Clinical trials and late‐stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014

Abstract

The modern era of drug development for Alzheimer’s disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer’s disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here we review the development of treatments for Alzheimer’s disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer’s disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild to moderate Alzheimer’s disease criteria, recently extending to early or prodromal Alzheimer disease or ‘mild cognitive impairment due to Alzheimer’s disease’, for drugs considered to be disease modifying. The duration of trials has remained at 6 to 12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early-stage Alzheimer’s disease trial samples by using biomarkers and phase-specific outcomes. In conclusion, validated drug targets for Alzheimer’s disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late-phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.

HPTLC Finger-Printing and Cholinesterase Inhibitory and Metal-Chelating Capacity of Various Citrus Cultivars and Olea europaea

“…It is a slowly progressive and degenerative disease that leads to loss of memory, decline in thinking and language skills. The pathogenesis of AD has been so far explained by cholinergic and amyloid hypotheses, and it has been stated that only drugs acting on cholinergic system have moderate, but steady eff ects in clinical trials (1). The cholinergic hypothesis is based on insuffi ciency of the acetylcholine (ACh) level in the brains of AD patients, which is hydrolyzed by acetylcholinesterase (AChE, EC 3.1.1.7) (2).…”

<i>In Vivo</i> Screening of Traditional Medicinal Plants for Neuroprotective Activity against Aβ42 Cytotoxicity by Using <i>Drosophila</i> Models of Alzheimer’s Disease

“…4,5) However, the beneficial effects of these drugs during the progression of AD are still in question. 6) Due to its complex etiology, a combination therapy including the use of medicinal plants with effective components has been proposed as an alternative choice for treatment of AD.…”

“…2,3) Several drugs have been approved to treat AD, given the dysfunction of cholinergic and glutamatergic neurotransmission; they function as acetylcholinesterase inhibitors or N-methyl-D-aspartate (NMDA) receptor antagonists. 4,5) However, the beneficial effects of these drugs during the progression of AD are still in question. 6) Due to its complex etiology, a combination therapy including the use of medicinal plants with effective components has been proposed as an alternative choice for treatment of AD.…”

Biomarkers in Pharmaceutical Research

“…Accordingly, CRP reduction in a small study of shortcourse infliximab contributed to rapid advancement of this compound, and the anti-TNF (tumor necrosis factor) mechanism more generally, to larger studies and eventual approval for rheumatoid arthritis treatment (30 ). In contrast, the lack of established disease activity markers for chronic neurodegenerative diseases, such as Alzheimer and Parkinson diseases, precludes efficacy estimation in small studies and has led to many high-profile failures in the late stage of clinical development-such that several pharmaceutical efforts in this area have been abandoned (1,31 ). Disease burden biomarkers allow rapid clinical development, perhaps most prominently in infectious disease.…”