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NeuroTherapeutics: Trials and Tribulations By Gail Schechter, Ph.D. The area of neurotherapeutics, from discovery to approval, faces enormous challenges, but some of the best brains in the business recently got together to prescribe new remedies for old maladies. Representatives from academia, industry, federal agencies, and advocacy groups focused on Translational Neurotherapeutics at the American Society for Experimental NeuroTherapeutics sixth annual meeting, held in Bethesda, MD, from March 11-13, 2004. Scientists reviewed the Alzheimer's disease (AD) pipeline and tackled such tough topics as the use of placebo controls, biomarkers, and animal models in order to highlight the optimal strategies for CNS drug discovery and development. Therapeutic Strategies for AD Of the more than 4 million persons in the U.S. with AD, only about 50% are diagnosed and only about 25% are treated (with drugs, vitamins, or various other remedies). Currently, the AD armamentarium consists solely of symptomatic treatments that do little to alter disease progression. In comparison, new disease-modifying agents have the potential to prevent cognitive decline and preserve function. The Alzheimer's disease treatment pipeline includes a range of approaches, as reviewed by Reisa Sperling, M.D. The mainstay treatments approved for Alzheimer's disease are the cholinesterase inhibitors. From oldest to newest, these include tacrine (rarely used now), donepezil, rivastigmine, and galantamine, all of which are aimed at bolstering cholinergic function. The newly approved agent memantine is an NMDA antagonist involved in glutamate modulation. In general, these neurotransmitter-related approaches confer only modest clinical benefit. Other neurotransmitter-based agents in development include phenserine, Huperzine A, and AMPA modulators. Several non-cholinergic strategies have recently received a great deal of attention. The statins (lipid-lowering drugs), non-steroidal anti-inflammatory drugs (NSAIDS), antioxidants (such as vitamin E), estrogen (this can be deleted now), clioquinol (a metal chealtor), and the herb Ginko biloba have all been tested with mixed or promising results that require further confirmation. The next generation of Alzheimer's disease treatments, amyloid-modifying interventions, directly target the underlying pathology, primarily aberrant ß-amyloid (Abeta). Prime amyloid-based strategies are to: inhibit amyloid production using ß and g secretase inhibitors; keep it from clumping using novel anti-aggregating agents; or increase its clearance. Recent research reported by Dale Shenk, Ph.D., suggests that ß-amyloid peptide immunotherapy can result in the clearance of amyloid plaques. Immunization with Abeta in a transgenic mouse model of AD reduces both age-related accumulation of Abeta in the brain and associated cognitive impairment. The first analysis of human immunization with Elan's Abeta (AN-1792) has now been completed. Preliminary results from early clinical trials suggest that changes seen in humans after Abeta immunotherapy correspond to those observed in mouse models of AD. The data suggest that the immune response generated against the peptide elicited clearance of Abeta plaques (in available patient autopsy data) produced antibodies to Abeta and may have improved cognition, although further details will be reported soon. T-lymphocyte meningoencephalitis developed in a subset of patients with AD after Abeta immunization, and most of those patients recovered fully. Further work in immunotherapy is an exciting avenue to pursue despite this setback. The intriguing next question is whether reduction of plaque burden will help restore memory and cognition in human subjects. Placebos and Active Controls The existence of approved treatments for neurodegenerative disorders, although imperfect, raises the dilemma of whether placebo-controlled trials are ethical in certain disease states. In AD, for example, where there are a handful of marketed pharmacological agents that provide modest symptom control, there is debate about whether to deny active treatment to clinical trial participants enrolled in a placebo group for periods of 6-12 months, or longer. Whereas the use of an existing treatment as an active control is perfectly feasible, there are scientific and other reasons to support the use of a placebo control group in the assessment of new agents, according to Robert Temple, M.D. Placebo-controlled trials allow for smaller, more rapid, and accurate trials and provide a true assessment of the magnitude of effectiveness compared to placebo, which is well-recognized to be a potent "wonder drug." A. Jon Stoessl, M.D, has demonstrated using PET that the placebo effect in Parkinson's disease is mediated by the release of dopamine in specific brain regions and that the degree of release is correlated with the patient's perceived assessment of treatment benefit. Other clinical trial-related topics included the design of so-called equivalence and non-inferiority trials, which are becoming more common due to the increasing use of head-to-head comparisons in CNS trials. The well-known statistical concepts of intent-to-treat (which remains the gold standard for primary analysis) and sufficient sample size to detect a specified margin of non-inferiority (equivalence margin) remain important. The fascinating topic of equipoise in clinical trials was presented by Ira Shoulson, M.D. Defined as a state of genuine uncertainty on the part of the clinical investigator, research participants, study monitors, and clinical community regarding the comparative therapeutic merits of each arm in a trial, equipoise is essential for the success of all controlled clinical trials (randomized, placebo-controlled, double-blinded). If the trial is successfully concluded, then clinical equipoise will be disturbed and the safety and efficacy of the successful treatment will be clearly demonstrated. An essential element of clinical trial design and execution is patient consent, recruitment, compliance, and participation, as noted by Jeffrey Martin, Esq., eloquent patient advocate and Parkinson's disease patient. He recommends including patients in all phases of the planning process and simplifying the consent form so that is understandable to all patients. From the discussions at this conference, it is clear that the joining together of the FDA, NIH, academic researchers, biopharmaceutical industry, and patient advocates is necessary to enhance clinical trial design, patient participation, and ultimate success. Biomarkers in Clinical Trials Russell Katz, M.D., and Marc Walton, M.D., Ph.D., from the FDA provided a regulatory perspective on the role of biomarkers in translational research. Biomarkers can have important advantages in terms of increasing the speed and decreasing the expense of clinical trials. Biomarkers and surrogate endpoints offer alternatives to clinical endpoints to examine between group differences that may not be available in small clinical studies. However, biomarkers must show a reasonable correlation with an effect on a true clinical outcome in order to capture the net effect of the intervention. Biomarkers must be related to the underlying biological process, reflect the response to treatment, and correlate with disease progression. As markers of disease activity and drug response, they can be used, for example, to show the dose effect on the biomarker, identify a patient sub-population with a specific genotype, provide early indications of effectiveness, or present evidence of toxicity. In particular, neuroimaging has evolved into a sensitive and useful marker for several CNS disorders. Imaging markers from MRI and PET have been shown to reflect the rate of hippocampal atrophy over time in Alzheimer's patients, and future research is likely to validate additional biomarkers related directly to plaque burden or other objective disease indicators. Gene Expression in Mouse Brain In his keynote address, Floyd Bloom, M.D., described efforts to develop, integrate, and apply tools to extend the information harvested from the human and mouse genome projects into the complexities of brain circuitry, gain insight into neuronal attributes and their complex interactions, and develop diagnostic and therapeutic approaches to prevent and treat brain disorders. New platform technologies being developed at Neurome, Inc., (following genome and proteome) will enable scientists to accelerate the pace of determining where genes and gene products are expressed in the mouse brain, measure the quantitative differences in gene expression between mouse strains, and provide the neuroinformatic tools to visualize these differences across time and experimental conditions. An integrated software system allows for the quantitative acquisition, display, and analysis of cellular and subcellular morphological and molecular information from the microscope. It is now possible to produce, collect, and integrate accurate, 3-dimensional volumetric data on gene expression within the brain and to correlate the data with knowledge about the architecture and functions of brain structures, circuits, and cells. The innovative advances in neurotherapeutics presented at this conference will, hopefully, translate into new treatment opportunities for millions of patients with intractable brain disorders. Intense research activity, at each stage from discovery to approval, is helping to overcome the many challenges facing CNS drug development. -------------------------------------------------------------------------------- Source: Gail Schechter, Ph.D., a Neuroscience Medical Writer in San Francisco, California, (415-921-8541, Brains@BioIntelligence.com ) covered the American Society for Experimental NeuroTherapeutics sixth annual meeting, "Translational Neurotherapeutics," in Bethesda, MD, March 11-13, 2004, www.ASENT.org , for this review. 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