PPPM in neurodegenerative diseases

EPMA Journal (2011) 2 (Suppl 1):S143–S150 DOI 10.1007/s13167-011-0122-x ABSTRACT PPPM in neurodegenerative diseases BIOMARKERS FOR PREDICTION AND TARGETED PREVENTION OFALZHEIMER’S AND PARKINSON’S DISEASES: EVALUATION OF DRUG CLINICAL EFFICACY Mandel SA1, Korczyn AD2 1 Eve Topf Center for Neurodegenerative Diseases Research and Department of Molecular Pharmacology, Faculty of Medicine, Technion, Haifa, Israel 2 Tel-Aviv University Medical School, Ramat-Aviv, Israel Neurodegenerative diseases like Parkinson’s disease (PD) and Alzheimer’s disease (AD) are considered disorders of multifactorial origin, inevitably progressive and having a long preclinical period. Currently, the clinical diagnosis of PD can be made when motor symptoms occur, though the disease has originated several years earlier. Furthermore, at its initial stages PD may be confounded by other diseases, such as essential tremor, multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Similar to PD, the pathological process characteristic of AD begins decades before the first symptoms of cognitive dysfunctions, thus making it difficult to reliably identify pathology based on the clinical phenotype alone. AD may share clinical features with many other dementing disorders including vascular dementia, dementia with Lewy bodies, PSP and others. Therefore, the availability of biological markers or biomarkers (BMs) for early disease diagnosis will impact the management of AD and PD in several dimensions; it will 1) help to capture high-risk individuals before symptoms develop, a stage where prevention efforts might be expected to have their greatest impact; 2) provide a measure of disease progression that can be evaluated objectively, while clinical measures are much less accurate; 3) help to discriminate between true AD or PD and other causes of a similar clinical syndrome; 4) delineate pathophysiological processes responsible for the disease; 5) determine the clinical efficacy of novel, disease-modifying (neuroprotective) strategies. BMs have been defined as “cellular, biochemical or molecular alterations that are measurable in the biological media such as human tissues, cells or fluids”. BMs for detection of neurodegenerative disorders can be divided into three main categories: genetic, neuroimaging, and biochemical. Normally, neuroimaging and biochemical BMs mark the presence of pathology, while genetic markers can only serve for risk assessment. Neurochemical BMs measured in the periphery by means of proteomics/ metabolomics in blood plasma, CSF and other tissues, may be useful adjuncts to imaging and clinical assessment tools for AD and PD. They may also provide valuable information about pathogenic mechanisms during clinical testing of neuroprotective/disease modifying drugs, which is especially relevant to personalized treatment. Since both AD and PD have a long preclinical period, future efforts should be focused on this time window to begin a neuroprotective treatment. Early screening, detection, and diagnosis of AD and PD will allow intervention with disease modifying therapies at earlier stages and thus may potentially improve clinical outcome. Large multicenter studies are warranted to evaluate the diagnostic value of the combined application of BMs with multiple modalities for prediction, targeted prevention and evaluation of disease modifying therapies in AD and PD. ALZHEIMER’S DISEASE: DIAGNOSTICS, PROGNOSTICS AND THE ROAD TO PREVENTION Grossman I Cabernet Pharmaceuticals, USA Alzheimer’s disease (AD) presents one of the leading healthcare challenges of the 21st century, with a projected world-wide prevalence of >107 million cases by 2025. While biomarkers have been identified which may correlate with disease progression or sub-type for the purpose of S144 disease monitoring or differential diagnosis, dependable prediction of late onset disease risk has not been available until now. This deficiency in reliable predictive biomarkers, coupled with the devastating nature of the disease, places AD at a high priority for focus by predictive, preventive and personalized medicine (PPPM). Recent data, discovered using phylogenetic analysis, suggest that a variable length poly-T sequence polymorphism in the TOMM40 gene, adjacent to the APOE gene, is predictive of risk of AD age-of-onset. This finding has been confirmed in several independent cohorts, thus offering hope for reliable assignment of disease risk within a 5–7 year window. This scientific finding is now being utilized in a pharmacogenetic-enrichment global clinical trial for the first AD preventative therapy. This clinical trial will also prospectively validate the utility of this marker as a standalone prognostic of incipient disease. DISCOVERY, DEVELOPMENT, VALIDATION AND QUALIFICATION OF MARKERS WITH CLINICAL UT IL IT Y TO T HE DE LAY O F O NSE T OF ALZHEIMER’S DISEASE CLINICAL TRIAL Roses AD Duke University and Zinfandel Pharmaceuticals, Inc., USA A novel clinical trial design is being used for the simultaneous development of a predictive test algorithm, a companion genetic diagnostic [predictor] and testing the efficacy of a drug to delay the onset of Alzheimer’s disease (AD). The TOMM40 gene encodes the translocase of the outer mitochondrial membrane pore subunit, and is in linkage disequilibrium with the APOE gene. The length of a poly-T variant (“523”) within intron 6 of TOMM40 has been shown to predict the age of onset of late onset Alzheimer’s disease (LOAD). These data allow the design of a prospective epidemiologic-ascertained longitudinal study to assess the onset of neuropsychological signs of cognitive impairment and the progression of clinical impairment. By using the group predictions to segment subjects’ risk based on their age, APOE genotype, and TOMM40-523 genotype, the positive and negative predictive values obtained from placebo treated subjects can be computed at the end of the study. These prospective data are necessary before the data can be used as a prognostic test for the risk of disease and its age of onset. The design of the clinical study to assess the clinical utility of a predictive algorithm provides the opportunity to simultaneously perform a clinical trial. This trial will assess whether a drug can delay onset of cognitive impairment of the type leading to AD. The design of OPAL [Opportunity to Prevent Alzheimer’s disease] was considered with the EPMA Journal (2011) 2 (Suppl 1):S143–S150 FDA Voluntary Exploratory Data Submission group before any drug was nominated and was determined to be a welldesigned pharmacogenetic-assisted clinical trial. It is important to point out that the predictions proposed for the study are simply being used to segment high and lower risk groups for the purpose of evaluation of the predictive value [both positive and negative] and the effect of a safe drug for which there is a rationale to slow or prevent the AD process. Clinical utility demands that the pu (...truncated)