A4
(2023)Objective
Solanezumab – To determine whether solanezumab could slow cognitive decline in cognitively unimpaired older adults (preclinical AD) with elevated brain amyloid.
Study Summary
• Showed only modest effects on amyloid accumulation and no functional benefit.
Intervention
Randomized, double-blind, placebo-controlled, multicenter phase 3 trial. Participants aged 65–85 received intravenous solanezumab 1600 mg every 4 weeks or placebo for 240 weeks. Trial design included baseline PET screening, cognitive composites, and stratification by APOE ε4 status. Conducted across 67 sites internationally (2014–2022).
Inclusion Criteria
Cognitively unimpaired individuals aged 65–85 with elevated amyloid PET (≥1.15 SUVR), CDR global score of 0, MMSE ≥25, Logical Memory Delayed Recall 6–18. Excluded if major medical instability, recent Alzheimer's medications, or abnormal cognitive testing outside defined bounds.
Study Design
Arms: Solanezumab vs. Placebo
Patients per Arm: Solanezumab: 564, Placebo: 583
Outcome
• CFI combined score: 2.09 (solanezumab) vs 1.51 (placebo); difference 0.58 (not significant)
• ADL partner score: –2.24 vs –1.63; difference –0.61
• CDR-SB: 0.71 vs 0.60; difference 0.12
• Global CDR progression at 240 weeks: 35% (solanezumab) vs 32% (placebo)
• Amyloid PET: Mean amyloid increased 11.6 centiloids (solanezumab) vs 19.3 (placebo)
• Tau PET and volumetric MRI: No group differences
• Adverse events: ARIA-microhemorrhage in 29.2% (solanezumab) vs 32.8% (placebo); serious events in 30.1% vs 26.7%
Bottom Line
Solanezumab did not slow cognitive decline compared to placebo over 240 weeks in persons with preclinical Alzheimer's disease. Despite evidence of target engagement (slowed amyloid accumulation), there was no clinical benefit, and numerical worsening was observed in the treatment group.
Major Points
- 1169 cognitively unimpaired persons with elevated brain amyloid randomized 1:1 to solanezumab vs placebo
- Dose increased mid-trial from 400 mg to 1600 mg IV every 4 weeks due to concerns from prior trial suggesting inadequate dosing
- Primary endpoint (PACC score change at 240 weeks) showed no significant difference (P=0.26) with numerically greater decline in solanezumab group
- Solanezumab slowed amyloid accumulation (11.6 vs 19.3 centiloids) but did not reduce amyloid below baseline levels
- Tau PET showed similar increases in both groups, suggesting no effect on tau pathology
- ARIA-E was rare (<1% both groups); ARIA-H rates were similar between groups
- 33.4% of participants had progression of CDR score to >0 at 240 weeks
- Results suggest slowing amyloid accumulation without reducing fibrillar amyloid levels below baseline does not slow clinical progression
- Trial complicated by mid-trial dose increase and COVID-19 pandemic disruptions
Study Design
- Study Type
- Phase 3 randomized controlled trial
- Randomization
- Yes
- Blinding
- Double-blind; participants, investigators, site personnel, coordinating center, and sponsor staff blinded to treatment assignment; independent DSMB reviewed masked data quarterly
- Sample Size
- 1169
- Follow-up
- 240 weeks (4.5 years)
- Centers
- 67
- Countries
- United States, Canada, Australia, Japan
Primary Outcome
Definition: Change in Preclinical Alzheimer Cognitive Composite (PACC) score at 240 weeks - sum of 4 z-scores (FCSRT, Logical Memory IIa delayed recall, Digit Symbol Substitution Test, MMSE)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| −1.13 (95% CI −1.45 to −0.81) | −1.43 (95% CI −1.83 to −1.03) | - (−0.82 to 0.22) | 0.26 |
Limitations & Criticisms
- Participants not representative of general older population at risk for cognitive decline; few Black participants enrolled
- Mid-trial dose increase from 400 mg to 1600 mg complicated interpretation
- COVID-19 pandemic caused widespread site disruption, affecting visit timing and assessments
- Numerical worsening in solanezumab group was unexpected; possible that 4-fold dose increase severely depleted monomeric Aβ causing harm similar to secretase inhibitors
- Final-visit PACC observations missing for ~30% of participants in both groups
- Solanezumab does not bind fibrillar deposits, limiting ability to reduce existing plaque burden
- Conjecture that monomeric Aβ depletion may have caused cognitive worsening requires further investigation
Citation
N Engl J Med 2023;389:1096-107