Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE, Mathis CA, Blennow K, Barakos J, Okello AA, Rodriguez Martinez de Liano S, Liu E, Koller M, Gregg KM, Schenk D, Black R, Grundman M11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol 9:363-372
Carbon-11-labelled Pittsburgh compound B ((11)C-PiB) PET is a marker of cortical fibrillar amyloid-beta load in vivo. We used (11)C-PiB PET to investigate whether bapineuzumab, a humanised anti-amyloid-beta monoclonal antibody, would reduce cortical fibrillar amyloid-beta load in patients with Alzheimer's disease.
Patients with mild-to-moderate Alzheimer's disease were randomly assigned to receive intravenous bapineuzumab or placebo in a ratio of seven to three in three ascending dose groups (0.5, 1.0, or 2.0 mg/kg). Each dose group was enrolled after safety review of the previous group. Randomisation was by interactive voice response system; masking was achieved with numbered kit allocation. Patients, investigators, study site personnel, sponsor staff, and carers were masked to treatment. Patients received up to six infusions, 13 weeks apart, and had (11)C-PiB PET scans at baseline and at weeks 20, 45, and 78. The primary outcome was the difference between the pooled bapineuzumab group and the pooled placebo group in mean change from screening to week 78 in (11)C-PiB cortical to cerebellar retention ratio averaged across six cortical regions of interest. Analysis was by modified intention to treat. This study is registered with EudraCT, number 2004-004120-12; ISRCTN17517446.
28 patients were assigned to bapineuzumab (n=20) or placebo (n=8). 19 patients in the bapineuzumab group and seven in the placebo group were included in the modified intention-to-treat analysis. Estimated mean (11)C-PiB retention ratio change from baseline to week 78 was -0.09 (95% CI -0.16 to -0.02; p=0.014) in the bapineuzumab group and 0.15 (95% CI 0.02 to 0.28; p=0.022) in the placebo group. Estimated mean difference in (11)C-PiB retention ratio change from baseline to week 78 between the bapineuzumab group and the placebo group was -0.24 (95% CI -0.39 to -0.09; p=0.003). Differences between the bapineuzumab group and the placebo group in the individual regions of interest were similar to the overall mean difference. Adverse events were typically mild to moderate in severity and transient. Two patients in the 2.0 mg/kg bapineuzumab group had transient cerebral vasogenic oedema.
Treatment with bapineuzumab for 78 weeks reduced cortical (11)C-PiB retention compared with both baseline and placebo. (11)C-PiB PET seems to be useful in assessing the effects of potential Alzheimer's disease treatments on cortical fibrillar amyloid-beta load in vivo.
Elan Pharmaceuticals and Wyeth Research.
"Apparently conflicting results obtained in clinical trials of anti-amyloid therapies highlight the need for a more complete understanding of the types and toxicity of Ab assemblies that are seen during the progression of AD. Passive immunization with two monoclonal antibodies that recognize Ab fibrils, bapineuzumab and gantenerumab , reduced amyloid burdens but failed to provide cognitive or functional benefits (Alzforum, 2015a, 2015b; Ostrowitzki et al., 2012; Rinne et al., 2010). However, preliminary reports that a third antibody, aducanumab, practically eliminates plaques and slows cognitive and functional declines in patients with prodromal or mild AD have generated tremendous excitement in the field (Strobel, 2015). "
"In addition, among non-apoE4 carrier patients significant (but small) benefits were documented on the ADAS-cog, Neuropsychological Test Battery (NTB), MMSE, and Clinical Dementia Rating (CDR) scales. The Bapineuzumab-treated subjects showed a reduction in cortical fibrillar amyloid deposits compared to both baseline measures and controls over the 78 weeks of the trial, as evaluated by 11C-PiB positron emission tomography (PET) imaging in a subset of participants (Rinne et al., 2010). "
"However the reduction in parenchymal amyloid is associated with increased deposition of Aβ around the cerebral vasculature, and an increased incidence of cerebral micro-hemorrhage (Wilcock et al., 2004c). Data from clinical trials has shown that certain antibodies such as Bapineuzumab (hIgG1 anti Aβ) are able to reduce or at least stabilize amyloid load in the brains of AD patients, measured by PET scan (Rinne et al., 2010; Salloway et al., 2014). However MRI scans of Bapineuzumab treated patients have also revealed similar vascular side effects to APP mice. "
[Show abstract][Hide abstract] ABSTRACT: There are an estimated 18 million Alzheimer’s disease (AD) sufferers worldwide and with no disease modifying treatment currently available, development of new therapies represents an enormous unmet clinical need. AD is characterised by episodic memory loss followed by severe cognitive decline and is associated with many neuropathological changes. AD is characterised by deposits of amyloid beta (Aβ), neurofibrillary tangles, and neuroinflammation. Active immunisation or passive immunisation against Aβ leads to the clearance of deposits in transgenic mice expressing human Aβ. This clearance is associated with reversal of associated cognitive deficits, but these results have failed to translate to humans, with both active and passive immunotherapy failing to improve memory loss. One explanation for these observations is that certain anti-Aβ antibodies mediate damage to the cerebral vasculature limiting the top dose and potentially reducing efficacy. Fc gamma receptors (Fcγ) are a family of immunoglobulin like receptors which bind to the Fc portion of IgG, and mediate the response of effector cells to immune complexes. Data from both mouse and human studies suggest that cross-linking Fc receptors by therapeutic antibodies and the subsequent pro-inflammatory response mediates the vascular side effects seen following immunotherapy. Increasing evidence is emerging that Fc receptor expression on CNS resident cells, including microglia and neurons, is increased during aging and functionally involved in the pathogenesis of age-related neurodegenerative diseases. We propose that increased expression and ligation of Fc receptors in the CNS, either by endogenous IgG or therapeutic antibodies, has the potential to induce vascular damage and exacerbate neurodegeneration. To produce safe and effective immunotherapies for AD and other neurodegenerative diseases it will be vital to understand the role of Fc receptors in the healthy and diseased brain.
Frontiers in Neuroscience 08/2014; 8(8):235. DOI:10.3389/fnins.2014.00235 · 3.66 Impact Factor
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