MedicalResearch.com Interview with:
Dr. Petr Kocis PhD
Vice President Preclinical Development
University of Oxford
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Researchers widely accept that amyloid plaques are the hallmark of Alzheimer’s disease. However, for many years, drug development has focused on the solid amyloid plaque as a primary disease culprit. Recent advances show that it is more likely that early stage soluble beta amyloid oligomers play a key role in the pathogenic process of Alzheimer’s disease.
A paper recently published by Alzheon, a company developing medicines for Alzheimer’s disease and other neurological disorders, suggests a new therapeutic mechanism for targeting toxic amyloid beta oligomers with a small molecule, tramiprosate, the active agent in the drug candidate, ALZ-801. ALZ-801 is a Phase 3-ready drug candidate that is an optimized prodrug of tramiprosate, with a substantially improved pharmacokinetic and safety profile compared to tramiprosate.
Alzheon scientists discovered that tramiprosate acts to inhibit the production of neurotoxic beta amyloid oligomers by ‘enveloping’ the amyloid peptide to prevent its misfolding into soluble amyloid aggregates. Beta amyloid oligomers are believed to be key drivers of the pathogenic process in Alzheimer’s disease (AD). This novel enveloping mechanism of tramiprosate prevents the self-assembly of misfolded proteins into beta amyloid oligomers that lead to amyloid aggregation and, subsequently, cause neuronal toxicity and clinical progression in Alzheimer’s disease. These results were published in the medical journal, CNS Drugs, and the paper is available through Open Access here. [“Elucidating the Aß42 Anti-Aggregation Mechanism of Action of Tramiprosate in Alzheimer’s Disease: Integrating Molecular Analytical Methods, Pharmacokinetic and Clinical Data”]
MedicalResearch.com: What should readers take away from your report?
Response: While it has been recognized for nearly four decades that amyloid plaques are the hallmark of Alzheimer’s disease, the emerging insights are pointing to small protein aggregates that exhibit many of the properties of prions, as the key driver of neuronal degeneration. By showing the therapeutic potential to intervene in the formation of prion-like protein aggregates, this study on tramiprosate’s mechanism of action opens the door to the development of a new class of drugs with disease-modifying potential for Alzheimer’s as well as other neurodegenerative disorders caused by protein misfolding.
The challenge in modulating the conformational dynamics of Aß42 amyloid has been a major reason why this relatively small protein has been such an elusive target in Alzheimer’s drug development. These new data provide essential insights into the pathogenic role of soluble toxic oligomers in Alzheimer’s and related neurological diseases. Previous analyses showed that tramiprosate significantly improved cognition and function in Alzheimer’s disease patients with the genetic risk factor of two ε4 alleles of apolipoprotein E (APOE4/4 homozygotes), and now we understand the mechanism supporting this clinical efficacy.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: Without question, the disease modification effects of an anti-oligomer treatment is a promising approach to pursue for Alzheimer’s disease.
There is strong evidence that amyloid beta – in some shape or form – plays a key role in AD. New science and clinical results are emerging every day. Anti-oligomer insights are an example of the new research that continues to open new paths for treatments and hope for Alzheimer’s patients. The field continues to pursue anti-amyloid beta therapies, including anti-oligomer therapy, as potential therapeutic approaches to slow the progression of AD, leading to more effective treatments.
MedicalResearch.com: Is there anything else you would like to add?
Response: In recent years, there have been numerous ‘ups and downs’ of confidence in the amyloid hypothesis. However, we have made major advances in our understanding of the pathogenesis of Alzheimer’s and oligomers appear to be the key missing link. We are building our base of knowledge about the very complex disease and putting together more and more pieces of the puzzle.
One of the most important insights that has recently emerged is the role of toxic amyloid beta oligomers in the disease process of Alzheimer’s. During the three years from 2012 to 2015, more than 1,000 scientific papers have studied how toxic amyloid beta oligomers are involved in Alzheimer’s pathogenesis. All of this data continues to support amyloid as a target for treatment trials, and our drug candidate ALZ-801, as a potential therapeutic approach to inhibit this key pathogenic step in Alzheimer’s disease.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
Elucidating the Aβ42 Anti-Aggregation Mechanism of Action of Tramiprosate in Alzheimer’s Disease: Integrating Molecular Analytical Methods, Pharmacokinetic and Clinical Data
Petr Kocis, Martin Tolar, Jeremy Yu, William Sinko, Soumya Ray, Kaj Blennow, Howard Fillit, John A. Hey
Kocis, P., Tolar, M., Yu, J. et al. CNS Drugs (2017). doi:10.1007/s40263-017-0434-z
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