Aβ-Immunotherapeutic strategies: a wide range of approaches for Alzheimer's disease treatment

2016 ◽  
Vol 18 ◽  
Author(s):  
Laia Montoliu-Gaya ◽  
Sandra Villegas
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
State Of The Art ◽  
Phase Iii ◽  
Disease Treatment ◽  
Passive Immunotherapy ◽  
Wide Range ◽  
Current Therapies ◽  
Underlying Causes

Current therapies to treat Alzheimer's disease (AD) are focused on ameliorating symptoms instead of treating the underlying causes of AD. The accumulation of amyloid β (Aβ) oligomers, whether by an increase in production or by a decrease in clearance, has been described as the seed that initiates the pathological cascade in AD. Developing therapies to target these species is a vital step in improving AD treatment. Aβ-immunotherapy, especially passive immunotherapy, is a promising approach to reduce the Aβ burden. Up to now, several monoclonal antibodies (mAbs) have been tested in clinical trials on humans, but none of them have passed Phase III. In all likelihood, these trials failed mainly because patients with mild-to-moderate AD were recruited, and thus treatment may have been too late to be effective. Therefore, many ongoing clinical trials are being conducted in patients at the prodromal stage. New structures based on antibody fragments have been engineered intending to improve efficacy and safety. This review presents the properties of this variety of developing treatments and provides a perspective on state-of-the-art of passive Aβ-immunotherapy in AD.

scholarly journals What We Learn from the CTAD 2018 (Clinical Trials Alzheimer’s Disease)

2018 ◽  
pp. 1-2
Author(s):  
B. Vellas ◽  
P. Aisen ◽  
M. Weiner ◽  
J. Touchon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Safety Data ◽  
Phase Iii ◽  
Drug Trials ◽  
New Developments ◽  
Fda Guidance ◽  
Clinical Biomarkers ◽  
Early Alzheimer’S Disease

We are happy to publish the CTAD 2018 abstracts in the present JPAD issue. As you can see many new interesting studies are presented in this issue of the journal: from new drug trials to biomarkers, imaging studies, as well as new clinical outcomes. More specifically, we will have several hot topics presentation on: 1. Major drug trials using bace inhibitors (verubecestat, lanabecestat, atabecestat, elenbecestat…) in the early phase of the disease (APECS early trials…). Both clinical, biomarkers (MRI, CSF, PET) and safety data will be presented. 2. New data on blood biomarkers including a keynote from R. Bateman, and presentations from Araclon and Roche biomarkers. 3. Results from phase III and IIB trials including a novel and multi-targeted oligosaccharide in patients with mild-moderate AD in China; the AMBAR (Alzheimer’s Management By Albumin Replacement) study, the TOMMORROW trial: a trial to delay the onset of MCI due to AD and qualify a genetic biomarker algorithm, the 18-month STEADFAST trial of azeliragon in participants with mild Alzheimer’s Disease; a longitudinal 148-week extension 4. Results 18 from F-AV-1451-A16: a clinicopathological study of the correspondence between flortaucipir PET imaging and post-mortem assessment of tau pathology. 5. Latest developments in anti-amyloid monoclonal antibodies including aducanumab nonnegligible, and new results and data analyses of the BAN2401 study 201 in early AD. 6. New developments with safety and efficacy of lemborexant for sleep-wake regulation in patients with irregular sleep-wake rhythm disorders and Alzheimer’s Disease dementia. 7. Advances with the ABBV-8E12, a humanized anti-tau monoclonal antibody, for the treatment of early Alzheimer’s Disease. 8. Endpoints for early Alzheimer’s Disease clinical trials: interpretation and application of the draft FDA guidance. And many others… It is important to underline that a not negligible number of abstracts concern non amyloid targets (eg: Tau-related targets but also targets outside the classical AD cascade).

Learning from the Past: A Review of Clinical Trials Targeting Amyloid, Tau and Neuroinflammation in Alzheimer’s Disease

2020 ◽  
Vol 17 (2) ◽  
pp. 112-125 ◽  
Author(s):  
Kelly Ceyzériat ◽  
Thomas Zilli ◽  
Philippe Millet ◽  
Giovanni B. Frisoni ◽  
Valentina Garibotto ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Animal Models ◽  
Phase Iii ◽  
Current Status ◽  
Central Feature ◽  
Phase Iii Trial ◽  
The Past ◽  
Positive Results

Alzheimer’s Disease (AD) is the most common neurodegenerative disease and cause of dementia. Characterized by amyloid plaques and neurofibrillary tangles of hyperphosphorylated Tau, AD pathology has been intensively studied during the last century. After a long series of failed trials of drugs targeting amyloid or Tau deposits, currently, hope lies in the positive results of one Phase III trial, highly debated, and on other ongoing trials. In parallel, some approaches target neuroinflammation, another central feature of AD. Therapeutic strategies are initially evaluated on animal models, in which the various drugs have shown effects on the target (decreasing amyloid, Tau and neuroinflammation) and sometimes on cognitive impairment. However, it is important to keep in mind that rodent models have a less complex brain than humans and that the pathology is generally not fully represented. Although they are indispensable tools in the drug discovery process, results obtained from animal models must be viewed with caution. In this review, we focus on the current status of disease-modifying therapies targeting amyloid, Tau and neuroinflammation with particular attention on the discrepancy between positive preclinical results on animal models and failures in clinical trials.

P3-370: A pilot survey to explore attitudes toward primary prevention, secondary prevention and Alzheimer's disease treatment clinical trials

2012 ◽  
Vol 8 (4S_Part_16) ◽  
pp. P586-P586
Author(s):  
Kulwant Dosanjh ◽  
Lijie Di ◽  
Jenny Kotlerman ◽  
David Elashoff ◽  
John Ringman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Primary Prevention ◽  
Secondary Prevention ◽  
Disease Treatment ◽  
Pilot Survey

Novel approaches to incorporating pharmacoeconomic studies into phase III clinical trials for Alzheimer's disease

2010 ◽  
Vol 14 (8) ◽  
pp. 640-647 ◽  
Author(s):  
H. Fillit ◽  
J. Cummings ◽  
P. Neumann ◽  
T. Mclaughlin ◽  
P. Salavtore ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Novel Approaches

scholarly journals New Approacher in the Development of Alzheimer’s Disease Modifying Drugs

2021 ◽  
pp. 88
Author(s):  
◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Tau Protein ◽  
Phase Iii ◽  
Disease Modifying Drugs ◽  
Phase Iii Clinical Trials ◽  
Research Level ◽  
Disease Modifying ◽  
Pathological Stages

Introduction: Alzheimer’s disease is a more common neurodegenerative disease, affecting 25 million people worldwide, or accounting for about 60 to 70% of all dementia cases. There is currently no exact mechanism to explain the pathophysiology of Alzheimer’s disease, however, cascading metabolic amyloid and post-translational review of tau protein are used as major hypotheses. Objective: To demonstrate in the literature new approaches in the development of Alzheimer’s disease modifiers. Methodology: For the accomplishment of this study made in the bibliographical survey of scientific literature and respect to the approached subject, in the databases PUBMED, ScienceDirect, Scielo and Scopus. Results: Alzheimer’s disease-modifying drugs are not yet available, but many patients may, however, develop phase III clinical trials and are intended to modify as pathological stages leading to the disease. As disease-modifying therapies under study, these changes also affect Aβ and tau protein and also cause inflammation and oxidative damage. The results obtained in the clinical trials performed were positive and promising and are still under study. The results show that there is still a long way to go in the development of Alzheimer’s disease modifying drugs. Conclusion: The results demonstrated that there is still a long way to go in the development of Alzheimer’s disease modifying drugs, but nevertheless levels at the research level should be continued in order to improve the pathophysiology of the disease and find an effective treatment for this disease the same.

Alzheimer's Disease: Progress in the Development of Anti-amyloid Disease-Modifying Therapies

CNS Spectrums ◽  
2007 ◽  
Vol 12 (2) ◽  
pp. 113-123 ◽  
Author(s):  
Daniel D. Christensen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Amyloid Β ◽  
Phase Iii ◽  
Peroxisome Proliferator ◽  
Serious Adverse Events ◽  
Amyloid Disease ◽  
Aβ Aggregation ◽  
Disease Modifying

ABSTRACTThe amyloid hypothesis—the leading mechanistic theory of Alzheimer's disease—states that an imbalance in production or clearance of amyloid β (Aβ) results in accumulation of Aβ and triggers a cascade of events leading to neurodegeneration and dementia. The number of persons with Alzheimer's disease is expected to triple by mid-century. If steps are not taken to delay the onset or slow the progression of Alzheimer's disease, the economic and personal tolls will be immense. Different classes of potentially disease-modifying treatments that interrupt early pathological events (ie, decreasing production or aggregation of Aβ or increasing its clearance) and potentially prevent downstream events are in phase II or III clinical studies. These include immunotherapies; secretase inhibitors; selective Aβ42-lowering agents; statins; anti-Aβ aggregation agents; peroxisome proliferator-activated receptor-gamma agonists; and others. Safety and serious adverse events have been a concern with immunotherapy and γ-secretase inhibitors, though both continue in clinical trials. Anti-amyloid disease-modifying drugs that seem promising and have reached phase III clinical trials include those that selectively target Aβ42 production (eg, tarenflurbil), enhance the activity of α-secretase (eg, statins), and block Aβ aggregation (eg, transiposate).

scholarly journals Monoclonal antibodies: a new trend for the treatment of Alzheimer’s disease?

2021 ◽  
Author(s):  
Letícia Escorse Requião ◽  
Giulia Freitas ◽  
Mayanna Macedo ◽  
Hanny Gondim ◽  
Blenda Antunes ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Amyloid Peptide ◽  
Phase Iii ◽  
Functional Improvement ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Pubmed Database

Introduction: Alzheimer’s disease (AD) is the main form of senile dementia. Most of the supposedly disease-modifying treatments in development are directed against the β-amyloid peptide, the administration of exogenous anti-Aβ monoclonal antibodies is a passive immunization strategy aimed at resolving the aggregation of this substance. Objective: Analyze the effectiveness of monoclonal antibodies in the treatment of Alzheimer’s disease. Methods: This is a literature review, based on randomized clinical trials published between 2014 and 2021. The search was conducted in the PubMed database. Results: According to the eligibility criteria, 10 articles were selected. Two of the randomized, double-blind, placebo-controlled phase III studies, one published in 2018 and the other published in 2016, evaluated the intervention with Solanezumab and Bapineuzumab, respectively. Both were not shown to be statistically significant (P = 0.10) for the outcome improvement of the score in the cognitive subscale of 14 and 11 items “Alzheimer’s Disease Assessment Scale” (ADAS-cog14 / 11). However, in a phase II randomized placebo-controlled clinical trial, published in 2021, the use of Donanemab in patients with early Alzheimer’s disease resulted in statistically significant cognitive and functional improvement (P = 0.04) for the outcome change in the scale “Integrated Alzheimer’s Disease Rating” (iADR). Conclusion: Although the use of Donanemab has resulted in cognitive and functional improvement, randomized, double-blind, placebo-controlled, phase III clinical trials need to be conducted to prove the efficacy and safety of its use in clinical practice. Other monoclonal antibodies evaluated did not demonstrate evidence of benefit.

Insights into the Drug Repositioning Applied to the Alzheimer's Disease Treatment and Future Perspectives

2018 ◽  
Vol 15 (12) ◽  
pp. 1161-1178 ◽  
Author(s):  
Alexandre A. de Castro ◽  
Elaine F.F. da Cunha ◽  
Ander F. Pereira ◽  
Flavia V. Soares ◽  
Daniel H.S. Leal ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Late Onset ◽  
Drug Repositioning ◽  
Amyloid Β ◽  
Disease Treatment ◽  
Beneficial Effects ◽  
Relevant Evidence ◽  
Treatment Conditions

Introduction: Alzheimer's disease is known to be a chronic disease, with an estimated prevalence of about 10-30%, considering the population over 60 years of age. Most patients with this disorder (> 95%) present the sporadic form, being characterized by a late onset (80-90 years of age), and it is the consequence of the failure to clear the amyloid-β (Aβ) peptide from the interstices of the brain. Significant numbers of genetic risk factors for the sporadic disease have been researched. Some existing drugs for Alzheimer's disease provide symptomatic benefit for up to 12 months, but there are no approved disease- modifying therapies. In this line, a complementary strategy based on repositioning drugs which are approved for the treatment of other disorders could be interesting. It is noteworthy the fact that some clinical trials indicate that several classes of drugs own potent and beneficial effects on the Alzheimer's disease treatment. In this present work, we present the details and evaluation of these alternative treatments. It has highlighted several compounds with relevant evidence for this purpose, which deserves further investigation to clarify optimal treatment conditions in the clinical trials of patients with Alzheimer's disease.

scholarly journals Cognitive Decline in Alzheimer’s Disease: Limited Clinical Utility for GWAS or Polygenic Risk Scores in a Clinical Trial Setting

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 501
Author(s):  
Jack Euesden ◽  
Sivakumar Gowrisankar ◽  
Angela Xiaoyan Qu ◽  
Pamela St. Jean ◽  
Arlene R. Hughes ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Decline ◽  
Clinical Utility ◽  
Phase Iii ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Genome Wide ◽  
A Genome

Introduction: Alzheimer’s disease (AD) is a progressive and irreversible neurological disease. The genetics and molecular mechanisms underpinning differential cognitive decline in AD are not well understood; the genetics of AD risk have been studied far more assiduously. Materials and Methods: Two phase III clinical trials measuring cognitive decline over 48 weeks using Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog, n = 2060) and Clinical Dementia Rating-Sum of Boxes (CDR-SB, n = 1996) were retrospectively genotyped. A Genome-Wide Association Study (GWAS) was performed to identify and replicate genetic variants associated with cognitive decline. The relationship between polygenic risk score (PRS) and cognitive decline was tested to investigate the predictive power of aggregating many variants of individually small effect. Results: No loci met candidate gene or genome-wide significance. PRS explained a very small percentage of variance in rates of cognitive decline (ADAS-cog: 0.54%). Conclusions: These results suggest that incorporating genetic information in the prediction of cognitive decline in AD currently appears to have limited utility in clinical trials, consistent with small effect sizes estimated elsewhere. If AD progression is more heritable soon after disease onset, genetics may have more clinical utility.

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