Alzheimer’s Disease Research Summit 2012: Path to Treatment and Prevention Session 4: Drug Repurposing and Combinatorial Therapy Suzanne Craft, Ph.D. (University of Washington) (Session Chair): I think this is a rather new area for many of us in AD therapeutics with respect to how often repurposing is used as a strategy, and there’s a strong rationale for doing this. First of all, usually there’s a fairly dramatic reduction in the cost or the timeline relative to novel drug discovery and development. Partly due to the fact that there’s a much better characterization of the adverse event profile going in, although we should be cautioned that the AD profile might be quite different for patients with Alzheimer’s disease or older adults, or for populations in which the drug has not yet been tested. There’s also greater information about the therapeutic mechanism or target for the drug, but often, of course, off-target actions exist that provide the rationale for repurposing or make the drug a good candidate for Alzheimer’s. With respect to combinatorial therapy, I think we’ve heard, over the last couple of days, an interesting discussion about whether or not the best approach in therapeutics is to go after the most selective molecule possible. The so-called “silver bullet approach.” Or whether the multisystem pathology that we all are now coming to know typifies AD, and a particular lateonset AD requires more of a multisystem approach, which could be achieved through combinatorial therapy or potentially through pleiotropy of pharmacologic agents. As you might expect, the complexity of combinatorial therapy is daunting. And this is something that can be addressed by approaches such as network pharmacology. And we’ll hear a little bit about that in our session today. And so there are some examples, and I’ll take one from our own work, of ways in which repurposing—and I would argue combinatorial therapy—can be used potentially successfully for mild cognitive impairment and early AD. It comes from studies that we carried out with insulin. We developed this approach, it was really a rationale-based approach rather than a discoverybased approach, based on existing evidence that insulin resistance in type 2 diabetes is a risk factor in AD, and based on accruing evidence that there’s a defect in brain insulin signaling in Alzheimer’s. In response to this, we developed a method for getting insulin into the brain using an intranasal delivery device. We have been pleased with the promising results. We hoped to be able to take those further into more definitive trials, but this is one example that exists within the field already. Many others with respect to, for example a combination of an MDA receptor, memantine and cholinergic agents together, as well as some of the combinations that can address neuropsychiatric symptoms and cognitive symptoms in Alzheimer’s disease that we’ll also hear about today. So I’d like to go ahead and invite our first speaker, Dr. Donald Frail from AstraZeneca, who will tell us today his experiences with drug repurposing. Donald Frail, Ph.D. (AstraZeneca): 1 Good morning, thanks to Neil and Suzanna and the organizers for the invitation. My roots are in Alzheimer’s research, but I’ve strayed, so it’s nice to be home for a little bit with others. I was asked to talk about our experiences with drug repositioning, and I’m going to talk about two different aspects. One is a bit of the rationale for it, and then I’m going to talk quite a bit about some partnerships that are focused on drug repositioning that also form a model of partnership for drug development. I have been in industry for more than 20 years, and I can tell you that drug discovery and development is incredibly hard. And I think those who were on the panel yesterday and have experience in this from academia realize too just how difficult it can be. There are certain truths about drug development and one is that most candidates fail. They particularly fail in Phase II testing, when we do efficacy trial testing that tests hypotheses. It is important to note that on this graph, the Y axis is a success rate, not a failure rating, dipping below 20 percent in the last rolling 3 years that this analysis was done. If you were a major league baseball player, you’d be out. And the other truth about drug discovery is that it takes a long time and a lot of money, 10 to 12 years, minimum, typically, and we can talk about the costs. But an interesting part

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