Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval

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 (K_D) 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 [15,16,17,18, 24]

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