Monday, July 26, 2010

Drug Development for Neurodegenerative Diseases Conference Part 3

After a bit of a hiatus (following the departure of Meghan Kallman, our fearless former Communications Manager), we now bring you Part III of our blog series covering the marcus evans 2nd Annual Drug Discovery For Neurodegeneration Conference (see Part I here and Part II here).

Switching tracks, the next speaker, Dr. Gregory Stewart, Director of CNS Drug Therapy R&D for Medtronic, offered a slightly different perspective on therapeutic development in his talk entitled: Targeted Drug Delivery for Neurodegenerative Disease: A New Hope.

Medtronic is the world’s largest medical technology company. One of their major markets is drug-infusion pumps. With current revenues over $1.4B annually, drug delivery is a good market to be in!

Dr. Stewart discussed many of the reasons why drug developers should be thinking carefully about drug delivery. Questions of safety, cost, speed, compliance, and intellectual property may all be factors influencing drug delivery. As one example, if a patient takes morphine orally for pain relief, they need 300 times (30,000%!!!) more drug then if the morphine were delivered locally (via a pump for example).

As another example, patients taking a drug orally can get effects (including side effects) anywhere in their bodies, as most organs of the body will be exposed to a given drug (whereas, as Stewart pointed out, using a pump limits exposure of a given drug to the organ of interest). This can be a good thing, as when you take an aspirin for a headache and then go on to stub your toe (the aspirin can affect the pain in both places) but can be less good when you take that same aspirin for your headache and it upsets your stomach.

Targeted delivery has the further benefit of bypassing the liver (which constantly breaks down and filters out substances in your body), which can lead to a reduction of drug dosage at the desired target. Dr. Stewart provided several other compelling benefits for use of targeted delivery for drugs, particularly when the brain is the target.

In Medtronic’s view, the key failure of biotechnology to date has been the problem of failing to understand the nuances of drug delivery. Now that we have a vastly improved understanding of delivery principles, the drug development community is poised to make great advances, particularly at the final frontier of crossing the blood-brain-barrier and getting drugs directly to the brain and spinal cord.

With the increasing number of big and bulky drugs like antibodies and cell-based therapeutics being developed for ALS, drug delivery issues will only continue to grow in importance. Dr. Stewart urged drug developers to think about drug delivery issues early in the process, as this will impact the ultimate efficacy of any candidate therapeutic.

Friday, July 23, 2010

Drug Discovery for Neurodegenerative Diseases Part II

After a bit of a hiatus (following the departure of Meghan Kallman, our fearless former Communications Manager), we now bring you Part II of our blog series covering the marcus evans 2nd Annual Drug Discovery For Neurodegeneration Conference (see Part I here and Part III here).

We thought that there were some points worth mentioning from a presentation entitled: Translational AD Drug Discovery and Development: The Potential Role of In Vivo Multi-modal Imaging Techniques (yes, it is a mouthful), presented by Dr. Feng Luo of Abbott Laboratories.

Dr. Luo started off by reminding the audience of the recent dismal track record of developing treatments targeting neurodegenerative diseases. Over the past several years, there has been a 90% attrition rate in drugs for neurodegeneration. Clearly, this high failure rate suggests that the drug development community has a problem. The question is, how do we fix it?

Dr. Luo started off his presentation by telling the audience that he and his colleagues at Abbott Labs believe that one of the keys to more effective drug development is finding better biomarkers and creating more relevant “translatable” preclinical studies. They are specifically interested in answering the question “How could we incorporate biomarkers into early [i.e. preclinical] phases of drug development to increase R&D efficiency?” He went on to explain that the approach they are most interested in is the development of more reliable animal imaging tools. In pursuing this approach, they are adapting the most widely-used human imaging (PET, MRI) methods for mice. As a test of this, they sought to characterize one of the most widely-used mouse models of Alzheimer’s Disease (AD), the Tg2576 mouse.

It has long been observed that the human Alzheimer’s brain shows lowered energy usage (hypometabolism). Luo’s group was interested in exploring whether this hypometabolism could serve as a preclinical biomarker; however, no one had ever looked to see whether the Tg2576 mice display this feature of AD. Using three different imaging methods (FDG-PET, fMRI, and MRS) Luo and his group analyzed brain metabolism of the Tg2576 mouse over time. They were shocked to find that 7 month old Tg2576 mice, the age in which animals normally begin to display Alzheimer’s symptoms, not only failed to show decreased brain metabolism, but were instead hypermetabolic (meaning rather than using less energy, the brains of these mice were using more energy)!

As these studies showed, the Tg2576 mouse does not model all aspects of the disease in humans, suggesting that the Tg2576 mouse model may be of limited use in the development of imaging-based disease biomarkers for AD. As Dr. Luo noted in his presentation, animal models are often poorly characterized from a translational perspective. If we are to be able to assess the true utility of any potential therapy, it is critical to show that the therapy acts at its intended target early in the discovery and development process.

This finding in the AD model calls attention to the critical importance of careful characterization of animal models used to research other neurodegenerative diseases such as ALS. While it is generally accepted in the medical research community that there is no perfect animal model for any human disease (meaning disease in an animal will never perfectly mimic disease in a human), developing a detailed description and understanding of all relevant aspects of a given animal model enables researchers to understand the limitations inherent to any particular model so that results can be properly interpreted. The availability and use of multiple animal models for pre-clinical testing increases the probability of finding a drug that will translate to humans.

Although imperfect, animal models have long served as valuable drug development tools, leading to FDA approval of multiple important drugs now widely and safely used in humans. Fortunately for those interested in breakthroughs in ALS therapeutics, extensive characterization of the SOD1 mouse model by researchers at ALS TDI and many other institutions have enabled better and more interpretable studies using this valuable drug development tool. ALS TDI recently announced that extensive characterization of the new TDP-43 mouse model of ALS is also underway (http://quest.mda.org/news/als-tdi-full-speed-ahead).