The battle of Alzheimer's Disease - the beginning of the future Unleashing the potential of academic discoveries

Abstract

Alzheimer's Disease (AD) is the most common form of dementia, affecting approximately 36 million people worldwide. To date there is no preventive or curative treatment available for AD, and in absence of major progress in therapeutic development, AD manifests a concrete socioeconomic threat. The awareness of the growing problem of AD is increasing, exemplified by the recent G8 Dementia Summit, a meeting held in order to set the stage and steer the compass for the future. Simultaneously, and paradoxically, we have seen key players in the pharmaceutical industry that have recently closed or significantly decreased their R&D spending on AD and other CNS disorders. Given the pressing need for new treatments in this area, other actors need to step-in and enter this drug discovery arena complementing the industrial efforts, in order to turn biological and technological progress into novel therapeutics. In this article, we present an example of a novel drug discovery initiative that in a non-profit setting, aims to integrate with both preclinical and clinical academic groups and pharmaceutical industry to explore the therapeutic potential of new concepts in patients, using novel biology, state of the art technologies and rapid concept testing.

Keywords: Alzheimer’s disease; collaborative research; drug discovery and development; non-profit; pharmaceutical; technology.

FIGURE 1

This cartoon illustrates the proposed AlzeCure business (A) and strategy models (B) to develop new therapies and medicinal technology products, highlighting the proof-of-mechanism (PoM)/proof-of-concept (PoC) as an important milestone in drug discovery and development process. Traditionally, in order to reach clinical PoM and PoC with “standard peripherally administered” drug candidates in a chronic condition, the drug needs to display key and optimized features including adsorption, distribution, metabolism, tolerability, and BBB permeability, in addition to its desired pharmacology and safety. This is seldom achieved despite significant medicinal chemistry, an effort that takes place over a very long time in the discovery phase. As a consequence, many suboptimal compounds are being explored in the clinic without being able to test the hypothesis they were aimed for in a conclusive manner. Building the need to get strong evidence for PoM/PoC, including close collaboration with international academic preclinical research, utilizing new Translational enabling technologies into the discovery process, is crucial. To reduce the attrition due to lack of efficacy and safety, it is important to design the first clinical trials, a design based on appropriate animal models, pharmacokinetic/pharmacodynamic modeling, and utilizing biomarkers and surrogate markers, in the “right patients,” to facilitate that the molecular target is being hit at an expected concentration to give the anticipated physiological response without safety issues. Optimally, the PoM/PoC clinical trials are conducted at Clinical Trial Centers that are closely involved in the discovery research. It is also important to have a rapid feed-back to the drug discovery process from positive or failed PoM/PoC studies to improve the understanding of mechanisms, and to accelerate the development of follow-up compounds that address the same mechanism, but with improved drug-like characteristics or to identify related mechanistic targets that will lead to new clinical studies.