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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| Format: | Article |
| Language: | English |
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BMC
2021-11-01
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| Series: | Alzheimer’s Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13195-021-00927-z |
| _version_ | 1819003380321746944 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-20T23:20:05Z |
| format | Article |
| id | doaj.art-75d2847abf9c4438ab9936c7a8f4ae9a |
| institution | Directory Open Access Journal |
| issn | 1758-9193 |
| language | English |
| last_indexed | 2024-12-20T23:20:05Z |
| publishDate | 2021-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj.art-75d2847abf9c4438ab9936c7a8f4ae9a2022-12-21T19:23:33ZengBMCAlzheimer’s Research & Therapy1758-91932021-11-011311910.1186/s13195-021-00927-zThe Alzheimer’s disease drug development landscapePieter van Bokhoven0Arno de Wilde1Lisa Vermunt2Prisca S. Leferink3Sasja Heetveld4Jeffrey Cummings5Philip Scheltens6Everard G. B. Vijverberg7Industry Alliance Office, Amsterdam Neuroscience, Amsterdam University Medical CentersLife Science Partners (LSP)Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMCIndustry Alliance Office, Amsterdam Neuroscience, Amsterdam University Medical CentersIndustry Alliance Office, Amsterdam Neuroscience, Amsterdam University Medical CentersChambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas (UNLV)Life Science Partners (LSP)Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMCAbstract 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.https://doi.org/10.1186/s13195-021-00927-zAlzheimer’s diseaseDrug development, Drug targetsTherapy |
| spellingShingle | 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 Alzheimer’s Research & Therapy Alzheimer’s disease Drug development, Drug targets Therapy |
| title | 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_short | The Alzheimer’s disease drug development landscape |
| title_sort | alzheimer s disease drug development landscape |
| topic | Alzheimer’s disease Drug development, Drug targets Therapy |
| url | https://doi.org/10.1186/s13195-021-00927-z |
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