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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).
What have we learned from past failures of investigational drugs for Alzheimer’s disease?
Published in Expert Opinion on Investigational Drugs, 2021
Bruno P. Imbimbo, Mark Watling
To date, prevention studies with anti-Aβ drugs have also repeatedly failed to arrest or slow down cognitive decline [19] (Table 1). Such studies have tested two BACE1 inhibitors (atabecestat and umibecestat) and an active anti-Aβ vaccine (CAD106) in cognitively unimpaired populations, and all were terminated early because of cognitive worsening compared to placebo. Three remaining major preventive trials are ongoing in SAD, all with monoclonal antibodies (solanezumab and lecanemab). Two long-term prevention studies have been undertaken in subjects with ADAD. The DIAN-TU-APT study tested solanezumab (a humanized IgG1 monoclonal antibody that recognizes the soluble monomeric form of Aβ) and gantenerumab (a fully human IgG1 monoclonal antibody that mainly recognizes fibrillary forms of Aβ), in 144 pre-symptomatic or mildly symptomatic affected subjects with ADAD. Both drugs failed to show cognitive or clinical benefits despite gantenerumab significantly affecting biomarkers relevant to its intended mechanism of action [20]. Paradoxically, solanezumab significantly accelerated cognitive decline in both asymptomatic and symptomatic subjects [20]. The API-ADAD trial is presently testing crenezumab (a fully humanized IgG4 monoclonal antibody selective for oligomeric and fibrillar forms of Aβ) in 252 pre-symptomatic ADAD subjects. The failure of these prevention clinical trials in asymptomatic subjects at risk of developing AD further undermines the hypothesis that reducing Aβ accumulation in the brain may produce clinical benefits.
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].
Antibodies to watch in 2018
Published in mAbs, 2018
Hélène Kaplon, Janice M. Reichert
Gantenerumab (RO4909832) is a human mAb targeting fibrillar amyloid-β that is undergoing investigation as a treatment for Alzheimer's disease. The effects of monthly SC administration of 105 mg or 225 mg of gantenerumab to patients with prodromal (i.e., pre-dementia) Alzheimer's disease were evaluated in the placebo-controlled Phase 3 SCarlet RoAD (NCT01224106) study; however, the primary endpoint of the study, mean change from baseline in clinical dementia rating scale sum of boxes total score at week 104, was not met.58 Gantenerumab continues to be evaluated in the placebo-controlled Phase 3 Marguerite RoAD (NCT02051608) study in patients with mild dementia due to Alzheimer's disease. The primary outcome measures of the study are mean change from baseline in Alzheimer's disease activity scale-cognitive subscale 13 scores at week 104 and mean change from baseline in Alzheimer's disease cooperative study-activities of daily living scores at week 104. The study also includes an open-label extension for participating patients; the primary outcome measure for this second part of the study is the percentage of participants with adverse events or serious adverse events from baseline to week 104. Initiated in March 2014, the Phase 3 NCT02051608 study has primary completion date in July 2018. MorphoSys announced in March 2017 that Roche intends to commence preparations for two Phase 3 studies, expected to start later in 2017. As of October 2017, details are not yet available.59