Beyond immunotherapy: new approaches for disease modifying treatments for early Alzheimer’s disease

ABSTRACT

Introduction: Current pharmacological recommendations for the treatment of Alzheimer’s disease (AD) include the cholinesterase inhibitors and the N-methyl-D-aspartate antagonist, memantine. However, these medications only manage symptoms of AD, and do not target Aβ plaques and neurofibrillary tangles. As such, there is a need to develop effective and safe disease modifying treatments that directly target AD pathology and alter the course of AD progression.

Areas covered: This review evaluates ongoing phase 2 and 3 clinical trials, as well as those completed or published over the past five years. Studies for this review were obtained from clinicaltrials.gov, alzforum.org/therapeutics, and PubMed. Keywords and search criteria included: phase 2, or 3 trials related to Alzheimer’s disease, mild cognitive impairment, amyloid-beta and tau. Immunotherapies for AD have not been included as this is beyond the scope of this review.

Expert opinion: A substantial number of trials investigating disease modifying drugs in AD target amyloid-beta and tau pathology. However, many of these trials have relatively short treatment duration and do not include combined assessment of biomarkers and clinical outcomes. Future investigations are recommended to include biomarker assessments and clinical outcomes over a minimum treatment duration of 18 months in order to establish disease-modifying effects.

KEYWORDS:

• Phase 2
• phase 3
• amyloid-beta
• tau
• disease modifying
• Alzheimer’s disease

Article highlights

• Disease modifying drugs target one of the following AD pathologies: 1) amyloid-beta (Aβ) production, 2) Aβ aggregation, or 3) tau pathology

• Several past and ongoing phase II and III are unable to confirm disease modifying efficacy due to limitations with trial design

• Studies investigating the efficacy of disease modifying drugs should include: 1) biomarker outcomes, 2) clinical outcomes, and 3) a study duration of greater than 18 months

• BACE1 inhibitors and azeliragon, a RAGE inhibitor are the most advanced in investigating disease modifying efficacy for AD, however results are pending

• Leviteracetam, benfotiamine, scyllo-inositol and MTC may also have potential disease modifying properties, however their study designs have limitations

• Future clinical trials should include the investigation of biomarkers and clinical outcomes over 18 months, and also consider targeting asymptomatic individuals who are genotyped positive for developing AD as disease modifying drugs may have greater efficacy in that population group

This box summarizes key points contained in the article.

Declaration of interest

M. Ruthirakuhan is supported by a Canadian Institutes of Health Research Doctoral Research Award. N. Herrmann is supported by peer-reviewed grants from the Alzheimer Society of Canada (grant 15-17), Canadian Institute of Health Research, Heart and Stroke Foundation (grant T 6383), Ontario Ministry of Health and Long Term Care AFP Provincial Innovation Fund and Ontario Brain Institute in addition to research contracts funded by Pfizer Canada, F. Hoffman-La Roche Ltd., Elan Pharma International Ltd., and Lundbeck Canada Inc. K Lanctôt is supported by peer reviewed grants from the Alzheimer Society of Canada (grant 15-17), Alzheimer’s Drug Discovery Foundation (grant 20140503), Canadian Institute of Health Research, National Institute on Aging of the National Institutes of Health (grant R01AG046543), and the Heart and Stroke Foundation (grant NA 7220) in addition to research contracts funded by AbbVie Pharmaceuticals, F. Hoffman-La Roche Ltd., Elan Pharma International Ltd., and Lundbeck Canada Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed

Additional information

Funding

This paper was not funded.