Alzheimer’s Disease: Key Insights from Two Decades of Clinical Trial Failures

C. Kwon Kim; Yin Rui Lee; Lynnett Ong; Michael Gold; Amir Kalali; Joydeep Sarkar

doi:10.3233/jad-215699

journal article Open Access May 03, 2022

Alzheimer’s Disease: Key Insights from Two Decades of Clinical Trial Failures

C. Kwon Kim Yin Rui Lee Lynnett Ong Michael Gold

Amir Kalali Joydeep Sarkar

Journal of Alzheimer’s Disease Vol. 87 No. 1 pp. 83-100 · SAGE Publications

View at Publisher Save 10.3233/jad-215699

Abstract

Given the acknowledged lack of success in Alzheimer’s disease (AD) drug development over the past two decades, the objective of this review was to derive key insights from the myriad failures to inform future drug development. A systematic and exhaustive review was performed on all failed AD compounds for dementia (interventional phase II and III clinical trials from ClinicalTrials.gov) from 2004 to the present. Starting with the initial ∼2,700 AD clinical trials, ∼550 trials met our initial criteria, from which 98 unique phase II and III compounds with various mechanisms of action met our criteria of a failed compound. The two recent reported phase III successes of aducanumab and oligomannate are very encouraging; however, we are awaiting real-world validation of their effectiveness. These two successes against the 98 failures gives a 2.0% phase II and III success rate since 2003, when the previous novel compound was approved. Potential contributing methodological factors for the clinical trial failures were categorized into 1) insufficient evidence to initiate the pivotal trials, and 2) pivotal trial design shortcomings. Our evaluation found that rational drug development principles were not always followed for AD therapeutics development, and the question remains whether some of the failed compounds may have shown efficacy if the principles were better adhered to. Several recommendations are made for future AD therapeutic development. The whole database of the 98 failed compounds is presented in the Supplementary Material.

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Details

Published: May 03, 2022
Vol/Issue: 87(1)
Pages: 83-100
License: View

Authors

C

C. Kwon Kim

Holmusk, New York, NY, USA

Y

Yin Rui Lee

Holmusk, New York, NY, USA

L

Lynnett Ong

Holmusk, New York, NY, USA

M

Michael Gold

Neuroscience Development, AbbVie, North Chicago, IL, USA

A

Amir Kalali

Chairman, CNS Summit, San Diego, CA, USA

J

Joydeep Sarkar

Holmusk, New York, NY, USA

Cite This Article

C. Kwon Kim, Yin Rui Lee, Lynnett Ong, et al. (2022). Alzheimer’s Disease: Key Insights from Two Decades of Clinical Trial Failures. Journal of Alzheimer’s Disease, 87(1), 83-100. https://doi.org/10.3233/jad-215699

Alzheimer’s Disease: Key Insights from Two Decades of Clinical Trial Failures

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