Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research

Abstract

Despite all scientific efforts and many protracted and expensive clinical trials, no new drug has been approved by FDA for treatment of Alzheimer disease (AD) since 2003. Indeed, more than 200 investigational programs have failed or have been abandoned in the last decade. The most probable explanations for failures of disease-modifying treatments (DMTs) for AD may include late initiation of treatments during the course of AD development, inappropriate drug dosages, erroneous selection of treatment targets, and mainly an inadequate understanding of the complex pathophysiology of AD, which may necessitate combination treatments rather than monotherapy. Clinical trials’ methodological issues have also been criticized. Drug-development research for AD is aimed to overcome these drawbacks. Preclinical and prodromal AD populations, as well as traditionally investigated populations representing all the clinical stages of AD, are included in recent trials. Systematic use of biomarkers in staging preclinical and prodromal AD and of a single primary outcome in trials of prodromal AD are regularly integrated. The application of amyloid, tau, and neurodegeneration biomarkers, including new biomarkers—such as Tau positron emission tomography, neurofilament light chain (blood and Cerebrospinal fluid (CSF) biomarker of axonal degeneration) and neurogranin (CSF biomarker of synaptic functioning)—to clinical trials allows more precise staging of AD. Additionally, use of Bayesian statistics, modifiable clinical trial designs, and clinical trial simulators enrich the trial methodology. Besides, combination therapy regimens are assessed in clinical trials. The above-mentioned diagnostic and statistical advances, which have been recently integrated in clinical trials, are relevant to the recent failures of studies of disease-modifying treatments. Their experiential rather than theoretical origins may better equip potentially successful drug-development strategies.

Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease

“…While recent failures in phase 3 clinical trials by Merck, Pfizer, J&J, Eli Lilly and Roche have been rather discouraging, the most probable explanation for these failures may be derived from the inadequacy of animal models used, initiation of treatment at late/irreversible stages during the course of AD development, complications arising from drug dosage, and targeting ineffective targets. These factors are due in large part to an incomplete understanding of complexities in AD pathophysiology [634].…”

Apolipoprotein E isoforms differentially regulate matrix metallopeptidase 9 function in Alzheimer’s disease

“…There has not been a new drug approved by the FDA for treatment of AD since 2003 [253]. At present, the drugs used for treatment of AD include cholinesterase inhibitors (donepezil, galantamine and rivastigmine) and an N-methyl-D-aspartate receptor antagonist (memantine), which aim to sustain neuronal communication by enhancing the chemical pathways that are disrupted following neurodegeneration [254]- [257].…”

“…However, a closer evaluation points towards technical limitations as opposed to Aβ being an erroneous treatment target [253], [295], [297]. There are several reasons postulated to explain these failures, including not intervening early enough, incorrect drug doses, flawed treatment targets and not comprehending in depth the contribution of Aβ and other factors in AD [259], [296].…”

CRISPR-Cas9: A Promising Genome Editing Therapeutic Tool for Alzheimer’s Disease—A Narrative Review

“…In the last decade, over 200 research investigations were futile or have been dumped. The most likely reasons for failures of disease-modifying treatments (DMTs) for AD might include starting of treatments late during the course of AD progress, inappropriate drug doses, invalid target selection, and predominantly an insufficient knowledge of the complex pathophysiology of AD, which may require specific and combination treatments [19].…”