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Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval
The body of evidence suggesting a causative, initiating role of beta amyloid (Aβ) in the pathogenesis of Alzheimer’s disease (AD) is substantial. Yet, only a few anti-amyloid agents have shown meaningful efficacy in clinical trials. We evaluated the unifying characteristics of anti-amyloid agents wi...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424995/ https://www.ncbi.nlm.nih.gov/pubmed/32787971 http://dx.doi.org/10.1186/s13195-020-00663-w |
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author | Tolar, Martin Abushakra, Susan Hey, John A. Porsteinsson, Anton Sabbagh, Marwan |
author_facet | Tolar, Martin Abushakra, Susan Hey, John A. Porsteinsson, Anton Sabbagh, Marwan |
author_sort | Tolar, Martin |
collection | PubMed |
description | The body of evidence suggesting a causative, initiating role of beta amyloid (Aβ) in the pathogenesis of Alzheimer’s disease (AD) is substantial. Yet, only a few anti-amyloid agents have shown meaningful efficacy in clinical trials. We evaluated the unifying characteristics of anti-amyloid agents with positive clinical or biomarker effects in long-duration trials and analyzed how pharmacological characteristics determine their clinical product profiles. Four agents with the potential for near term approval fulfill these criteria: the injectable antibodies, aducanumab, gantenerumab, and BAN2401, and a small molecule oral agent, ALZ-801. Aducanumab and BAN2401 showed significant efficacy on both clinical and biomarker outcomes; gantenerumab showed significant biomarker effects, with no clinical efficacy reported to date; and ALZ-801 showed significant clinical effects in the high-risk population of patients homozygous for the ε4 allele of apolipoprotein E gene (APOE4) and a dose-dependent preservation of hippocampal volume. We explored how the pharmacological properties of these agents, namely selectivity for Aβ oligomers, plasma half-life, brain penetration, and time to peak brain exposure, determine their clinical profiles. A crucial characteristic shared by these agents is their ability to engage neurotoxic soluble Aβ oligomers, albeit to various degrees. Aducanumab and gantenerumab partially target oligomers, while mostly clearing insoluble amyloid plaques; BAN2401 preferentially targets soluble protofibrils (large oligomers) over plaques; and ALZ-801 blocks the formation of oligomers without binding to plaques. The degree of selectivity for Aβ oligomers and brain exposure drive the magnitude and onset of clinical efficacy, while the clearance of plaques is associated with vasogenic brain edema. Only the highest doses of aducanumab and BAN2401 show modest efficacy, and higher dosing is limited by increased risk of vasogenic edema, especially in APOE4 carriers. These limitations can be avoided, and efficacy improved by small molecule agents that selectively inhibit the formation or block the toxicity of Aβ oligomers without clearing amyloid plaques. The most advanced selective anti-oligomer agent is ALZ-801, an optimized oral prodrug of tramiprosate, which demonstrated efficacy in homozygous APOE4/4 AD subjects. ALZ-801 selectively and fully inhibits the formation of Aβ42 oligomers at the clinical dose, without evidence of vasogenic edema, and will be evaluated in a phase 3 trial in homozygous APOE4/4 patients with early AD. In addition to clinical measures, the phase 3 trial will include cerebrospinal fluid, plasma, and imaging biomarkers to gain further insights into the role of soluble Aβ oligomers in the pathogenesis of AD and their impact on disease progression. |
format | Online Article Text |
id | pubmed-7424995 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-74249952020-08-16 Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval Tolar, Martin Abushakra, Susan Hey, John A. Porsteinsson, Anton Sabbagh, Marwan Alzheimers Res Ther Review The body of evidence suggesting a causative, initiating role of beta amyloid (Aβ) in the pathogenesis of Alzheimer’s disease (AD) is substantial. Yet, only a few anti-amyloid agents have shown meaningful efficacy in clinical trials. We evaluated the unifying characteristics of anti-amyloid agents with positive clinical or biomarker effects in long-duration trials and analyzed how pharmacological characteristics determine their clinical product profiles. Four agents with the potential for near term approval fulfill these criteria: the injectable antibodies, aducanumab, gantenerumab, and BAN2401, and a small molecule oral agent, ALZ-801. Aducanumab and BAN2401 showed significant efficacy on both clinical and biomarker outcomes; gantenerumab showed significant biomarker effects, with no clinical efficacy reported to date; and ALZ-801 showed significant clinical effects in the high-risk population of patients homozygous for the ε4 allele of apolipoprotein E gene (APOE4) and a dose-dependent preservation of hippocampal volume. We explored how the pharmacological properties of these agents, namely selectivity for Aβ oligomers, plasma half-life, brain penetration, and time to peak brain exposure, determine their clinical profiles. A crucial characteristic shared by these agents is their ability to engage neurotoxic soluble Aβ oligomers, albeit to various degrees. Aducanumab and gantenerumab partially target oligomers, while mostly clearing insoluble amyloid plaques; BAN2401 preferentially targets soluble protofibrils (large oligomers) over plaques; and ALZ-801 blocks the formation of oligomers without binding to plaques. The degree of selectivity for Aβ oligomers and brain exposure drive the magnitude and onset of clinical efficacy, while the clearance of plaques is associated with vasogenic brain edema. Only the highest doses of aducanumab and BAN2401 show modest efficacy, and higher dosing is limited by increased risk of vasogenic edema, especially in APOE4 carriers. These limitations can be avoided, and efficacy improved by small molecule agents that selectively inhibit the formation or block the toxicity of Aβ oligomers without clearing amyloid plaques. The most advanced selective anti-oligomer agent is ALZ-801, an optimized oral prodrug of tramiprosate, which demonstrated efficacy in homozygous APOE4/4 AD subjects. ALZ-801 selectively and fully inhibits the formation of Aβ42 oligomers at the clinical dose, without evidence of vasogenic edema, and will be evaluated in a phase 3 trial in homozygous APOE4/4 patients with early AD. In addition to clinical measures, the phase 3 trial will include cerebrospinal fluid, plasma, and imaging biomarkers to gain further insights into the role of soluble Aβ oligomers in the pathogenesis of AD and their impact on disease progression. BioMed Central 2020-08-12 /pmc/articles/PMC7424995/ /pubmed/32787971 http://dx.doi.org/10.1186/s13195-020-00663-w Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Review Tolar, Martin Abushakra, Susan Hey, John A. Porsteinsson, Anton Sabbagh, Marwan Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval |
title | Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval |
title_full | Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval |
title_fullStr | Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval |
title_full_unstemmed | Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval |
title_short | Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval |
title_sort | aducanumab, gantenerumab, ban2401, and alz-801—the first wave of amyloid-targeting drugs for alzheimer’s disease with potential for near term approval |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424995/ https://www.ncbi.nlm.nih.gov/pubmed/32787971 http://dx.doi.org/10.1186/s13195-020-00663-w |
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