Background and Description: Alzheimer’s Disease Research Summit 2012
Need: The fact that basic science advances in Alzheimer’s disease (AD) research have not yet resulted in effective therapeutics for treatment or prevention emphasizes the need for continued evaluation of scientific opportunities and priorities for future research. This includes a need to critically evaluate and expand our knowledge of basic biological processes and pathogenic mechanisms, to re-examine the major therapeutic hypotheses, and the existing models of preclinical and clinical therapy development, and to optimize approaches for the selection and validation of therapeutic targets.
Goal: In light of this, the key goal of the AD Research Summit 2012 is to formulate an integrated multidisciplinary research agenda that will accelerate the development of successful therapies for AD across the disease continuum. The Summit will also identify what types of resources/infrastructure and new public private partnerships are necessary to successfully implement this research agenda.
Program agenda: The program will be organized around 6 major themes presented in consecutive sessions which will evaluate issues of critical importance for identification of successful interventions for Alzheimer’s disease. The program will begin with two plenary lectures and then each session will feature up to three 15-20 minute presentations that will highlight key issues. Each set of presentations will be followed by a moderated panel discussion that will include the speakers and 5-8 additional panelists with relevant expertise. View agenda
Speakers: The composition of speakers and panelists for each session will include representatives from academia, industry, federal agencies, and private foundations. Each session will bring together experts working in different disciplines since one of the major goals of the meeting is to enable integration of research areas, research expertise, and research resources for the purpose of optimizing scientific discovery and its translation to efficacious therapies for AD.
Outcome: The general program will be followed by an executive session during which a select group of experts together with NIA/NIH staff and representatives from other AD-funding agencies will identify research priorities and milestones for measuring progress toward the goal of accelerating delivery of successful treatments for AD.
Session 1: Interdisciplinary approach to discovering and validating the next generation of therapeutic targets for AD
The enormous complexity of the human brain and the processes involved in development and progression of disease are recognized as major barriers for successful translation of basic discoveries to effective therapies for AD.
One of the new perspectives emerging from recent research is that AD is a network disorder affecting a large number of neuronal cell types, organized into functionally connected networks across many brain regions, and not simply a disease of discrete lesions limited to specialized brain regions associated with cognition and learning. Within this network concept AD is believed to be a response to a shift from normal to pathological networks, and not just a response to a pathogenic change in a single target. The lack of understanding of the molecular, cellular and physiological underpinnings of the transition from normal to pathological networks poses a special challenge in regards to the selection of truly disease- relevant therapeutic targets. To overcome this challenge there is a need to formulate an integrated interdisciplinary basic science research agenda that will lead to a better understanding of the cellular and tissue level networks that participate in the AD disease process and will enable the identification and selection of disease relevant therapeutic targets.
The overarching goal of this session is to develop an integrated and interdisciplinary basic research agenda that will better inform the identification of novel therapeutic targets.
This session will provide an overview of the current state of knowledge about the disease mechanisms and ongoing efforts to identify new therapeutic targets. The follow-up discussion will address issues associated with identification, selection and validation of disease-relevant therapeutic target(s):
- how can we best analyze multiple types of existing data (genomic, epigenomic, expression profiling, imaging, phenotypic data) and identify what types of new data are needed to advance our understanding of disease mechanisms and to select disease relevant targets?
- how can we best achieve integration of scientific disciplines required for identification and validation of therapeutics targets (genetics, epidemiology, mechanistic research, disease modeling)?
- what new directions in basic research are needed to seamlessly connect it to drug discovery?
- what are the pros and cons of using a single target approach vs. multi-target/pathway based approach?
- what are the therapeutic targets best suited for early intervention?
- what are the therapeutic targets best suited for later stages of the disease?
Session 2: Challenges in preclinical therapy development
In 2006 PhRMA, the pharmaceutical industry’s advocacy group, reported over 80 therapies in clinical development for AD. To date, none of these therapies has been successful in late-phase clinical trials, with at least 20 failing in Phase III and many more failing in Phase II.
The goal of this session is to address the major causes for the pre-clinical to clinical development gap. These are: 1) insufficient understanding of drug action on human physiology (target-related and off-target effects); 2) lack of translatable pharmacodynamic biomarkers; and 3) the poor predictive power of animal model preclinical efficacy studies. These factors lead to failure of AD drugs in the clinic either due to lack of efficacy or due to unforeseen toxicity. Major topics for discussion will be:
- challenges related to the use of animal models in translational research
- the need for other disease models (iPS cells; virtual models)
- new approaches aimed at optimizing target validation
- new approaches to predict off-target effects and toxicity during preclinical drug development
- development of translatable pharmacodynamic biomarkers and biomarkers of toxicity
Session 3: Who to treat, when to treat and what outcomes to measure?
AD is a highly heterogeneous, multifactorial disorder with a very long prodromal period. There is growing realization that identifying successful interventions for AD will require stratification of patients across multiple criteria. This session will address the challenges associated with patient selection – specifically, how to identify which patients will benefit from a specific treatment and how to select and assess diverse populations. The presentations will give an overview of the current state of science and methods (such as endophenotyping and pharmacogenetics) used to stratify patients and predict their responsiveness to treatment. Other major topics for discussion will be what types of biomarkers would be informative for patient selection and for predicting responsiveness to treatment as well as challenges associated with recruitment and retention of clinical trial participants.
The AD field has made significant advances in characterizing the prodromal asymptomatic phase of the disease. These findings open new opportunities for early diagnostics and interventions. At the same time the number of patients with clinical disease is rapidly growing, and this requires the development of treatments for both the cognitive and neuropsychiatric symptoms of the disease. This session will also address the following questions associated with intervening at different stages of the disease:
- what outcomes should we measure at the various disease stages?
- what is the state of development of staging biomarkers?
- what are the latest regulatory guidelines for AD prevention vs. treatment?
Session 4: Drug repurposing and combinatorial therapy
Drug repurposing has a number of advantages over the development of new drugs and has been done successfully for a number of disease conditions. Despite several failed attempts at drug repurposing for AD, this approach is considered as a promising therapeutic avenue and is being actively pursued. The session will revisit lessons learned from the failures and successes with drug repurposing and discuss the best way forward.
The second half of this session will focus on the extraordinary challenges associated with pursuing a combinatorial therapy approach. As we learn about the enormous complexity of AD pathogenesis and the associated co-morbid conditions, it is becoming apparent that efficacious treatment for an individual patient will need to target multiple aspects of the disease and be directed towards several pathogenic processes and as a result require a combinatorial treatment. This is not adequately addressed in the ongoing AD therapeutics efforts. The session will feature a novel network pharmacology approach to combinatorial therapy currently pursued for a rare neurological disease.
Session 5: Non-pharmacological interventions
Non-pharmacological interventions such as exercise and cognitive training are potentially promising therapeutic avenues for AD prevention and treatment. This session will focus on the unique challenges related to the selection, testing, and implementation of non-pharmacological interventions. Major questions for discussion will include:
- how do we best integrate findings from epidemiology and basic and translational research to select the right intervention(s)?
- what do we need to know to develop an effective non-pharmacologic therapeutic regimen?
- what are the difficulties associated with successful implementation of non-pharmacological interventions (e.g. patient and caregiver burden)?
Session 6: New models of Public-Private Partnership (PPP)
It is clear that the formidable challenge of identifying successful therapies for AD will require not only a high level of integration of scientific disciplines but also a real partnership among government agencies, academia, industry, and non-profit organizations. This session will feature new models of public-private partnerships that may be useful for the advancement of various stages of AD therapy development such as precompetitive PPP, product development PPPs, and industry models of PPP. Existing barriers to the successful pursuit of these new enterprises such as intellectual property/patent issues will also be addressed.