The Alzheimer’s disease drug development landscape

Abstract Background Alzheimer’s disease (AD) is a devastating neurodegenerative disease leading to dementia. The field has made significant progress over the last 15 years. AD diagnosis has shifted from syndromal, based on signs and symptoms, to a biomarker construct based on the pathological hallma...

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Autores principales:	Pieter van Bokhoven, Arno de Wilde, Lisa Vermunt, Prisca S. Leferink, Sasja Heetveld, Jeffrey Cummings, Philip Scheltens, Everard G. B. Vijverberg
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Alzheimer’s disease Drug development, Drug targets Therapy Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/75d2847abf9c4438ab9936c7a8f4ae9a
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spelling	oai:doaj.org-article:75d2847abf9c4438ab9936c7a8f4ae9a2021-11-14T12:39:11ZThe Alzheimer’s disease drug development landscape10.1186/s13195-021-00927-z1758-9193https://doaj.org/article/75d2847abf9c4438ab9936c7a8f4ae9a2021-11-01T00:00:00Zhttps://doi.org/10.1186/s13195-021-00927-zhttps://doaj.org/toc/1758-9193Abstract Background Alzheimer’s disease (AD) is a devastating neurodegenerative disease leading to dementia. The field has made significant progress over the last 15 years. AD diagnosis has shifted from syndromal, based on signs and symptoms, to a biomarker construct based on the pathological hallmarks of the disease: amyloid β deposition, pathologic tau, and neurodegeneration. Numerous genetic risk factors for sporadic AD have been identified, providing further insight into the molecular underpinnings of the disease. For the last two decades, however, drug development for AD has been proven to be particularly challenging. Here, we provide a unique overview of the drug development landscape for AD. By comparing preclinical and clinical drug development pipelines, we aim to describe trends and differences regarding target classes and therapeutic modalities in preclinical and clinical development. Methods We analyzed proprietary and public databases and company websites for drugs in preclinical development for AD by the pharmaceutical industry and major clinical trial registries for drugs in clinical development for AD. Drugs were categorized by target class and treatment modality. Results We found a higher proportion of preclinical interventions targeting molecular pathways associated with sporadic AD genetic risk variants, compared to clinical stage interventions. These include apolipoprotein E (ApoE) and lipids, lysosomal/endosomal targets, and proteostasis. Further, we observed a trend suggesting that more traditional therapeutic modalities are developed for these novel targets, while more novel treatment modalities such as gene therapies and enzyme treatments are in development for more traditional targets such as amyloid β and tau. Interestingly, the percentage of amyloid β targeting therapies in preclinical development (19.2%) is even higher than the percentage in clinical development (10.7%), indicating that diversification away from interventions targeting amyloid-beta has not materialized. Inflammation is the second most popular target class in both preclinical and clinical development. Conclusions Our observations show that the AD drug development pipeline is diversifying in terms of targets and treatment modalities, while amyloid-targeting therapies remain a prominent avenue of development as well. To further advance AD drug development, novel companion diagnostics are needed that are directed at disease mechanisms related to genetic risk factors of AD, both for patient stratification and assessment of therapeutic efficacy in clinical trials.Pieter van BokhovenArno de WildeLisa VermuntPrisca S. LeferinkSasja HeetveldJeffrey CummingsPhilip ScheltensEverard G. B. VijverbergBMCarticleAlzheimer’s diseaseDrug development, Drug targetsTherapyNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571Neurology. Diseases of the nervous systemRC346-429ENAlzheimer’s Research & Therapy, Vol 13, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Alzheimer’s disease Drug development, Drug targets Therapy Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
spellingShingle	Alzheimer’s disease Drug development, Drug targets Therapy Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429 Pieter van Bokhoven Arno de Wilde Lisa Vermunt Prisca S. Leferink Sasja Heetveld Jeffrey Cummings Philip Scheltens Everard G. B. Vijverberg The Alzheimer’s disease drug development landscape
description	Abstract Background Alzheimer’s disease (AD) is a devastating neurodegenerative disease leading to dementia. The field has made significant progress over the last 15 years. AD diagnosis has shifted from syndromal, based on signs and symptoms, to a biomarker construct based on the pathological hallmarks of the disease: amyloid β deposition, pathologic tau, and neurodegeneration. Numerous genetic risk factors for sporadic AD have been identified, providing further insight into the molecular underpinnings of the disease. For the last two decades, however, drug development for AD has been proven to be particularly challenging. Here, we provide a unique overview of the drug development landscape for AD. By comparing preclinical and clinical drug development pipelines, we aim to describe trends and differences regarding target classes and therapeutic modalities in preclinical and clinical development. Methods We analyzed proprietary and public databases and company websites for drugs in preclinical development for AD by the pharmaceutical industry and major clinical trial registries for drugs in clinical development for AD. Drugs were categorized by target class and treatment modality. Results We found a higher proportion of preclinical interventions targeting molecular pathways associated with sporadic AD genetic risk variants, compared to clinical stage interventions. These include apolipoprotein E (ApoE) and lipids, lysosomal/endosomal targets, and proteostasis. Further, we observed a trend suggesting that more traditional therapeutic modalities are developed for these novel targets, while more novel treatment modalities such as gene therapies and enzyme treatments are in development for more traditional targets such as amyloid β and tau. Interestingly, the percentage of amyloid β targeting therapies in preclinical development (19.2%) is even higher than the percentage in clinical development (10.7%), indicating that diversification away from interventions targeting amyloid-beta has not materialized. Inflammation is the second most popular target class in both preclinical and clinical development. Conclusions Our observations show that the AD drug development pipeline is diversifying in terms of targets and treatment modalities, while amyloid-targeting therapies remain a prominent avenue of development as well. To further advance AD drug development, novel companion diagnostics are needed that are directed at disease mechanisms related to genetic risk factors of AD, both for patient stratification and assessment of therapeutic efficacy in clinical trials.
format	article
author	Pieter van Bokhoven Arno de Wilde Lisa Vermunt Prisca S. Leferink Sasja Heetveld Jeffrey Cummings Philip Scheltens Everard G. B. Vijverberg
author_facet	Pieter van Bokhoven Arno de Wilde Lisa Vermunt Prisca S. Leferink Sasja Heetveld Jeffrey Cummings Philip Scheltens Everard G. B. Vijverberg
author_sort	Pieter van Bokhoven
title	The Alzheimer’s disease drug development landscape
title_short	The Alzheimer’s disease drug development landscape
title_full	The Alzheimer’s disease drug development landscape
title_fullStr	The Alzheimer’s disease drug development landscape
title_full_unstemmed	The Alzheimer’s disease drug development landscape
title_sort	alzheimer’s disease drug development landscape
publisher	BMC
publishDate	2021
url	https://doaj.org/article/75d2847abf9c4438ab9936c7a8f4ae9a
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The Alzheimer’s disease drug development landscape

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