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. 2021 Nov 11;13(1):186.
doi: 10.1186/s13195-021-00927-z.

The Alzheimer's disease drug development landscape

Pieter van Bokhoven  1 , Arno de Wilde  2 , Lisa Vermunt  3   4 , Prisca S Leferink  5 , Sasja Heetveld  5 , Jeffrey Cummings  6 , Philip Scheltens  2   3 , Everard G B Vijverberg  3
Affiliations

The Alzheimer's disease drug development landscape

Pieter van Bokhoven et al. Alzheimers Res Ther. .

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.

Keywords: Alzheimer’s disease; Drug development, Drug targets; Therapy.

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Conflict of interest statement

PvB, PL, SH, and JV declare that they have no competing interests. LV receives administrative support paid to her institution by Olink for CORAL. JV and PvB are advisory consultants for several pharmaceutical companies in the field of neurodegeneration. PS is employed by LSP and Amsterdan University Medical Centers. Dr Scheltens has received consultancy fees (paid to Amsterdam University Medical centers) from AC Immune, Brainstorm Cell, EIP, ImmunoBrain Checkpoint, Genentech, Novartis, Novo Nordisk. He is PI of studies with AC Immune, FUJI-film/Toyama, UCB, and Vivoryon (fees paid to Amsterdam University Medical Center).

Figures

Fig. 1
Fig. 1
AD drugs in development, preclinical vs clinical. The number of drugs per target class in preclinical development is shown as a percentage of all drugs in preclinical development, and the number of drugs per target class in clinical development is shown as a percentage of all drugs in clinical development
Fig. 2
Fig. 2
Number of AD drugs by clinical development stage, stratified by target class. The size of the dotted circles indicates the number of drugs as reflected in the legend
Fig. 3
Fig. 3
AD drugs per target class, stratified by treatment modality
See this image and copyright information in PMC

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