ABBV-916
(2026)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
* 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
Inclusion Criteria
Adults 50–90 years with stage 3–4 AD (NIA-AA 2018), MMSE 20–28, elevated plasma amyloid probability score, and screening amyloid PET ≥37 Centiloids (florbetapir).
Study Design
Arms: ABBV-916 (multiple ascending IV doses 10–3000 mg Q4W) vs placebo
Patients per Arm: 80 ABBV-916 (across 6 dose cohorts) vs 26 placebo (total N=106)
Outcome
• Amyloid negativity at week 24: 100% (900 mg), 54.6% (300 mg)
• Plasma biomarkers: Aβ42/Aβ40 +15–16%, p-tau217 -24–30%, GFAP -20–-32% at 300–900 mg vs placebo
• ARIA-E 33.8%, ARIA-H 25.0% overall on ABBV-916; strongly APOE ε4 dose-dependent
Clinical Question
In adults with early Alzheimer's disease, does IV ABBV-916 (an anti-AβpE3 humanized IgG1 monoclonal antibody) safely reduce brain amyloid plaque burden over 24 weeks?
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
Study Design
- Study Type
- Randomized Controlled Trial (Phase 1b/2 multiple ascending dose)
- Randomization
- Yes
- Blinding
- Double-blind, placebo-controlled
- Sample Size
- 106
- Follow-up
- 24-week double-blind period + 16-week safety follow-up (or 2-year extension)
- Centers
- Multicenter, global
- Countries
- USA (multiple sites; central IRB Advarra)
Primary Outcome
Definition: Safety, PK, and change from baseline to week 24 in brain amyloid plaque deposition by florbetapir PET (Centiloids)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - | - |
Limitations & 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
Citation
Alzheimers Dement 2026;22(8):e71715