ABBV-916
A randomized phase 1b/2 trial of ABBV-916 in adults with early Alzheimer's disease
Study Overview
Objective
Evaluate the safety, pharmacokinetics, and amyloid-lowering efficacy of ABBV-916 (an anti-AβpE3 monoclonal antibody) in adults with early Alzheimer's disease.
Study Summary
* ABBV-916 significantly reduced brain amyloid at 24 weeks, with greater reductions at higher doses. * Amyloid negativity was achieved in 55% (300 mg), 100% (900 mg), and 71% (2000→900 mg). * ARIA-E occurred in 34% and ARIA-H in 25%, with ARIA-E highest in APOE ε4 homozygotes (83%); development was discontinued for business reasons.
Intervention
IV ABBV-916 (anti-AβpE3 humanized IgG1 monoclonal antibody) 10–3000 mg every 4 weeks x6 doses vs placebo
Patients per Arm
80 ABBV-916 (across 6 dose cohorts) vs 26 placebo (total N=106)
Bottom Line
ABBV-916 at ≥300 mg IV every 4 weeks produced dose-dependent amyloid-plaque clearance and blood-biomarker changes broadly comparable to approved anti-amyloid therapies, with substantial ARIA rates (ARIA-E 33.8%, ARIA-H 25.0%) that were strongly APOE ε4–dependent; the program was subsequently discontinued for business reasons.
Major Points
- Dose-proportional PK; amyloid PET reduced significantly vs placebo at 30 mg (-25.1 CL), 300 mg (-61.9 CL), and 900 mg (-83.7 CL) at week 24
- Week-24 amyloid negativity (<24.1 CL): 100% at 900 mg, 54.6% at 300 mg, 71.4% in 2000→900 mg down-titrated cohort
- ARIA-E in 33.8% and ARIA-H in 25.0% of ABBV-916 patients; symptomatic ARIA-E in 10.0%; no macrohemorrhage; no deaths in the double-blind period
- ARIA risk rose with APOE ε4 gene dose: 16.7% (non-carrier), 38.6% (heterozygote), 83.3% (homozygote) for ARIA-E
- Selective targeting of pyroglutamate-modified Aβ (AβpE3) did NOT reduce ARIA versus approved therapies
- Sponsor (AbbVie) discontinued the program before dose expansion due to lack of differentiation from approved anti-amyloid therapies
Design
Study Type: Randomized Controlled Trial (Phase 1b/2 multiple ascending dose)
Randomization: 1
Blinding: Double-blind, placebo-controlled
Allocation Ratio: 3:1 ABBV-916:placebo within each cohort
Enrollment Period: Aug 15, 2022 - May 9, 2024
Follow-up Duration: 24-week double-blind period + 16-week safety follow-up (or 2-year extension)
Centers: Multicenter, global
Countries: USA (multiple sites; central IRB Advarra)
Sample Size: 106
Analysis: Full analysis set (all randomized patients receiving ≥1 dose with baseline amyloid PET); MMRM for amyloid change; hypothetical strategy for intercurrent events
Registration: NCT05291234
Inclusion Criteria
- Adults aged 50–90 years
- Met NIA-AA 2018 Research Framework criteria for stage 3 or 4 AD
- MMSE score 20–28
- Plasma amyloid probability score (C2N Diagnostics) consistent with increased likelihood of positive amyloid PET
- Amyloid PET scan ≥37 Centiloids by florbetapir
- No clinically significant findings for laboratory parameters as assessed by the investigator
Exclusion Criteria
- MRI findings of vasogenic edema
- ≥4 cerebral microhemorrhages on MRI
- Any area of superficial siderosis
- Any macrohemorrhage
- Severe white matter disease
- Other clinically significant or unstable medical conditions
- History that would make the patient unsuitable for the study per investigator
Arms
| Field | Control | ABBV-916 10 mg | ABBV-916 30 mg | ABBV-916 100 mg | ABBV-916 300 mg | ABBV-916 900 mg | ABBV-916 2000→900 mg |
|---|---|---|---|---|---|---|---|
| Intervention | IV placebo every 4 weeks x6 doses over 24 weeks | 10 mg IV Q4W x6 | 30 mg IV Q4W x6 | 100 mg IV Q4W x6 | 300 mg IV Q4W x6 | 900 mg IV Q4W x6 (cohorts 5 + 7 combined) | 2000 mg IV first dose(s), down-titrated to 900 mg from week 4 due to safety review |
| Duration | 24 weeks (double-blind) | 24 weeks | 24 weeks | 24 weeks | 24 weeks | 24 weeks | 24 weeks |
| N | 26 | 6 | 8 | 8 | 17 | 28 | 13 |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Safety, PK, and change from baseline to week 24 in brain amyloid plaque deposition by florbetapir PET (Centiloids) | Primary | Placebo (mean baseline): 97.9 CL · ABBV-916 30 mg vs placebo at week 24: -25.1 CL difference (p < 0.05) · ABBV-916 300 mg vs placebo at week 24: -61.9 CL difference (p < 0.0001) · ABBV-916 900 mg vs placebo at week 24: -83.7 CL difference (p < 0.0001) · ABBV-916 900 mg absolute change from baseline: -77.0 CL at week 24 (-50.4 CL at week 12) | |||
| Amyloid negativity (<24.1 CL) at week 24 - 300 mg | Secondary | Value: 54.6% | |||
| Amyloid negativity (<24.1 CL) at week 24 - 900 mg | Secondary | Value: 100% | |||
| Amyloid negativity (<24.1 CL) at week 24 - 2000→900 mg | Secondary | Value: 71.4% | |||
| Plasma Aβ42/Aβ40 change at 24 wk (300 mg) | Secondary | Value: +15.3% · Placebo: -2.3% | |||
| Plasma Aβ42/Aβ40 change at 24 wk (900 mg) | Secondary | Value: +15.7% · Placebo: -2.3% | |||
| Plasma p-tau217 change at 24 wk (300 mg) | Secondary | Value: -23.8% · Placebo: +15% | |||
| Plasma p-tau217 change at 24 wk (900 mg) | Secondary | Value: -29.8% · Placebo: +15% | |||
| Plasma GFAP change at 24 wk (300 mg) | Secondary | Value: -20.0% · Placebo: +11.9% | |||
| Plasma GFAP change at 24 wk (900 mg) | Secondary | Value: -31.5% · Placebo: +11.9% | |||
| Antidrug antibodies | Secondary | Value: 3.8% (3/80) transient low-titer | |||
| Any TEAE (placebo) | Adverse | 69.2% | |||
| Any TEAE (ABBV-916 all) | Adverse | 78.8% | |||
| Serious AE (placebo) | Adverse | 0% | |||
| Serious AE (ABBV-916) | Adverse | 11.3% | |||
| Discontinuation due to AE (placebo) | Adverse | 0% | |||
| Discontinuation due to AE (ABBV-916) | Adverse | 20.0% | |||
| ARIA-E (ABBV-916 all) | Adverse | 33.8% | |||
| ARIA-H (ABBV-916 all) | Adverse | 25.0% | |||
| Symptomatic ARIA-E | Adverse | 10.0% (8/80) | |||
| Symptomatic microhemorrhage | Adverse | 5.0% (4/80) | |||
| Superficial siderosis | Adverse | 13.8% (11/80) | |||
| Macrohemorrhage | Adverse | 0% | |||
| Headache (ABBV-916) | Adverse | 15.0% (vs 3.8% placebo) | |||
| Falls (ABBV-916) | Adverse | 10.0% (vs 0% placebo) | |||
| UTI (ABBV-916) | Adverse | 10.0% (vs 11.5% placebo) | |||
| Dizziness (ABBV-916) | Adverse | 7.5% | |||
| Nausea (ABBV-916) | Adverse | 7.5% | |||
| COVID-19 (ABBV-916) | Adverse | 6.3% | |||
| Hypertension (ABBV-916) | Adverse | 6.3% | |||
| Infusion-related reactions (900 mg) | Adverse | 10.7% | |||
| Deaths (double-blind period) | Adverse | 0 | |||
Subgroup Analysis
ARIA-E incidence by APOE ε4 status: non-carrier 16.7% (5/30), heterozygous carrier 38.6% (17/44), homozygous carrier 83.3% (5/6). ARIA-H incidence: non-carrier 13.3%, heterozygous 29.5%, homozygous 50.0%. Clear APOE ε4 gene-dose relationship for ARIA risk.
Criticisms
- Very small sample size (N=106) and short 24-week double-blind duration
- Predominantly White population (88.8%) limits generalizability across race/ethnicity
- Program terminated before dose expansion (Stage B) due to sponsor's business/strategic reasons, so optimal dose and long-term efficacy/safety could not be established
- Cohort 6 required mid-study down-titration from 2000 mg to 900 mg due to safety, confounding dose-response interpretation for the highest planned dose
- No clinical/cognitive outcomes (CDR-SB, iADRS, etc.) - amyloid PET surrogate only
- Interruptions and early discontinuations may have introduced confounding for the amyloid clearance analysis
- Selective targeting of AβpE3 did not translate into the hypothesized ARIA reduction versus approved anti-amyloid antibodies
Funding
AbbVie Inc.
Based on: ABBV-916 (Alzheimer's & Dementia, 2026)
Authors: Lynch SY et al.
Citation: Alzheimers Dement 2026;22(8):e71715
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