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| November 10, 2009 – Issue 6 “Bridging the Gap” – Part 1 This issue of Invenio will be released in two installments. Part 1 addresses the vast opportunities and challenges of CNS drug development research. Part 2 offers a different approach to early development research that CRI has been active in for the last several years. There are both great opportunities and significant risks in developing novel drugs for central nervous system (CNS) diseases. The opportunities stem from advances being made in our understanding of the structure and function of the human brain as a result of neuroscience and molecular biology research. The human genome project has been completed and now the effort is underway to identify and understand the functional significance of all the single nucleotide polymorphisms which make each of us unique individuals both externally and internally. This effort has already born fruit but these discoveries, while remarkable, will pale in comparison with those that will follow. The reason is that there are an estimated 5,000 brain-specific proteins which are the product of specific genes. With the completion of the human genome project, the genes’ coding for these proteins is now being identified. That will permit determination of their structure and, in turn, permit the development of drugs which can selectively interact with these sites. That is the good news. CNS drug discovery teams will have a vast array of targets and tools to develop novel CNS compounds. As Cramer of “Mad Money” might say: “Now is the time to be bullish on CNS drug development.” What is the downside? While CNS drug discovery is firmly in the 21st century, CNS clinical research has not kept pace due to a lack of knowledge about, and tools to study, the fundamental pathophysiology of psychiatric and neurologic diseases. Precious little is known about the cause of such chronic illnesses as schizophrenia and major depression. The sheer percentage of our population affected by these illnesses and their chronicity is the reason that drugs to treat such CNS diseases are among the largest revenue generating drugs in many pharmaceutical companies' portfolios. However, the vagaries of drug development in this area make CNS drug discovery a highly speculative venture. One significant problem that can be addressed is the substantial gap that has to be crossed from preclinical to clinical drug development. This gap is larger than in any other therapeutic area for several reasons. First is the lack of knowledge of the relevant pathophysiology of the disease processes, making it impossible to develop appropriate animal models. Second, the vast difference between the human brain and the brain of other animals is such that it may not be possible to model these illnesses in animals even if we knew the pathophysiology. For the same reason, we cannot assess in animals many of the symptoms and signs that are the targets of the drug therapy such as hallucinations, delusions, disturbed mood and thought disorder. Despite these problems, many companies will launch into full-scale, pivotal phase II studies with a new chemical entity (NCE) after the usual single- and multiple-dose phase I studies in normal volunteers to determine safety, tolerability and pharmacokinetics. This approach is highly speculative. The study may be testing the drug in the wrong condition or with the wrong endpoint. That is expensive from two standpoints: There is the cost of the study itself and there is the possibility that the development of what could be a useful and commercially-successful drug could be discontinued on the basis of studies done in the wrong way or in the wrong patient population. The problem is the old fashion but conventional, multi-site proof-of-concept studies are not a good way to gain a true understanding of the clinical pharmacology of new CNS drugs. These studies have a preselected outcome of interest (e.g. antidepressant efficacy), a rigid design which makes midcourse corrections difficult, if not impossible, and generally are multi-site. While the latter is usually dictated by power calculations, it means that no single investigator will likely develop much "feel" for the unique pharmacology of the drug. This approach is like limiting oneself to either hitting a home run or striking out every time. In Part 2 we’ll speak to an approach to early phase research that has proven to not only save millions of dollars in development costs but delivered actionable results that would have been missed in a conventional phase II trial. |
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