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Pharmacological Management of Alzheimer’s Disease
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Rakesh Kumar, Rajan Kumar, Abhinav Anand, Neha Sharma, Navneet Khurana
Bapineuzumab, a humanized monoclonal antibody and investigated by Elan/Johnson & Johnson, can have the potential therapeutic effect for the remedy of the AD. It was found to acknowledge the N-terminal five residues of Aβ peptide in a helical conformation. This is stabilized by internal hydrogen bonds involving the first three amino acids. It is speculated to cause changes in the underlying AD neuropathology (Miles et al., 2013). After getting an active immunization with it, the AD patients were found to have positive with the reduction of plaques, but 6% subjects developed aseptic meningitis, and hence the clinical trial was stopped (Woodhouse et al., 2007). Bapineuzumab is in clinical development for the remedy of the AD (Salloway et al., 2014).
Disorders
Published in Jonathan P Rogers, Cheryl CY Leung, Timothy RJ Nicholson, Pocket Prescriber Psychiatry, 2019
Jonathan P Rogers, Cheryl CY Leung, Timothy RJ Nicholson
Immunotherapy: Active immunisation (Ab 1-42 vaccination) research suspended as can ⇒ meningoencephalitis. Passive immunization (e.g. monoclonal Ab against amyloid, e.g. bapineuzumab and solanezumab) under investigation but trials in established dementia have not been positive; potential for disease modification if given early (at pre-clinical dementia stage) is currently under investigation. Secretase inhibitors (e.g. semagacestat): targets buildup of Ab fragments. Currently no evidence of efficacy.
Alzheimer's Disease
Published in Marc E. Agronin, Alzheimer's Disease and Other Dementias, 2014
There are several monoclonal antibodies in large clinical trials, listed in Table 4.6. Bapineuzumab was the first of this group, but although it showed reductions in CSF levels of Ab42 and phosphylated tau protein, it failed to demonstrate significant benefit over placebo in individuals with mild to moderate AD (Tayeb, Murray, Price, & Tarazi, 2013). All clinical trials have since been stopped. Solanezumab also failed to showed improvement in cognitive outcome measures in mildly impaired AD patients, but pooled data revealed a slowing of cognitive decline by around 34% (Eli Lilly, 2012). As a result, solanezumab remains in active trials. Both agents have shown a low but clinically relevant incidence of vasogenic edema and cerebral microhemorrhages, believed to be related to the mobilization of Ab proteins in the brain, particularly in small blood vessels. These occurrences are visualized on MRI scans and typically not associated with clinical symptoms (Tayeb et al., 2013). Vasogenic edema appears to resolve with interruption of treatment and is not usually recurrent when treatment is later resumed. Several other monoclonal antibodies are being studied, listed in Table 4.6. Recently, the FDA has modified its take on these studies, indicating that slowing cognitive decline is a reasonable endpoint in early-stage AD patients as opposed to considering only cognitive improvement (Kozauer & Katz, 2013).
Grasping at straws: the failure of solanezumab to modify mild Alzheimer’s disease
Published in Expert Opinion on Biological Therapy, 2018
The Aβ cascade hypothesis is that reducing Aβ levels in the brain will be beneficial in Alzheimer’s disease. Consequently, many agents have been developed, or are being developed, to potentially reduce Aβ levels in the brain. This development includes passive immunotherapy using anti-Aβ monoclonal antibodies [3], but the results with some of these have been disappointing. Thus, despite reducing the levels of fibrillar Aβ [4], bapineuzumab, a humanized N-terminal-specific anti-Aβ antibody, did not improve cognition or function in subjects with mild-to-moderate Alzheimer’s disease. In addition, bapineuzumab increased amyloid-related imaging abnormalities with edema in these subjects [5]. Gantenerumab is a human anti-Aβ antibody that binds to the aggregated Aβ, which reduced brain amyloid load in subjects with mild-to-moderate Alzheimer’s disease in Phase 1, but also, at a higher dose, increased inflammation or vasogenic edema [6]. Thus, only a lower dose of gantenerumab was used in the Phase 3 trial in prodromal Alzheimer’s disease, and this was shown to have no effect on cognition, function, or brain amyloid load, while increasing amyloid-related imaging abnormalities [7]. Another humanized monoclonal antibody, crenezumab, binds to both the monomers and aggregated Aβ. In Phase 2, the effects of crenezumab on brain amyloid load were not reported, but it was shown to have no effect on cognition or function in 431 subjects with mild-to-moderate Alzheimer’s disease [8].
The development of biological therapies for neurological diseases: moving on from previous failures
Published in Expert Opinion on Drug Discovery, 2018
With regards to passive immunization, several anti-Aβ mAbs have been developed. The first two, bapineuzumab and solanezumab, failed to meet their primary clinical endpoints of improved cognition in Phase-III clinical trials [15,16]. In addition, bapineuzumab showed a high risk of brain vascular side effects at the dose for optimal brain exposure. Discontinuation of this patients’ cohort from the study explain the lack of clinical efficacy due to suboptimal brain exposure in the low-dose patients’ cohort. Solanezumab binds to the soluble monomeric Aβ forms. Preclinical studies showed that solanezumab therapeutic effect depends on a relatively high brain exposure as it binds the abundant soluble Aβ [17]. Thus, presumably due to its low central exposure in humans, solanezumab failed to improve cognition or functional ability of mild-to-moderate AD patients in two phase-III clinical trials [18].
Drug development for Alzheimer’s disease: review
Published in Journal of Drug Targeting, 2019
Kejing Lao, Naichun Ji, Xiaohua Zhang, Wenwei Qiao, Zhishu Tang, Xingchun Gou
Bapineuzumab (AAB-001) is a fully humanised monoclonal antibody directed against the N terminus of Aβ (Aβ1–5), which binds more strongly to deposited amyloid plaques than to soluble Ab monomers [59]. In phase II studies in patients with mild-to-moderate AD, bapineuzumab reduced cortical fibrillar Aβ load and phosphorylated tau (p-tau) protein in CSF [60]. However, two large multicenter randomised double-blind placebo controlled parallel-group phase III trials were terminated due to a failure to meet primary outcome measures of cognition and activities of daily living [61]. The current trials showed no significant difference between bapineuzumab and placebo for the co-primary endpoints and no effect of bapineuzumab on amyloid load or cerebrospinal fluid phosphorylated tau.