GRADUATE I & II
(2023)Objective
Gantenerumab – To evaluate the clinical efficacy, safety, and biomarker effects of subcutaneous gantenerumab in persons with early Alzheimer's disease.
Study Summary
• Failed to demonstrate significant clinical benefit over placebo at 116 weeks.
Intervention
Two multinational, phase 3, randomized, double-blind, placebo-controlled, parallel-group trials. Gantenerumab was titrated to 510 mg subcutaneously every 2 weeks over 36 weeks. Treatment lasted 116 weeks, with option for open-label extension. Participants were stratified by clinical stage, APOE ε4 genotype, Alzheimer’s medications, and biomarker substudy participation.
Inclusion Criteria
Adults 50–90 years with mild cognitive impairment or mild dementia due to Alzheimer’s disease, CDR-Global Score 0.5 or 1, MMSE ≥22, and confirmed amyloid positivity by PET or CSF. Exclusions included significant cerebrovascular pathology or recent use of GV-971.
Study Design
Arms: Gantenerumab vs. Placebo (GRADUATE I and II)
Patients per Arm: GRADUATE I: Gantenerumab 499, Placebo 485; GRADUATE II: Gantenerumab 498, Placebo 477
Outcome
• ADAS-Cog13: Differences were –1.25 (GRADUATE I) and –1.28 (GRADUATE II), not statistically significant.
• ADCS-ADL: Differences were 1.11 (GRADUATE I) and 0.82 (GRADUATE II), not statistically significant.
• Amyloid PET: Amyloid reduction of –66.4 centiloids (GRADUATE I) and –56.5 centiloids (GRADUATE II).
• Amyloid-negative status: Achieved in 28.0% (I) and 26.8% (II) of gantenerumab participants.
• CSF: Gantenerumab lowered p-tau181 and increased Aβ42.
• ARIA-E occurred in 24.9% of gantenerumab vs. 2.7% placebo participants; 5.0% were symptomatic.
• No effect on tau PET accumulation; MRI showed greater brain atrophy in treatment group.
Bottom Line
Gantenerumab did not significantly slow clinical decline over 116 weeks despite partial amyloid plaque removal. Only approximately one quarter of participants achieved amyloid-negative status, suggesting that rapid and complete plaque clearance may be necessary for clinical benefit within the trial timeframe.
Major Points
- Primary endpoint not met in either trial: CDR-SB difference was −0.31 (P=0.10) in GRADUATE I and −0.19 (P=0.30) in GRADUATE II
- Amyloid reduction was lower than predicted: mean amyloid levels remained elevated (40-45 centiloids) after treatment
- Only 28.0% (GRADUATE I) and 26.8% (GRADUATE II) of gantenerumab participants achieved amyloid-negative status (≤24 centiloids)
- No treatment effect on tau accumulation on PET despite reductions in CSF and plasma phosphorylated tau 181
- Greater brain volume loss and ventricular enlargement observed with gantenerumab vs placebo on volumetric MRI
- ARIA-E incidence was 24.9% overall, approximately doubling with each APOE ε4 allele (13.1% noncarriers, 24.5% heterozygotes, 47.8% homozygotes)
- Symptomatic ARIA-E occurred in 5.0% of gantenerumab participants; serious symptomatic ARIA-E in 1.1%
- Results suggest rapid plaque reduction to below detection threshold may be necessary for clinical efficacy
Study Design
- Study Type
- Two parallel, multicenter, randomized, double-blind, placebo-controlled phase 3 trials
- Randomization
- Yes
- Blinding
- Double-blind; personnel preparing/administering drug not involved in assessments; clinical raters unaware of assignments; CDR raters had no ARIA data; MRIs assessed by independent blinded neuroradiologists
- Sample Size
- 1965
- Follow-up
- 116 weeks (extended from planned 104 weeks due to COVID-19)
- Centers
- 288
- Countries
- United States, Canada, United Kingdom, Germany, Spain, France, Japan, Australia, and 22 others
Primary Outcome
Definition: Change from baseline in CDR-SB score at week 116 (range 0-18, higher = worse)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - | - |
Limitations & Criticisms
- Amyloid plaque removal was lower than predicted despite similar ARIA-E incidence as modeled, suggesting different mechanisms may drive ARIA and plaque clearance
- Only ~27% achieved amyloid-negative status, potentially insufficient for clinical benefit
- The dose-escalation scheme was previously untested in this trial design
- Lack of racial diversity in U.S. trial population limits generalizability
- COVID-19 pandemic caused missed visits and delayed assessments, requiring extension to 116 weeks
- Greater brain volume loss with gantenerumab (though potentially related to amyloid removal rather than neurodegeneration)
- No effect on tau PET accumulation despite CSF/plasma p-tau181 reductions
- Subcutaneous administration may result in different pharmacokinetics compared to IV antibodies that showed efficacy
- Trial design differences from other anti-amyloid antibody trials make cross-trial comparisons difficult
Citation
N Engl J Med 2023;389:1862-76