An Overview of Drug Discovery for Neurodegenerative Disease

Plenary Lecture — Jeffrey Nye, MD, PhD, Johnson and Johnson Pharmaceutical R&D, LLC

The scope of discovering, developing and delivering a drug for neurodegenerative disease is routinely underappreciated by those who have not been directly involved in pre-clinical research and clinical development. Success requires an extremely broad and coordinated multidisciplinary effort. Impacts on success can arise from a large number of sources, including but not limited to: the qualities of the biochemical target; tractability of the related medicinal chemistry; ability to achieve a comprehensible structure-activity relationship of appropriate chemical series; selectivity and chemical properties of the prioritized compound(s); the availability and successful application of informative pre-clinical in vivo pharmacodynamic models; the compound's metabolism, distribution, formulation, delivery, and safety; the ability to translate effects on the target to therapeutically relevant dosing and outcomes in humans; and the pharmacologic baseline of the patient population being tested. A discussion of these challenges within a context of currently considered promising targets for treating neurodegenerative diseases will be presented.

 

Session I. Target Identification & Validation:  How Our Understanding of the Biology of Neurodegeneration Can Be Employed

Chair — Peter Reinhart, PhD, Wyeth Research

This session will present the early, exploratory phases of drug discovery. Speakers will focus on the identification and validation of drug discovery targets for neurodegenerative disease. Examples of key questions to be addressed include: 1) Can we utilize knowledge of the pathophysiology of neurodegenerative disease, especially Alzheimer's disease, to develop novel therapeutics that affect disease progression? 2) How are basic science investigations, such as elucidation of a macromolecular structure or biological pathway, used as a starting point for identification of a potential drug discovery target? 3) What is the process by which drug discovery targets are validated or linked to the disease?

Session II. Lead Identification & Optimization: Unique Aspects of Chemistry in Neurodegenerative Disease

Chair — D. Martin Watterson, PhD, Northwestern University

Session III. Lead Discovery: In-Vitro Models of Neurodegenerative Disease

Chair — Ross Stein, PhD, Harvard Medical School

A key component of the development of new therapeutic agents is the identification of molecules that can serve as foundational lead structures on which drug discovery programs can be built. High-throughput screening of large collections of drug-like molecules for modulatory activity in disease-relevant assays is an important means to discovering these lead molecules. This session will first address general issues of the development of assays that are suitable for high-throughput screening and then review specific case studies relevant to neurodegenerative diseases. The session will end with a discussion of an academic center that is actively engaged in drug discovery, development and delivery for neurodegenerative disease and how it might serve as a model.

Session IV. Pre-Clinical Proof-of-Concept & Development: Neurodegenerative Disease

Chair — Jordan Tang, PhD, Oklahoma Medical Research Foundation

Research designed for pre-clinical proof-of-concept is particularly important for the development of drugs for neurodegenerative diseases. This is because neurodegenerative diseases require drugs that can penetrate the blood-brain-barrier and are also particularly difficult to assess for efficacy. Proof­of-concept pre-clinical studies are aimed to critically evaluate therapeutic candidates before embarking on expensive clinical trials. This session focuses on the overall requirements and organization of these studies, the necessary steps leading to clinical trials, and the use and development of neuroimaging, biomarkers and surrogates in clinical development.

Session V. Resources and Services for Advancing Drug Discovery

Chair — Neil Buckholtz, PhD, National Institute on Aging

This session will focus on descriptions of the resources available through a variety of mechanisms within academia, the National Institutes of Health (NIH) and through commercial vendors. Speakers will focus on resources for assay development, target identification, drug discovery, drug development, pre-clinical toxicology evaluation, and other components needed for the translation of pre-clinical drug candidates into potential therapies tested in clinical trials. In particular, it will include specific descriptions of programs available to academic investigators through individual NIH Institutes, including the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS), as well as trans-NIH programs including the NIH Roadmap for Medical Research and the NIH Blueprint for Neuroscience Research.

Session VI. Disease Specific Issues in Drug Discovery for Neurodegenerative Disease Chair

— Elias Michaelis, MD, PhD, University of Kansas

This session will separate the participants of the workshop into five working groups that will focus upon disease-specific problems in drug discovery. Each breakout group will be led by facilitators to guide the discussion. Participants will be given a list of specific questions to address which will be compiled as a PowerPoint slide presentation. At the end of the session, the breakout groups will reconvene and present the conclusions from their discussions back to the other participants. The ultimate aim of this session is to inform participants of specific obstacles related to the drug discovery process in certain disease areas, to devise potential solutions to these problems, and to inform the funding agencies of where cros-cutting issues should be addressed by specific funding or legislative initiatives.