Evaluating Sabirnetug in Early Alzheimer’s: Targeting Soluble Aβ Oligomers

Despite progress in immunotherapy for Alzheimer’s, most approved antibodies focus on plaques rather than earlier, soluble forms of amyloid-beta.

But now, the INTERCEPT-AD Phase 1 trial evaluated sabirnetug, a monoclonal antibody selective for toxic Aβ oligomers, in participants with mild cognitive impairment or mild dementia due to Alzheimer’s disease.

The study assessed safety, pharmacokinetics, target engagement, and early biomarker response to determine whether targeting soluble oligomers could produce central engagement and downstream effects without relying on direct plaque binding.

Study Design and Dosing Framework

INTERCEPT-AD was a randomized, double-blind, placebo-controlled first-in-human trial conducted at 15 sites across the United States. Participants were adults aged 55 to 90 with amyloid-positive PET scans and a clinical diagnosis of early symptomatic Alzheimer’s disease. The trial was divided into two parts: a single ascending dose (SAD) phase and a multiple ascending dose (MAD) phase.

In the SAD phase, 32 participants were randomized in a 6:2 ratio to receive one intravenous infusion of sabirnetug (2, 10, 25, or 60 mg/kg) or placebo. In the MAD phase, 33 new participants were randomized in an 8:2 ratio to receive three infusions of sabirnetug (10 mg/kg or 60 mg/kg every four weeks, or 25 mg/kg every two weeks) or placebo.

Participants were monitored for up to 20 weeks post-infusion in SAD and 10-20 weeks post-final dose in MAD, with pharmacokinetic, CSF, imaging, and safety assessments throughout.

Eligibility criteria excluded those with recent investigational drug use, significant cerebrovascular disease, or more than four microhemorrhages on baseline MRI. APOE genotyping was conducted, but not used for stratification.

Safety and Target Engagement Findings

Looking at the results, sabirnetug was generally well tolerated. Among participants receiving active treatment, 56.3% experienced at least one treatment-emergent adverse event (TEAE), compared to 42.9% in the placebo group. Events were mostly mild or moderate.

Five participants (10.4%) developed amyloid-related imaging abnormalities with edema/effusion (ARIA-E), all of whom were women. Only one case was symptomatic and resolved without intervention. No ARIA-E or ARIA-H occurred in any of the six APOE ε4 homozygotes who received sabirnetug.

Pharmacokinetic analyses showed dose-proportional increases in serum and cerebrospinal fluid (CSF) concentrations. A validated immunoassay demonstrated formation of sabirnetug–AβO complexes in CSF in a dose-dependent manner, confirming central target engagement.

Amyloid PET Signal Reduction

Although sabirnetug was designed to avoid plaque binding, participants in the higher-dose MAD cohorts exhibited reductions in brain amyloid as measured by PET.

In contrast, participants receiving placebo or lower doses showed minimal change or an increase in signal. These findings raise the possibility of indirect effects on plaque stability or re-equilibration of soluble and insoluble amyloid pools.

The apparent lack of ARIA-E in APOE ε4 homozygotes contrasts with results from plaque-targeting agents such as aducanumab and lecanemab, where APOE ε4 status has been associated with elevated ARIA risk. However, the sample size was not powered to detect genotype-specific differences.

Cognitive Measures and Phase 2 Transition

No statistically significant changes were observed in exploratory cognitive assessments. Given the limited dosing exposure and short duration of follow-up in this early-phase trial, though, clinical signals were not expected.

However, the results informed dosing selection for the ongoing Phase 2 ALTITUDE-AD trial, which is evaluating 35 mg/kg and 50 mg/kg every four weeks. These doses were modeled to maintain ≥70% of maximal target engagement throughout the dosing interval and are expected to replicate the PET findings seen at 60 mg/kg.

Outlook for AβO-Targeting Strategies

The INTERCEPT-AD study met its primary objectives and provided evidence that selective AβO targeting is feasible, measurable, and biologically active in humans. The observed reductions in amyloid PET signal occurred despite the antibody’s low plaque affinity, suggesting mechanistic differentiation from plaque-clearing agents.

The Phase 2 ALTITUDE-AD trial will assess whether these central effects translate to cognitive benefit. If confirmed, sabirnetug may define a new class of Alzheimer’s immunotherapy focused on earlier, soluble drivers of neurotoxicity.

Reference:
Siemers E, Feaster T, Sethuraman G, et al. INTERCEPT-AD, a phase 1 study of intravenous sabirnetug in participants with mild cognitive impairment or mild dementia due to Alzheimer’s disease. J Prev Alzheimers Dis. 2025;12:100005. doi:10.1016/j.tjpad.2024.100005