ABBV-916 Shows Amyloid Clearance in Early Alzheimer Disease Before Program Discontinuation

In a phase 1b/2 study published in Alzheimer's & Dementia, ABBV-916 (AbbVie), an investigational anti-amyloid monoclonal antibody, demonstrated dose-dependent reductions in brain amyloid plaque burden in adults with early Alzheimer disease (AD), with the greatest reductions observed at doses of 300 mg and 900 mg administered every 4 weeks. The study also showed changes in plasma biomarkers consistent with amyloid clearance, although amyloid-related imaging abnormalities (ARIA) occurred frequently at higher exposure levels.¹

The global, multicenter, randomized, double-blind, placebo-controlled trial enrolled 106 patients with early AD, with 80 assigned to ABBV-916 and 26 to placebo. Participants received intravenous treatment every 4 weeks for 24 weeks across multiple ascending dose cohorts ranging from 10 mg to 3000 mg. The highest planned dose was initially reduced from 3000 mg to 2000 mg and subsequently down-titrated to 900 mg after safety reviews identified earlier onset of ARIA-E and ARIA-H.

Senior author Hana Florian, MD, Neuroscience Developmer at AbbVie, and colleagues designed the trial to proceed from the multiple ascending dose stage into a dose-expansion stage; however, the program was discontinued before dose expansion because of sponsor business considerations. Investigators noted that although ABBV-916 demonstrated meaningful amyloid clearance, its efficacy and safety profiles did not show a clear advantage over currently approved anti-amyloid therapies.

Dose-Dependent Amyloid Clearance

At week 24, ABBV-916 produced significant reductions in brain amyloid plaque levels compared with placebo at the 30-mg, 300-mg, and 900-mg doses. The estimated differences from placebo were −25.1 Centiloids, −61.9 Centiloids, and −83.7 Centiloids, respectively.¹

The proportion of patients achieving amyloid negativity, defined as less than 24.1 Centiloids, was also greatest at the higher doses. At week 24, 54.6% of patients receiving 300 mg achieved amyloid negativity, compared with 100% of those receiving 900 mg and 71.4% of those in the cohort initially treated with 2000 mg before down-titration to 900 mg. By comparison, no more than 20% of patients receiving the 10-mg, 30-mg, or 100-mg doses achieved amyloid negativity at either week 12 or week 24.

At the 900-mg dose, the mean change in amyloid burden was −50.4 Centiloids at week 12 and −77.0 Centiloids at week 24. The authors noted that these reductions were numerically comparable with those reported for currently approved disease-modifying AD therapies.

Plasma Biomarkers Showed Consistent Changes

Changes in plasma biomarkers were also observed at the 300-mg and 900-mg doses. After 24 weeks, the plasma Aβ42/Aβ40 ratio increased by 15.3% with 300 mg and 15.7% with 900 mg, compared with a 2.3% decrease with placebo.¹

Plasma p-tau217 decreased by 23.8% and 29.8% with the 300-mg and 900-mg doses, respectively, compared with a 15% increase with placebo. GFAP levels similarly decreased by 20.0% with 300 mg and 31.5% with 900 mg, compared with an 11.9% increase with placebo.

Pharmacokinetic analyses showed dose-proportional increases in ABBV-916 serum concentrations following both the first and sixth doses. Trough concentrations reached steady state at approximately 16 weeks, while the cerebrospinal fluid-to-serum concentration ratio was approximately 0.2% to 0.4% after the sixth dose at doses of at least 30 mg administered every 4 weeks. Antidrug antibodies were detected in 3.8% of ABBV-916-treated patients, with all positive results being transient and occurring at low titers.

ARIA Increased With Higher Doses

Safety findings were largely driven by ARIA. Across all ABBV-916-treated patients, 78.8% experienced at least 1 treatment-emergent adverse event (TEAE), 11.3% experienced a serious adverse event, and 20.0% discontinued treatment because of an AE. Most AEs were mild or moderate and nonserious.¹

ARIA-E occurred in 33.8% of ABBV-916-treated patients, while ARIA-H occurred in 25.0%. Most cases emerged during or within 12 weeks of treatment initiation, and the incidence appeared to increase with dose. No patients in the placebo group experienced ARIA-E or ARIA-H.

Of the 27 patients who developed ARIA-E, 8 (29.6%) experienced symptomatic events. Two cases were considered serious, and 5 patients with symptomatic ARIA-E discontinued treatment. Among the 20 patients with ARIA-H, all experienced cerebral microhemorrhages, while 11 also developed superficial siderosis. Four patients with symptomatic ARIA-H discontinued treatment, and no macrohemorrhages were reported.

The investigators also observed an association between APOE ε4 status and ARIA. Among ABBV-916-treated patients, ARIA-E occurred in 44.0% of APOE ε4-positive patients compared with 16.7% of APOE ε4-negative patients. ARIA-H occurred in 32.0% and 13.3% of these groups, respectively. Among the small subgroup of 6 APOE ε4 homozygotes, 5 (83.3%) experienced an ARIA event.

Development Halted Before Dose Expansion

The investigators noted that ABBV-916 was designed to selectively bind Aβ peptides bearing a pyroglutamate residue at position 3, a modified amyloid species thought to be less abundant in the cerebral vasculature. Preclinical findings had suggested the potential for amyloid clearance without microhemorrhage, but the phase 1b/2 findings indicated that selective targeting of this amyloid species was not sufficient to eliminate ARIA risk.¹

Notably, treatment discontinuations were more frequent in cohorts associated with greater amyloid clearance. The authors said this finding suggested that tolerability may become more challenging at exposure levels needed to achieve clinically meaningful amyloid reduction, underscoring the importance of balancing amyloid clearance with ARIA risk when determining dose and treatment regimen.

The study was discontinued before the planned dose-expansion stage because of sponsor business considerations. According to the investigators, the decision reflected the lack of substantial differentiation in efficacy or safety compared with currently approved anti-amyloid therapies rather than an absence of biological activity. The early termination also prevented further evaluation of whether alternative dosing strategies, intermediate doses, or dose titration could have reduced ARIA risk while maintaining amyloid clearance.

The authors acknowledged several limitations, including the small sample size, relatively short treatment period, predominantly White study population, and early discontinuation of the program. Interruptions in dosing and treatment discontinuations related to adverse events may also have affected assessment of ABBV-916's full potential for amyloid clearance.

Ultimately, the investigators concluded that ABBV-916 demonstrated amyloid clearance and a safety profile generally comparable with currently approved anti-amyloid immunotherapies, but the study provided no clear evidence of greater benefit or meaningful differentiation that would support continued development.

REFERENCES
1. Lynch SY, Wang Y, Wang D, et al. A randomized phase 1b/2 trial of ABBV-916 in adults with early Alzheimer's disease. Alzheimer's Dement. 2026; 22:e71715. doi: 10.1002/alz.71715