Barriers to Closing the Alzheimer Pharmaceutical Gap 1

·         Lack of validated targets. AD requires a clinical diagnosis, and at present, there are no reliable tests to confirm a diagnosis. Definitive diagnosis can only be made postmortem from brain tissue. Despite years of research, there is still an unclear understanding on the pathogenesis of AD. Further research is still needed at the basic neuroscientific level.  Companies are already investing large amounts of money in AD, but the high risk and cost coupled with long clinical trials in disease modification, mean that at most a company could only take one or two approaches forward in disease modification trials at present. The problem is the high risk and the lack of markers to increase confidence in moving from Phase II to large Phase III trials.

·         Lack of animal models. There are no good animal models that reflect the disease state. Those models that do exist model only aspects of pathology e.g. amyloid over expression. Equally as important is the issue of access to animal models. Current animal models are not readily accessibly for research and drug screening at the preclinical level because of intellectual property and licensing issues. Many of these models belong to academia (not industry) and institutes and the costs of the models are prohibitive to academic scientists and small biotech companies.

·         Barriers in the design and implementation of clinical trials. Long trials are needed to determine the efficacy and safety of AD medicines. In an effort to control AD at the early stages, clinical studies are evaluating the effectiveness of therapies at mild cognitive impairment (MCI) stages, which is considered the prodromal stage to AD. Guideline’s for MCI studies have not been established. Another area that requires further work is the design and outcomes measures for AD prevention. Scientific evidence has determined that neuropathology processes resulting in AD occurs several years prior to the onset of AD symptoms. However, conducting long-term clinical studies to monitor a patient’s progression or decline in function is costly and requires a lot of effort.

·         Lack of surrogate markers. The lack of surrogate markers for therapeutic endpoints remains a major barrier in the clinical development of efficacious AD drugs. The availability of such surrogates would benefit and hasten AD drug development. Any reliable predictor of clinical outcome will step up the development of effective AD medicines. Much work in this area is already ongoing, however continued efforts are still required. Commonly accepted markers in cerebrospinal fluid (CSF) or blood such as alpha -amyloid and tau are still not adequately validated and may not be sensitive for longitudinal progression and treatment effects on AD. Additionally, neuroimaging markers, as determined by MRI are reasonably validated and sensitive for use in long-term trials but are not suitable for short-term duration, proof of-concept trials. There is also a need to develop an infrastructure to speed up validation studies, such as large-scale biologic sample collection from ongoing aging populations. The availability and development of specific imaging technology such as Positron Emission Tomography (PET) to determine whether changes in the brain or its function can be identified before the person develops symptoms of the disease is also needed. 3

·         Barriers in academia[i]. Academic drug discovery and development programs are usually under funded and lack infrastructure, in terms of staff and equipment especially at the preclinical level. Furthermore, the lack of communication, interaction and collaboration between necessary research groups can limit drug discovery and research. Today, science and medicine requires an interdisciplinary approach to solving medical conditions.

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[i] Eldick LVJ, Koppal T, Watterson DM, Barriers to Alzheimer Disease Drug Discovery and Development in Academia. Alzheimer Disease and Associated Disorders. 2002; 16: suppl 1: s18-s28