A Single Ascending Dose Study of Bapineuzumab in Patients With Alzheimer Disease

Abstract

The safety, tolerability, and pharmacokinetics (PKs) of bapineuzumab (AAB–001), a humanized monoclonal antibody to amyloid β, were evaluated in patients with mild-to-moderate Alzheimer disease in a phase 1, randomized, third-party unblinded, placebo-controlled, single ascending dose trial. Thirty patients received bapineuzumab infusion of 0.5, 1.5, or 5mg/kg or placebo (6 active, 2 placebo for 0.5 and 1.5-mg/kg cohorts; 10 active, 4 placebo for 5.0-mg/kg cohort). Three patients in the highest dose cohort (5.0mg/kg) developed magnetic resonance imaging abnormalities consistent with vasogenic edema, predominantly high signal abnormalities on fluid-attenuated inversion recovery sequences, all of which resolved over time. Plasma amyloid β was elevated from baseline, peaking approximately 24 hours after infusion. PK analysis demonstrated a half-life of 21 to 26 days, supporting a 13-week dosing interval for bapineuzumab. This small, single-dose study demonstrated the safety profile and PK characteristics of bapineuzumab and was used to design later safety and efficacy trials.

MR Imaging Features of Amyloid-Related Imaging Abnormalities

“…1,5 This constellation of imaging features is in keeping with the hypothesis of altered vascular permeability, 6,8 which is now recognized as part of the ARIA spectrum. ARIA-E specifically refers to associated parenchymal edema and sulcal effusions, whereas ARIA-H refers to hemosiderin deposits from blood products within the parenchyma or leptomeninges.…”

“…Imaging findings reported with bapineuzumab have occurred in both phase 1 and 2 clinical studies and have typically been identified in asymptomatic patients undergoing routine scheduled MR imaging surveillance. 1,5 These MR imaging findings were characteristic of transiently extravasated fluid within the brain parenchyma and were initially described as vasogenic edema among AD clinical specialists. 5 With time, a more diverse set of imaging changes was noted that could not be accurately described by the term "vasogenic edema."…”

“…Several agents specifically designed to lower cerebral A␤ burden have been associated with MR imaging abnormalities of the brain. [1][2][3][4] Reported MR imaging findings appear similar among various drugs, despite differences in the proposed mechanisms of action, indicating some commonality in effect. In this report, we specifically describe the imaging abnormalities associated with bapineuzumab, a humanized monoclonal antibody against cerebral A␤.…”

Chronic Rapamycin Restores Brain Vascular Integrity and Function Through NO Synthase Activation and Improves Memory in Symptomatic Mice Modeling Alzheimer’s Disease

“…It has been proposed that vascular dysfunction may be the first 'hit' in a 'two-hit' process that leads to AD, 12 in which the second hit is the abnormal accumulation of Ab. Because immunotherapy approaches to AD have shown adverse effects consistent with breakdown of BBB (such as a redistribution of amyloid from parenchyma to vasculature and increased microhemorrhage in mouse models, [56][57][58] as well as inflammation, vasogenic edema, and microhemorrhage in some AD patients, 59,60 ) it has been proposed 61 that Ab may have a protective role and may normally act to stabilize the BBB. In our studies, however, improved cerebral perfusion and vascular density were associated with decreased plaque deposition as well as with decreases in CAA and reduced microhemorrhage, which are not consistent with expected outcomes of chronic BBB destabilization.…”

An MRI Rating Scale for Amyloid-Related Imaging Abnormalities with Edema or Effusion

“…The latter are also naturally observed in AD, because lobar microbleeds are related to cerebral amyloid angiopathy and AD pathology. 5,10,[11][12][13][14][15] Because both findings are considered related to amyloid pathology, the term "amyloid-related imaging abnormalities" has been proposed. ARIA is further subdivided into ARIA-H, representing hemosiderin deposits or superficial hemosiderosis, and ARIA-E, representing parenchymal vasogenic edema or sulcal effusion.…”