Table 1.
Late-stage anti-amyloid agents: selectivity for amyloid oligomers and clinical and biomarker effects in phase 2 and 3 studies
| Clinical and biomarker profile |
Biogen Aducanumab IV infusion 10 mg/kg monthly |
Roche Gantenerumab SC injection monthly (225 mg and 1200 mg doses) |
Eisai BAN2401 IV infusion 10 mg/kg twice per month |
Alzheon ALZ-801/tramiprosate Oral tablet 265 mg twice daily |
|
|---|---|---|---|---|---|
| Amyloid oligomer selectivity | +/− | +/− | ++ |
+++ Blocks formation of oligomers |
|
| Study population |
Early AD All genotypes |
Early AD All genotypes |
Early AD All genotypes |
Early AD APOE4 carriers |
Mild AD APOE4/4 homozygotes |
|
Cognition ADAS-cog (% benefit versus placebo) |
27% p = 0.0097 |
No effect |
47% p = 0.017 |
84% Not reported |
125% p = 0.0001 |
|
Function CDR-SB (% benefit versus placebo) |
22% p = 0.012 |
No effect |
26% p = NS |
60% Not reported |
81% p = 0.0197 |
| CSF p-tau (% benefit versus placebo) | 15% | *31% | 13% | Not evaluated | |
| Effects on other biomarkers | Not reported |
*CSF t-tau **CSF t-tau **CSF NfL |
CSF neurogranin, CSF NfL | Preservation of hippocampal volume | |
| Amyloid plaque removal | +++ | +++ | +++ | No plaque interaction | |
| Brain edema ARIA-E (% of overall population and APOE4 carriers) |
35% (all genotypes) 42% (APOE4) |
$28%–#42% (all genotypes) | 10% (all genotypes) | 15% (APOE4) |
0% (all genotypes) 0% (APOE4) |
Abbreviations: IV intravenous, SC subcutaneous, NS not significant, ADAS-cog Alzheimer’s Disease Assessment Scale—cognitive subscale, CDR-SB Clinical Dementia Rating—Sum of Boxes, ARIA-E amyloid-related imaging abnormalities with effusion or edema
Assessment of amyloid oligomer selectivity: relative binding activity for soluble oligomers and protofibrils was measured by Biacore surface plasmon resonance. BAN2401 showed differential binding (KD) at 1.32 nM versus aducanumab 138 nM [10]; gantenerumab displays comparable affinity for oligomers and fibrils, and about 10× lower affinity for monomers [12]; ALZ-801/tramiprosate fully inhibits the formation of oligomer in the brain at target clinical dose [15]
Data sources: aducanumab phase 3 studies [11, 19]; gantenerumab phase 3 studies at 225 mg SC and *DIAN-TU at mix of 225 mg SC and 1200 mg SC [13, 20, 21]; gantenerumab safety data: **phase 3 SCarlet RoAD study [13]; $Marguerite RoAD open-label extension study [22]; #amyloid PET open-label extension study [20]; BAN2401 phase 2 study [23]; ALZ-801: tramiprosate phase 3 study [15–18, 24]