was comparable to approved and in-review therapies at similar time points, was observed in higher dose cohorts. This finding demonstrates ACU193’s activity in the brain and is a positive development given the relationship between robust plaque reduction and slowing clinical decline established by other Abeta-targeting antibodies. The amyloid positron emission tomography data for inclusion in the study were assessed using a hybrid approach to evaluating amyloid positivity in PET scans based on SUVr and, in some cases, visual reads, which may be useful in detecting amyloid positivity below the SUVr threshold. These visual reads may be of particular importance for patients with early AD. The presentation also explored potential mechanistic explanations for the unexpected plaque reduction effect of ACU193 with limited ARIA-E, given its selectivity for AbetaOs and minimal binding of other Abeta species. A Phase 2/3 study is planned to assess primarily the clinical efficacy of ACU193 and also to more fully understand its effect on plaques. Characteristics of Participants in INTERCEPT-AD Who Did or Did Not Develop ARIA with ACU193: As previously reported, the INTERCEPT-AD study demonstrated overall low incidence of ARIA-E, with five cases of ARIA-E in the 48 participants treated with ACU193. In further subgroup data, as presented by Dr. Stephen Salloway, M.D., M.S., Alpert Medical School of Brown University, four of the five cases of ARIA-E occurred in APOE4 heterozygotes and none in APOE4 homozygotes. The presentation also detailed characteristics among participants who did and did not experience amyloid plaque reduction, helping to shed light on possible explanations for the variability in the reduction of plaque load seen in different participants.