AMBAR, an Encouraging Alzheimer's Trial That Raises Questions.

David A. Loeffler

doi:10.3389/fneur.2020.00459

Abstract

Grifols' recent Alzheimer Management by Albumin Replacement (“AMBAR”) study investigated the effects of plasmapheresis with albumin replacement, plus intravenous immunoglobulin (IVIG) in some subjects, in patients with mild-to-moderate Alzheimer's disease (AD). AMBAR was a phase IIb trial in the United States and a phase III trial in Europe. There were three treatment groups (plasmapheresis with albumin replacement; plasmapheresis with low dose albumin and IVIG; plasmapheresis with high dose albumin and IVIG) and sham-treated controls. Disease progression in pooled treated patients was 66% less than control subjects based on ADAS-Cog scores (p = 0.06) and 52% less based on ADCS-ADL scores (p = 0.03). Moderate AD patients had 61% less progression, based on both ADAS-Cog and ADCS-ADL scores, than their sham-treated counterparts (p-values 0.05 and 0.002), and their CDR-Sb scores declined 53% less than their sham-treated counterparts. However, ADAS-Cog and ADCS-ADL scores were not significantly different between actively-treated and sham-treated mild AD patients, although CDR-Sb scores improved vs. baseline for treated mild AD patients. Patients administered both IVIG and albumin had less reduction in brain glucose metabolism than sham-treated patients. Questions raised by these findings include: what mechanism(s) contributed to slowing of disease progression? Is this approach as effective in mild AD as in moderate AD? Must IVIG be included in the protocol? Does age, sex, or ApoE genotype influence treatment response? Does the protocol increase the risk for amyloid-related imaging abnormalities? How long does disease progression remain slowed post-treatment? A further study should allow this approach to be optimized.

Highlights

The amyloid hypothesis [1] led to efforts to treat Alzheimer’s disease (AD) by reducing brain Aβ, including vaccination [2], anti-Aβ antibodies [3,4,5,6,7], Aβ aggregation inhibitors [8], β-secretase inhibitors [9], and γ-secretase modulators [10], and inhibitors [11]
This Perspective will discuss the results, significance, possible mechanisms, and questions raised by the recently-completed Alzheimer Management by Albumin Replacement (“AMBAR”) study (ClinicalTrials.gov ID: NCT01561053) [21] performed by Grifols (Instituto Grifols, S.A.)
Pooled data from treated subjects showed that these patients declined, on average, 66% less than control subjects based on ADAS-Cog scores (p = 0.06) and 52% less based on ADCS-ADL scores (p = 0.03)

Summary

INTRODUCTION

The amyloid hypothesis [1] led to efforts to treat Alzheimer’s disease (AD) by reducing brain Aβ, including vaccination [2], anti-Aβ antibodies [3,4,5,6,7], Aβ aggregation inhibitors [8], β-secretase inhibitors [9], and γ-secretase modulators [10], and inhibitors [11]. AMBAR: Results, Significance, and Questions antagonist Memantine HCl. Memantine and cholinesterase inhibitors are the only treatments currently approved by the United States Food and Drug Administration for AD; they provide symptomatic benefits to some patients but are not disease modifiers [20]. Memantine and cholinesterase inhibitors are the only treatments currently approved by the United States Food and Drug Administration for AD; they provide symptomatic benefits to some patients but are not disease modifiers [20] This Perspective will discuss the results, significance, possible mechanisms, and questions raised by the recently-completed Alzheimer Management by Albumin Replacement (“AMBAR”) study (ClinicalTrials.gov ID: NCT01561053) [21] performed by Grifols (Instituto Grifols, S.A.). The rationale for the study was that lowering plasma Aβ levels by this approach might reduce brain levels of soluble Aβ, as predicted by the “peripheral sink hypothesis” [22, 23], possibly slowing AD’s progression

BACKGROUND

Findings

DISCUSSION