Developing Effective Alzheimer’s Disease Therapies: Clinical Experience and Future Directions

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Abstract

Alzheimer’s disease (AD) clinical trials, focused on disease modifying drugs and conducted in patients with mild to moderate AD, as well as prodromal (early) AD, have failed to reach efficacy endpoints in improving cognitive function in most cases to date or have been terminated due to adverse events. Drugs that have reached clinical stage were reviewed using web resources (such as clinicaltrials.gov, alzforum.org, company press releases, and peer reviewed literature) to identify late stage (Phase II and Phase III) efficacy clinical trials and summarize reasons for their failure. For each drug, only the latest clinical trials and ongoing trials that aimed at improving cognitive function were included in the analysis. Here we highlight the potential reasons that have hindered clinical success, including clinical trial design and choice of outcome measures, heterogeneity of patient populations, difficulties in diagnosing and staging the disease, drug design, mechanism of action, and toxicity related to the long-term use. We review and suggest approaches for AD clinical trial design aimed at improving our ability to identify novel therapies for this devastating disease.

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Most cited references 45

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Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report.

Roy O Weller, David Wilkinson, James A R Nicoll … (2003)

Amyloid-beta peptide (Abeta) has a key role in the pathogenesis of Alzheimer disease (AD). Immunization with Abeta in a transgenic mouse model of AD reduces both age-related accumulation of Abeta in the brain and associated cognitive impairment. Here we present the first analysis of human neuropathology after immunization with Abeta (AN-1792). Comparison with unimmunized cases of AD (n = 7) revealed the following unusual features in the immunized case, despite diagnostic neuropathological features of AD: (i) there were extensive areas of neocortex with very few Abeta plaques; (ii) those areas of cortex that were devoid of Abeta plaques contained densities of tangles, neuropil threads and cerebral amyloid angiopathy (CAA) similar to unimmunized AD, but lacked plaque-associated dystrophic neurites and astrocyte clusters; (iii) in some regions devoid of plaques, Abeta-immunoreactivity was associated with microglia; (iv) T-lymphocyte meningoencephalitis was present; and (v) cerebral white matter showed infiltration by macrophages. Findings (i)-(iii) strongly resemble the changes seen after Abeta immunotherapy in mouse models of AD and suggest that the immune response generated against the peptide elicited clearance of Abeta plaques in this patient. The T-lymphocyte meningoencephalitis is likely to correspond to the side effect seen in some other patients who received AN-1792 (refs. 7-9).

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The genetics of Alzheimer disease: back to the future.

Lars Bertram, Christina Lill, Rudolph E. Tanzi (2010)

Three decades of genetic research in Alzheimer disease (AD) have substantially broadened our understanding of the pathogenetic mechanisms leading to neurodegeneration and dementia. Positional cloning led to the identification of rare, disease-causing mutations in APP, PSEN1, and PSEN2 causing early-onset familial AD, followed by the discovery of APOE as the single most important risk factor for late-onset AD. Recent genome-wide association approaches have delivered several additional AD susceptibility loci that are common in the general population, but exert only very small risk effects. As a result, a large proportion of the heritability of AD continues to remain unexplained by the currently known disease genes. It seems likely that much of this "missing heritability" may be accounted for by rare sequence variants, which, owing to recent advances in high-throughput sequencing technologies, can now be assessed in unprecedented detail. Copyright © 2010 Elsevier Inc. All rights reserved.

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A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease

Susanne Ostrowitzki, Robert A Lasser, Ernest Dorflinger … (2017)

Background Gantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-β (Aβ) and removes Aβ plaques by Fc receptor-mediated phagocytosis. In the SCarlet RoAD trial, we assessed the efficacy and safety of gantenerumab in prodromal Alzheimer’s disease (AD). Methods In this randomized, double-blind, placebo-controlled phase III study, we investigated gantenerumab over 2 years. Patients were randomized to gantenerumab 105 mg or 225 mg or placebo every 4 weeks by subcutaneous injection. The primary endpoint was the change from baseline to week 104 in Clinical Dementia Rating Sum of Boxes (CDR-SB) score. We evaluated treatment effects on cerebrospinal fluid biomarkers (all patients) and amyloid positron emission tomography (substudy). A futility analysis was performed once 50% of patients completed 2 years of treatment. Safety was assessed in patients who received at least one dose. Results Of the 3089 patients screened, 797 were randomized. The study was halted early for futility; dosing was discontinued; and the study was unblinded. No differences between groups in the primary (least squares mean [95% CI] CDR-SB change from baseline 1.60 [1.28, 1.91], 1.69 [1.37, 2.01], and 1.73 [1.42, 2.04] for placebo, gantenerumab 105 mg, and gantenerumab 225 mg, respectively) or secondary clinical endpoints were observed. The incidence of generally asymptomatic amyloid-related imaging abnormalities increased in a dose- and APOE ε4 genotype-dependent manner. Exploratory analyses suggested a dose-dependent drug effect on clinical and biomarker endpoints. Conclusions The study was stopped early for futility, but dose-dependent effects observed in exploratory analyses on select clinical and biomarker endpoints suggest that higher dosing with gantenerumab may be necessary to achieve clinical efficacy. Trial registration ClinicalTrials.gov, NCT01224106. Registered on October 14, 2010. Electronic supplementary material The online version of this article (doi:10.1186/s13195-017-0318-y) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Carmela Abraham: Role: Handling Associate Editor

Journal

Journal ID (nlm-ta): J Alzheimers Dis

Journal ID (iso-abbrev): J. Alzheimers Dis

Journal ID (publisher-id): JAD

Title: Journal of Alzheimer's Disease

Publisher: IOS Press (Nieuwe Hemweg 6B, 1013 BG Amsterdam, The Netherlands )

ISSN (Print): 1387-2877

ISSN (Electronic): 1875-8908

Publication date (Electronic, preprint): 27 August 2019

Publication date (Electronic, pub): 01 October 2019

Publication date (Electronic, collection): 2019

Volume: 71

Issue: 3

Pages: 715-732

Affiliations

[a ]Department of Radiology, Massachusetts General Hospital , Boston, MA, USA

[b ]AZTherapies Inc., Boston, MA, USA

[c ]Department of Neurology, Indiana University School of Medicine , Indianapolis, IN, USA

[d ]Molecular Imaging Center, Department of Radiology, Keck School of Medicine, University of Southern California , Los Angeles, CA, USA

[e ]Department of Surgery, Massachusetts General Hospital and Harvard Medical School , Boston, MA, USA

[f ]Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases (MIND) , Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA

Author notes

[* ]Correspondence to: David R. Elmaleh, PhD, Massachusetts General Hospital, Department of Radiology, 55 Fruit Street, Boston, MA 02114, USA. Tel.: +1 617 318 3430; Fax: +1 617 848 8703; E-mails: delmaleh@ 123456mgh.harvard.edu ; delmaleh@ 123456aztherapies.com .

Article

Publisher ID: JAD190507

DOI: 10.3233/JAD-190507

PMC ID: 6839593

PubMed ID: 31476157

SO-VID: 915be4f1-e47f-42ae-ae3a-48270ef5be47

License:

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Developing Effective Alzheimer’s Disease Therapies: Clinical Experience and Future Directions

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Most cited references 45

Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report.

The genetics of Alzheimer disease: back to the future.

A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease

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