Verubecestat-Prodromal
(2019)Objective
Verubecestat - To evaluate whether verubecestat, an oral BACE-1 inhibitor, could slow disease progression in patients with prodromal Alzheimer's disease (MCI with elevated brain amyloid)
Study Summary
• Higher rate of progression to dementia with verubecestat (25.5 vs 19.3 per 100 patient-years; HR 1.38)
• Trial terminated early for futility despite reducing brain amyloid on PET
Intervention
Verubecestat 12mg or 40mg daily vs placebo for 104 weeks
Inclusion Criteria
Age 50-85, subjective memory decline ≥1 year, RBANS Delayed Memory Index ≤85, MMSE 24-30, positive amyloid PET, no dementia
Study Design
Arms: Verubecestat 12mg vs Verubecestat 40mg vs Placebo
Patients per Arm: 485 (12mg), 484 (40mg), 485 (placebo)
Outcome
• Progression to dementia: HR 1.38 (40mg vs placebo, 97.51% CI 1.07-1.79)
• Amyloid PET decreased with verubecestat (-0.04 SUVR) but increased with placebo (+0.02)
Bottom Line
Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo, despite reducing brain amyloid levels
Major Points
- Phase 3 trial terminated early for futility after interim analysis
- Primary outcome not met: CDR-SB worsening was similar or greater with verubecestat vs placebo
- 40mg dose showed statistically worse outcome than placebo on CDR-SB (2.02 vs 1.58, p=0.01)
- Higher progression rate to dementia with verubecestat (HR 1.38 for 40mg vs placebo)
- Verubecestat effectively reduced brain amyloid on PET (decreased 0.04 SUVR vs increased 0.02 with placebo)
- Cerebrospinal fluid Aβ42 reduced >60% with verubecestat confirming target engagement
- Multiple secondary outcomes suggested worse cognition/function with verubecestat
- Cognitive worsening apparent by week 13 and did not progress further
- Adverse events more common with verubecestat including rash, sleep disturbance, weight loss, hair color change
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled, parallel group phase 3 trial
- Randomization
- Yes
- Blinding
- Double-blind; participants, investigators, and assessors blinded; audiorecorded assessments with central rater quality review
- Sample Size
- 1454
- Follow-up
- 104 weeks (planned); terminated early for futility
- Centers
- 238
- Countries
- United States, Canada, Europe (multiple), Australia, New Zealand, Japan
Primary Outcome
Definition: Change in CDR-SB score from baseline to week 104 (range 0-18, higher scores indicate worse cognition and daily function)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 1.58 | - | - (12mg vs placebo: -0.30 to 0.44; 40mg vs placebo: 0.04 to 0.84) | 12mg vs placebo: 0.67; 40mg vs placebo: 0.01 (favoring placebo) |
Limitations & Criticisms
- Trial terminated early for futility limiting statistical power for some analyses
- Cognitive worsening may reflect BACE-1 inhibition effects on synaptic function beyond amyloid
- BACE-2 inhibition may contribute to adverse effects (uncertain physiologic functions)
- Disease-modifying effect requires longer follow-up than 104 weeks to fully assess
- Prodromal stage may already be too late in disease course for amyloid-lowering benefit
- Only 47-49% of patients completed the trial due to early termination
- Cerebrospinal fluid substudy limited to 5-6 patients per group
- Higher discontinuation rate in verubecestat groups due to adverse events
- Amyloid reduction achieved but did not translate to clinical benefit
Citation
N Engl J Med 2019;380:1408-20