Advances in the therapy of Alzheimer's disease: Targeting amyloid beta and tau and perspectives for the future

Worldwide multidisciplinary translational research has led to a growing knowledge of the genetics and molecular pathogenesis of Alzheimer's disease (AD) indicating that pathophysiological brain alterations occur decades before clinical signs and symptoms of cognitive decline can be diagnosed. Consequently, therapeutic concepts and targets have been increasingly focused on early-stage illness before the onset of dementia; and distinct classes of compounds are now being tested in clinical trials. At present, there is a growing consensus that therapeutic progress in AD delaying disease progression would significantly decrease the expanding global burden. The evolving hypothesis- and evidence-based generation of new diagnostic research criteria for early-stage AD has positively impacted the development of clinical trial designs and the characterization of earlier and more specific target populations for trials in prodromal as well as in pre- and asymptomatic at-risk stages of AD

Clinical trials and late-stage drug development in Alzheimer’s disease: An appraisal from 1984 to 2014

The modern era of drug development for Alzheimer\u27s disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer\u27s 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\u27s 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\u27s 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\u27s disease criteria, recently extending to early or prodromal Alzheimer disease or ‘mild cognitive impairment due to Alzheimer\u27s disease’, for drugs considered to be disease modifying. The duration of trials has remained at 6–12 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\u27s disease trial samples using biomarkers and phase‐specific outcomes. In conclusion, validated drug targets for Alzheimer\u27s 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

Regulatory Issues in Cognitive Enhancement Treatment Development

Improvement of cognition by medicinal products is an accepted concept by regulatory agencies. In dementing conditions such as Alzheimer’s disease, improvement of cognition or slowing its deterioration is essential for approval, particularly in early and mild to moderate stages of Alzheimer’s disease. In conditions such as schizophrenia or major depression, treatment of cognitive impairment is not considered as a pseudospecific indication, and specific clinical trials for such an indication are underway. Assessment tools for measurements of change in cognition and its relevance in functional or global outcome parameters must be validated in well-described patient populations. Developers are strongly encouraged to request scientific advice by regulatory agencies early in their programs to avoid delays or setbacks due to methodological or policy issues.</p