Trial Details
Results from the Phase 1 INTERCEPT-AD trial demonstrated rapid, direct target engagement of amyloid β oligomers (AβOs) in a dose proportional manner, changes in biochemical biomarkers in cerebrospinal fluid (CSF), statistically significant amyloid plaque reduction within higher multiple-ascending-dose (MAD) cohorts, and a favorable safety and tolerability profile with a low overall incidence of amyloid-related imaging abnormalities with edema (ARIA-E).
Study Participants
Sixty-two study participants with early AD received study drug in the INTERCEPT-AD trial.
Dosage
The study design included single-ascending-dose (SAD) and MAD cohorts. Dosages were 2, 10, 25 and 60 mg/kg sabirnetug administered as one to three intravenous infusions.
Key Findings
Safety and Tolerability
Sabirnetug was well-tolerated, with no drug-related serious adverse events reported. The overall rate of amyloid related imaging abnormalities – edema (ARIA-E) was 10.4%, which included one case of mildly symptomatic ARIA-E (2.1%) with resolution. Additionally, there was no ARIA-E observed in APOE homozygotic participants. Four of the five cases of ARIA-E were in APOE heterozygotes.
Rapid Amyloid Plaque Reduction
An analysis of change in brain amyloid plaque load, as measured by positron emission tomography (PET), demonstrated a rapid, mean decrease at the higher dosages studied (60 mg/kg every 4 weeks [Q4W] and 25 mg/kg every 2 weeks [Q2W]). This amyloid plaque reduction after 6-12 weeks (from baseline to endpoint within cohorts) was statistically significant (p = 0.01). This finding provides evidence that sabirnetug is active in the brain and that targeting AβOs is relevant for AD pathology.
Central Target Engagement
PK results demonstrated dose proportional exposure in plasma and CSF. Dose-related central target engagement was observed as measured by sabirnetug-AβO complex, establishing clinical proof of mechanism and the first target engagement assay developed that is specific to an AβO-targeting antibody. In both the SAD and the MAD portions of the study, a statistically significant, dose-related increase in target engagement of AβOs was observed starting at the dose of 10 mg/kg and was correlated to concentrations of drug 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 dosages, sabirnetug concentrations approached saturation of AβOs, and active removal of target from the brain.
Biomarkers
Sabirnetug showed normalizing trends in the multiple ascending dose cohorts on CSF levels of the AD biomarkers p-tau181, p-tau217, total tau, and the Aβ42/Aβ40 ratio as well as the synaptic biomarkers VAMP2, neurogranin, and neuropentraxin 2. These findings are consistent with downstream pharmacodynamic effects of sabirnetug, after just three administrations, and with sabirnetug’s mechanism of action and target engagement of synaptotoxic AβOs. Additionally, the combined effect of sabirnetug on measured downstream biomarkers is consistent with the hypothesis that AβOs drive the downstream neurodegenerative process in AD.
