ACU193 treatment reduced amyloid plaques in early Alzheimer disease patients, suggesting AßOs as a viable target, with safety data and ARIA analysis presented at CTAD 2023.
In new exploratory findings from the phase 1, first-in-human INTERCEPT-AD trial (NCT04931459), treatment with ACU193 (Acumen Pharmaceuticals), an anti-amyloid-ß oligomer (AßO) antibody, demonstrated dose-dependent reductions in amyloid plaque among patients with early Alzheimer disease (AD). Overall, the data points to the validity of AßOs as a target in the treatment of AD.1
Presented at the 2023 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 24-27, in Boston, Massachusetts by Eric Siemers, MD, chief medical officer of Acumen, a 25% reduction was observed in Cohort 6 (60 mg/kg Q4W) at day 63 and a 20% reduction in Cohort 7 (25 mg/kg Q2W) at day 70 (P = .01 for both cohorts). Using composite cortical PET images expressed in centiloids, some baseline amyloid plaque load values were lower than those typically seen in other studies.
"Following Acumen’s announcement of positive topline results from the Phase 1, first-in-human trial of ACU193, we are excited to present more extensive insights into the trial data and novel target engagement of ACU193," Daniel O’Connell, president and chief executive officer at Acumen, said in a statement. "This deeper dive into our Phase 1 results offer further support that ACU193 may offer a differentiated, next-generation treatment to help address unmet needs of people living with Alzheimer’s disease."
The study featured two parts: a single-ascending dose portion where patients were randomized 6:2 to ACU193 (2, 10, 25, or 60 mg/kg) or placebo, and a multiple-ascending dose section where patients where patients were randomized 8:2 to ACU193 (10 or 60 mg/kg every 4 weeks or 25 mg/kg every 2 weeks or placebo. In total, 62 of the 65 patients included in the study received at least 1 dose of ACU193 or placebo. The trial’s primary outcome measures included incidence and severity of treatment-related adverse events (TEAEs) or serious TEAEs, changes in 12-lead ECGs, the Columbia-Suicide Severity Rating Scale, and in clinic laboratory tests and MRI findings.
In terms of safety, the most common TEAEs observed from all ACU193 dose groups combined were amyloid-related imaging abnormalities (ARIA)-edema (10.4%), ARIA-H (8.3%), COVID-19 (6.3%), hypersensitivity (6.3%), bronchitis (4.2%), headache (4.2%), fall (4.2%), and post lumbar puncture syndrome (4.2%). There were no drug-related serious AEs recorded.
Led by Stephen Salloway, MD, director of Neurology and the Memory and Aging Program at Butler Hospital, a second analysis presented at CTAD 2023 looked at the characteristics of participants from the study who did and did not develop ARIA while on active treatment. Overall, there were 5 cases of ARIA-E: 1 case at 10 mg/kg followed by the third administration of the drug (7.1%), 1 occurred at 25 mg/kg following the second administration of the drug (7.1%), and 3 occurring at 60 mg/kg (21.4% dose levels.2
For the 60 mg/kg group, 2 cases of ARIA-E were observed after a single dose and 1 case was found after 3 administrations of the drug. Additionally, there was 1 case of symptomatic ARIA-E that occurred after the administration of ACU193 at 60 mg/kg (2.1%). In terms of apolipoprotein (APOE) carriers, 4 of the 5 cases of ARIA-E were in ε4 heterozygotes, otherwise 47% of the study population, and none of the 6 ε4 homozygotes that received the agent developed ARIA-E, despite comprising 13% of the study population. Continued use of cortical PET imaging found baseline centiloids for the 5 ARIA cases ranging from 69.2 to 111.2, with all cases resulting in an end-of-study change from baseline ranging from –10% to –47.4%.3