Acumen Pharmaceuticals Presents Positive Topline Results from First-in-Human Phase 1 Study of ACU193 for Early Alzheimer’s Disease
Acumen Pharmaceuticals, Inc. (NASDAQ: ABOS), a clinical-stage biopharmaceutical company developing a novel therapeutic that targets soluble amyloid beta oligomers (AβOs) for the treatment of Alzheimer’s disease (AD), has presented positive topline results from the Phase 1 INTERCEPT-AD trial of ACU193, the first clinical-stage AβO targeting antibody therapy in early AD, at the Alzheimer’s Association International Conference (AAIC®) 2023, taking place in Amsterdam and online from July 16-20, 2023.
Topline results demonstrated that ACU193 was generally well-tolerated with a compelling overall safety profile, meeting the primary objective of this Phase 1, first-in-human, randomized, double-blind, placebo-controlled study in both single and multiple doses in 60 participants with early AD. Dose levels were 2, 10, 25, and 60 mg/kg for one to three doses administered intravenously. An analysis of change in amyloid plaque load, as measured by positron emission tomography (PET) SUVr, demonstrated a rapid, dose-related mean decrease at the higher dose levels studied (60 mg/kg every 4 weeks [Q4W] and 25 mg/kg every 2 weeks [Q2W]).
This finding is comparable to mean amyloid plaque decreases of approved Aß monoclonal antibodies at similar time points in their clinical development. The overall rate of amyloid-related imaging abnormalities – edema (ARIA-E) was 10.4%, which included one case of symptomatic ARIA-E (2.1%). Pharmacokinetic results in serum and cerebrospinal fluid (CSF) demonstrated statistically significant dose proportionality and support monthly dosing of ACU193. Statistically significant, dose-related central target engagement was observed as measured by ACU193-AßO complex, establishing the first target engagement assay developed that is specific to an AßO-targeting antibody. An exposure-response relationship (Emax) model revealed near-maximal target engagement with repeated dosing at 25 mg/kg and 60 mg/kg.
“We are very pleased to present the first clinical data from our Phase 1 INTERCEPT-AD study at AAIC. ACU193’s observed dose-related central target engagement, rapid reduction of amyloid plaque, and compelling safety profile validate our confidence in ACU193’s differentiated mechanism of action: selectively targeting amyloid beta oligomers,” said Daniel O’Connell, President and Chief Executive Officer of Acumen. “We believe that the robust data package generated by this comprehensive Phase 1 study establishes ACU193’s broad therapeutic index and guides a future clinical dosing rationale. We look forward to an anticipated interaction with the FDA in the fourth quarter to inform our next phase of development for ACU193.”
ACU193 Demonstrated Rapid, Dose-Related, Statistically Significant Amyloid Plaque Reduction
Higher doses of ACU193 (60 mg/kg Q4W and 25 mg/kg Q2W) showed a statistically significant reduction in amyloid plaque load as determined by amyloid PET after 6-12 weeks (from baseline to endpoint within cohorts (p = 0.01)). This finding provides evidence that ACU193 is active in the brain.
ACU193 was Well-Tolerated Across Dose Cohorts
ACU193 was well-tolerated throughout the single-ascending (SAD) and multiple-ascending (MAD) dose cohorts. Three treatment-emergent serious adverse events (SAEs) were observed after the administration of ACU193; all were deemed not related or unlikely related to ACU193. The most common treatment-emergent adverse events (AEs) from all dose groups combined were ARIA-E (10.4%), ARIA-H (hemorrhage) (8.3%), COVID-19 (6.3%), hypersensitivity (6.3%), bronchitis (4.2%), headache (4.2%), fall (4.2%) and post LP syndrome (4.2%). Of the five individuals who developed ARIA-E, only one had associated clinical symptoms, representing an overall symptomatic ARIA-E rate of 2.1% in the study. Of note, no APOE4 homozygote patients exhibited ARIA-E (n=6 treated).
ACU193 Demonstrated Consistent Dose-Related Pharmacokinetics (PK)
In both the SAD and MAD cohorts of the study, clear evidence of a dose relationship was observed for ACU193 exposure. Serum PK was dose-related without drug accumulation, and CSF PK was dose- and dose-regimen proportional. Levels of ACU193 detected in CSF in all cohorts were in excess of endogenous levels of AβOs reported in CSF. Evidence of treatment-emergent immunogenicity was observed; anti-drug antibodies were consistently low titer, and preliminary assessment revealed no apparent effect on serum PK. These data support monthly dosing of ACU193.
ACU193 Demonstrated Dose-Related Target Engagement of Toxic AβOs
In both the SAD and the MAD portions of the study, a statistically significant, dose-related increase in target engagement of toxic AβOs was observed starting at 10 mg/kg and was related to concentrations of the drug in CSF. This was evaluated by a novel assay of target engagement that assessed the concentration of the ACU193-AβO complex in CSF. Notably, maximal target engagement response was approached at the highest doses studied (25 mg/kg Q2W and 60 mg/kg Q4W), as assessed in an exposure-response relationship (Emax) model. This implies that at these dose levels, ACU193 concentrations approached saturation of AβOs, and suggests active removal of the target from the brain.
*One patient from Cohort 5 (10 mg/kg Q4W) was excluded because only received one administration of the drug (study drug discontinued after lacunar infarct).
“I am thrilled to announce that ACU193 bound to toxic AβOs in patients and did so in a dose-proportional manner with evidence of near-maximal target engagement. I’m also proud that our team has made significant progress developing the first target engagement assay for an Aβ oligomer-targeted antibody,” said Eric Siemers, M.D., Chief Medical Officer of Acumen. “Taken together with the compelling safety profile at doses that engage the target, and pharmacokinetic data that supports monthly dosing, ACU193 has the distinct potential to be a differentiated antibody for the treatment of early Alzheimer’s disease.”
Exploratory measures of potential acute drug effects, including assessment of cognition, as determined by a computerized cognitive battery, and changes in cerebral blood flow, as determined by arterial spin labeling (ASL) with magnetic resonance imaging (Siemens MRI), did not show discernible effects from the immediate administration of ACU193. This was not unexpected due to the short duration and small sample size of INTERCEPT-AD. Additional biofluids for assessment of biomarkers of downstream neurodegeneration were collected during the study, and analyses are in progress. These results will be presented at a later date and are not expected to show significant changes due to the short duration and small sample size of the trial.
In addition to the topline readout, Acumen also presented data during the Featured Research Session at AAIC describing the baseline characteristics for INTERCEPT-AD patients as well as study recruitment techniques that were used to help Acumen recruit a diverse population for the trial.
The full results of the INTERCEPT-AD study will be presented at a future medical congress and submitted for publication in a peer-reviewed clinical journal. Acumen plans to discuss these results with regulators to assess the next steps for the clinical development of ACU193 and determine a timeline for progressing to a Phase 2/3 clinical study.