Masterstudiengang "Drug Regulatory Affairs"


Regulatory Requirements for the Clinical Development of New Therapies for the Treatment of Alzheimer’s Disease ***

Dr. Susanne Vambrie (Abschlußjahr: 2009)

Language: English

Alzheimers disease is a very complex disorder which was described by Alois Alzheimer more than 100 years ago. Although its underlying pathology is still not entirely clear, research has accumulated a wealth of information on different mechanisms that account for one or the other aspect of the disease. Milestones in AD research were for example the identification of beta amyloid (A-beta 42) as the main component of amyloid plaques in 1984 by Glenner and Wong. This insight resulted in the formulation of the Amyloid Cascade Hypothesis by Hardy and Allsop in 1991 which claims that the disturbed metabolism of APP is the initiating event in AD pathogenesis. Thus, an important target for the development of new treatment approaches was identified which is still the basis of many research projects. Another milestone was the discovery that the intracellular neurofibrillary tangles observed in the brain of AD patients were composed of abnormally hyperphosphorylated tau protein. The regulation of tau phosphorylation and how this regulation may be influenced by beta-amyloid gave rise to many new questions. Likewise, the finding that the expression of inflammatory mediators is increased in post-mortem brains of patients suffering from AD opened an entire new research field. Consequently, a lot of different mechanisms of action are studied and a large number of compounds are developed for the potential treatment of AD. Many of these are putatively disease-modifying. Despite all these research activities, no clinical proof-of-concept could be obtained to date and none of the main targets suspected of playing a major role in the pathology of the disease, such as beta-amyloid, could be validated as a reliable biomarker.

The regulatory requirements in both Europe and the US are relatively clear. Furthermore, there are no great differences in the regulatory requirements that need to be fulfilled to gain approval for a new AD therapy. At least in the case of memantine, the EMEA distinguishes more stages of AD and is more flexible concerning the primary outcome measures. Although the EMEA recommends using a cognitive and a functional endpoint as primary efficacy measure, the Agency accepted also clinical trials with a functional and a global endpoint in the case of advanced AD. Contrary to the EMEA, the FDA only accepts clinical trials for the efficacy assessment if one of the two primary endpoints is from the cognitive domain, independent of the stage of AD to be claimed.

Although the regulatory framework is well defined, it has become more difficult to obtain a marketing authorisation for a new medicinal product to treat AD because the hurdles to show efficacy are higher today. Symptomatic improvement needs to be demonstrated on top of standard of care treatment, namely AChE inhibitors and/or memantine. This applies particularly to potentially disease-modifying treatments as these additionally need to demonstrate a correlation between a prospectively defined biomarker and clinically meaningful improvement of the core symptoms of AD. However, the analysis of the failure and subsequent discontinuation of the two most advanced and supposedly disease-modifying anti-Alzheimer therapies, namely Alzhemed® and Flurizan®, indicates that rather than the lack of regulatory guidance, the lack of relevant disease-specific targets was the cause of the disappointing results. Clearly, the best regulatory guidance is not able to bridge a gap in the scientific understanding of a disease. Thus, further intensive research will be required to identify the actual cause of AD and achieve a long awaited break-through in the treatment of this devastating disease.

Pages: 60,
Annexes: 3, pages: 20; 19; 17 (double-sided)

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