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Programmed Aging Paradigm and Aging of Perennial Neurons
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
The traditional hypothesis that the decisive factor for AD pathogenesis is the damage accumulation of substances such as β-amyloid and tau protein has been widely contradicted by the failures of the pharmaceutical industry in the trials based on this thesis. Drugs or vaccines used with the aim to counter the formation of β-amyloid plaques have been disappointing, not for their ability to eliminate the plaques but for the purpose of obtaining positive clinical effects (Abbott 2008). In particular, in 2008, a study showed that an experimental amyloid peptide vaccine was very effective in eliminating the plaques or in avoiding their formation, but: “Seven of the eight immunised patients who underwent post-mortem assessment, including those with virtually complete plaque removal, had severe end stage dementia before death” (Holmes et al. 2008) and the authors observed “Although immunization with Abeta42 resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not prevent progressive neurodegeneration” (Holmes et al. 2008). A recent authoritative study (Sevigny et al. 2016) has used a human monoclonal antibody (aducanumab) to eliminate the amyloid-β plaques. The technique has shown significant and dose-dependent effectiveness in eliminating the plaques, while the clinical results (for which one must observe that the study was not specifically designed) remain uncertain. After 1 year of treatment, one of the two clinical evaluation parameters (Mini Mental State Examination) showed positive results for the doses of antibody 3 and 10 mg/kg, but for the intermediate dose of 6 mg/kg, the result was similar to that of placebo.
Development of a Synergistic Combination of Huperzia serrata, Convolvulus pluricaulis, and Celastrus paniculatus for Optimal Brain Health and Functions
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Imtiaz Ahmad, Deepanshi Dhar, Jagadeesh S. Rao, Anand Swaroop, Tariq Ahmad, Debasis Bagchi
Extensive research strategies are being pursued to include a wide variety of potential drug targets (Table 19.1). AD-based research is currently exploring the possibility of developing N-methyl-d-aspartate (NMDA) receptor antagonists, acetylcholinesterase inhibitors, antioxidants, radical scavengers, monoamine oxidase inhibitors, and Aβ and tau aggregation inhibitors/dissolver as likely candidates (Sureda et al. 2011, Bautista-Aguilera et al. 2014; Rafii and Aisen 2009). AD clinical trials have been recurrently dominated by anti-Aβ therapies, where 70 of 146 small molecules and immunotherapies are directed against Aβ compared with 13 compounds addressing tau-related mechanisms and 62 compounds assessing neuroprotective approaches (Cummings et al. 2014). Other approach under consideration as a potential target in AD is the inhibition of asparagine endopeptidase (protease responsible for the cleavage of its substrates after asparagine residues) with small molecular inhibitors due to its suggested role in the pathological processing of the amyloid precursor protein and tau proteins. Suggestive leads on its mechanisms and inhibition could be further exploited in other age-related neurological diseases such as PD, ALS, and frontotemporal lobar degeneration (Zhang et al. 2016). At present, of the five FDA-approved drugs marketed only for halting the disease progression, donepezil, galantamine, rivastigmine and tacrine are based on acetylcholinesterase inhibition, while memantine has an antagonist influence on NMDA receptor. Previously designed immunotherapies for AD using monoclonal antibodies such as gantenerumab, crenezumab, and aducanumab generated failed outcomes due to unsuccessful clinical efficacy and major safety problems when administered at higher doses. Ineffective attempts were also partly credited to a variation in their antibody epitopes and a high variability in recognition of the structural conformation of Aβ species along with a late intervention in patients post-excessive Aβ accumulation (Van Bulck et al. 2019). Accordingly, multifactorial drug design resulted in the development of combination therapies where certain drugs with the affinity for at least two molecular targets of AD, primarily AChE and BACE1, were tested for their efficacy, while other combinations displayed less toxicity and increased potential in metal-chelating and antioxidant properties. Major emphasis was placed on screening the combinations of AChE with GSK3β inhibitors, MAO (Monoamine oxidase) inhibitors, metal chelators, NMDAR (N-Methyl-D-aspartate receptor) inhibitors, 5-HT (5-hydroxytryptamine) receptor inhibitors, histaminic receptor inhibitors, and phosphodiesterase inhibitors. While a few combinations developed this way reported to alleviate AD, however, most of these combination agents were discontinued due to their adverse effects or dismal activity (Zhang et al. 2019).
Toward the optimized assessment of clinical outcomes in studies of novel treatments for Alzheimer’s disease
Published in Expert Review of Neurotherapeutics, 2022
Richard B Lipton, Lauren Podger, Walter F Stewart, David Gomez-Ulloa, Wilton I Rodriguez, M Chris Runken, Frederick B Barnes, Daniel Serrano
The well-documented stage-specific progression of clinical outcomes supports the hypothesis that no single outcome (e.g. global cognition) is optimal for assessing treatment response across all stages of disease. Matching the outcomes and endpoints to the stage of illness may improve sensitivity to detecting true treatment effects. For example, caregiver burden is likely to be relatively low in the MCI and early AD phases; therefore, measures of caregiver burden may be relatively insensitive to treatment benefits during these stages. The disconnect between AD stage and selection of relevant outcomes and subsequent measures used to define trial endpoints may be one of the many factors that contribute to the abandonment or failure of 200+ clinical programs over the last decade [29,30]. Prior to 2003, only five therapies had been approved for the treatment of AD, all of which showed only a modest symptomatic improvement [31]. Efforts to develop a disease-modifying therapy (DMT) have been largely unsuccessful; only one DMT (aducanumab) has been approved by the Food and Drug Administration (FDA) since 2003, though there are other treatments in late-stage development [32]. Due to uncertainty of the true clinical benefit, reimbursement status for aducanumab in the USA is currently limited to patients enrolled in qualifying clinical trials [33].
Aducanumab and adenoviral COVID-19 vaccines: increased cerebral hemorrhage risk?
Published in Expert Review of Neurotherapeutics, 2022
ArunSundar MohanaSundaram, Shanmugarajan Thukani Sathanantham, Lukas Sveikata, Rakesh Shyam Lalla, Renata Sveikatienė, Ajeet Kaushik, Ravichandiran Velayutham
A recent investigator-led secondary analysis found that 19.1% and 35.2% of the aducanumab-treated patients demonstrated microhemorrhage (ARIA-H) and edema (ARIA-E), respectively [9]. In the clinical trials with aducanumab, perhaps due to controlled and highly-selective recruitment of AD patients, no fatal cases were reported. However, in early Aβ immunization trials, after the death of two subjects, advanced cerebral amyloid angiopathy (CAA) was identified. CAA is a well-characterized and common small vessel disease in older adults that is defined by vascular amyloid-β (Aβ) accumulation, perivascular inflammation, and vascular leakage [10]. Due to the high prevalence of CAA in older adults, the possibility of increased ARIA-associated morbidity and mortality in the real-world setting may be higher.
Antibodies to watch in 2020
Published in mAbs, 2020
Hélène Kaplon, Mrinalini Muralidharan, Zita Schneider, Janice M. Reichert
Aducanumab (BIIB037) is a human anti-amyloid beta (Aβ) IgG1 mAb studied for the treatment of early Alzheimer’s disease. Aducanumab binds a linear epitope formed by amino acids 3–7 of the Aβ peptide and discriminates between monomers and oligomeric or fibrillar aggregates based on weak monovalent affinity, fast binding kinetics and strong avidity for epitope-rich aggregates.75 In August 2016 aducanumab was accepted into EMA’s PRIME program. In September 2016 the FDA granted aducanumab Fast Track designation, and in April 2017 aducanumab was accepted into MHLW’s Sakigake Designation System. Aducanumab was evaluated in two Phase 3 studies of patients with early Alzheimer’s disease, EMERGE (NCT02484547) and ENGAGE (NCT02477800). Based on discussions with the FDA, Biogen Inc. and Eisai, Co., Ltd. plan to file a BLA in early 2020.76