1

Introduction and Overview1

Although there is a high burden associated with nervous system disorders, development of new therapeutics remains stagnant. During the past decade, fewer new drugs for nervous system disorders have garnered approval in comparison to other therapeutic areas. Current data suggest that drug development, from the start of a discovery program to regulatory approval, can take an average of 12 to 15 years (Wegener and Rujescu, 2013). This familiar statistic prompts an equally familiar question: Can this time line be shortened? Nervous system drugs, on average, have longer regulatory approval and mean clinical trial times (Tufts CSDD, 2012). In addition, there is an increased probability of clinical trial failures at later stages in the drug development pipeline, even though resource investments are high for these drugs (Bunnage, 2011). The science is challenging and the prospects for success are discouraging to the point that drug companies are moving away from neuroscience research programs (Abbott, 2011; Miller, 2010).

There are several challenges to the current drug development pipeline for nervous system disorders. The fundamental etiology and pathophysiology of many nervous system disorders are unknown and the brain is inaccessible to study, making it difficult to develop accurate models. Patient heterogeneity is high, disease pathology can occur years to dec-

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1The planning committee’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, and are not necessarily endorsed or verified by the Institute of Medicine, and they should not be construed as reflecting any group consensus.



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1 Introduction and Overview1 Although there is a high burden associated with nervous system dis- orders, development of new therapeutics remains stagnant. During the past decade, fewer new drugs for nervous system disorders have gar- nered approval in comparison to other therapeutic areas. Current data suggest that drug development, from the start of a discovery program to regulatory approval, can take an average of 12 to 15 years (Wegener and Rujescu, 2013). This familiar statistic prompts an equally familiar ques- tion: Can this time line be shortened? Nervous system drugs, on average, have longer regulatory approval and mean clinical trial times (Tufts CSDD, 2012). In addition, there is an increased probability of clinical trial failures at later stages in the drug development pipeline, even though resource investments are high for these drugs (Bunnage, 2011). The sci- ence is challenging and the prospects for success are discouraging to the point that drug companies are moving away from neuroscience research programs (Abbott, 2011; Miller, 2010). There are several challenges to the current drug development pipe- line for nervous system disorders. The fundamental etiology and patho- physiology of many nervous system disorders are unknown and the brain is inaccessible to study, making it difficult to develop accurate models. Patient heterogeneity is high, disease pathology can occur years to dec- 1 The planning committee’s role was limited to planning the workshop, and the work- shop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, and are not necessarily endorsed or verified by the Institute of Medicine, and they should not be construed as reflecting any group consensus. 1

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2 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS ades before becoming clinically apparent, and diagnostic and treatment biomarkers are lacking (Hyman, 2012; Insel, 2012a). In addition, the lack of validated targets, limitations related to the predictive validity of ani- mal models—the extent to which the model predicts clinical efficacy— and regulatory barriers can also impede translation and drug develop- ment for nervous system disorders (Riordan and Cutler, 2010). CHALLENGES WITH THE UTILITY AND TRANSLATION OF ANIMAL MODELS This workshop builds on a previous Institute of Medicine (IOM) workshop, Improving the Utility and Translation of Animal Models for Nervous System Disorders, held in 2012 by the Forum on Neuroscience and Nervous System Disorders (IOM, 2013). That workshop focused on strategies to maximize the translation of effective therapies for nervous system disorders from animal models to clinical practice. Richard Hodes, director of the National Institute on Aging and a co-chair of the work- shop planning committee, summarized the following key points high- lighted during the workshop:  Animal models can provide critical insight on specific disease mechanisms or targets of interest.  Many participants noted that animal models typically do not ful- ly mimic or recapitulate nervous system disorders.  Animal models and clinical research can inform each other through bidirectional translation; failures may be due to a mis- match between endpoints used in clinical trials and preclinical animal studies.  Reproducibility of animal studies might benefit from standardi- zation, improved experimental design, and appropriate statistical analysis.  Improved translation might result from establishment of realistic expectations about the predictive validity of animal models. Hodes noted that many have lost confidence in the ability of animal models to predict efficacy and that the models may, in fact, be screening out potentially effective compounds. Consequently, workshop partici- pants posed several questions: Under what circumstances would it be worthwhile and ethical to go directly into clinical trials after establishing

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INTRODUCTION AND OVERVIEW 3 safety? Should research continue to emphasize animal models or should more emphasis be placed on cellular models and/or Phase 0 trials?2 Are there alternative strategies to accelerate therapeutic development by combining animal models with new and emerging tools, technologies, and techniques? These questions set the stage, said Hodes, for the current workshop. WORKSHOP OBJECTIVES To explore these concepts, the IOM Forum on Neuroscience and Nervous System Disorders convened a workshop to examine opportuni- ties to accelerate early phases of drug development for nervous system drug discovery (see Box 1-1). Workshop participants discussed challeng- es in neuroscience research for enabling faster entry of potential treat- ments into first-in-human trials,3 explored how new and emerging tools and technologies may improve the efficiency of research, and considered mechanisms to facilitate a more effective and efficient development pipeline. ORGANIZATION OF THE REPORT The following report summarizes the presentations from expert speakers and discussions among workshop participants. Chapter 2 pro- vides an overview of the drug discovery and development pathway along with a review of the regulatory process for investigational new drug (IND) applications. Key challenges for improving and accelerating drug development are also highlighted in this chapter. The ensuing chapters review opportunities to improve target identification (Chapter 3) and val- idation (Chapter 4). Chapter 5 examines several opportunities for im- proving discovery research through novel approaches and infrastructural changes. Finally, perspectives on potential next steps identified by work- shop session chairs are summarized in Chapter 6. 2 An exploratory investigational new drug study, or Phase 0 study, is conducted very early in Phase I and involves microdosing in a very limited number of human participants (FDA, 2005b). 3 A first-in-human trial can refer to (1) the first clinical trial in which humans, usually healthy volunteers, are given a new drug, or (2) cellular and molecular studies of human cells and tissues during the early phases of drug discovery (FDA, 2005a).

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4 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS BOX 1-1 Statement of Task  Examine opportunities and challenges in neuroscience research for facilitating faster entry of potential treatments into first-in-human trials. o Identify avenues for moving directly from cellular models to hu- man trials minimizing the need for animal models to test efficacy. o Discuss the potential benefits and risks of such an approach.  Consider regulatory mechanisms, including those supported by the Food and Drug Administration’s Advancing Regulatory Science Initia- tive, which may facilitate faster entry of potential treatments into first- in-human trials. o Identify potential metrics for determining readiness for first-in- human trials.  Explore the potential usefulness of new neuroscience technologies and techniques that would hasten the translation of research and fa- cilitate the jump from cellular models to first-in-human trials (e.g., in- duced pluripotent stem cells, in vitro neuronal circuits, connectomics, brain imaging, etc.). o Explore the usefulness of alternative tools for validation (e.g., surrogate models).  Consider mechanisms for integration and proliferation of new tech- nologies and techniques to the broader neuroscience research community. TOPICS HIGHLIGHTED DURING PRESENTATIONS AND DISCUSSIONS4 Throughout the workshop, participants discussed a number of central themes. Discussions primarily focused on opportunities to improve early drug development with a focus toward preclinical trials. Many partici- pants noted that discussions regarding how to accelerate to first-in- human trials would be premature before considering improvements at earlier stages in the drug development process. These themes, listed on the next page, are expanded on in the succeeding chapters. 4 The following list highlights recurring topics and is provided here as part of the factu- al summary of the workshop. Items on this list should not be construed as reflecting any consensus of the workshop participants or any endorsement by the Institute of Medicine or the Forum on Neuroscience and Nervous System Disorders.

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INTRODUCTION AND OVERVIEW 5 Challenges  Limitations of current practices: After reviewing the current drug development pipeline, many participants noted the need for improved translational science—the application of fundamental research to therapeutic development—from discovery through clinical trials. As noted earlier, some pharmaceutical companies are moving away from nervous system drug development due to high failure rates following large financial investments. Several participants noted that there is a certain amount of uncertainty and risk associated with the current development process. These same participants suggested that developing mechanisms by which tolerance of risk could be increased might be a more pro- ductive approach moving forward. Potential mechanisms include identifying regulatory constraints and developing partnerships to share resource investments. Specific barriers include o Biological mechanisms of disease: Many participants reiter- ated that due to unknown pathophysiology of many nervous system disorders and the complexity of human behavior, de- veloping validated and targeted therapies is challenging. Several participants noted that failures along the drug devel- opment pipeline might be related to this lack of understand- ing of underlying mechanisms of disease. For example, a few participants noted that the underlying cause of Alz- heimer’s disease is unclear due to several unknown factors, including the role of β-amyloid. o Animal models: A number of participants noted that animal models are often valuable at capturing a particular aspect of disease or specific target of interest, but rarely recapitulate an entire disorder or disease. Several participants asked: How much of the problem is due to poor animal models compared to researchers prematurely rushing forward with answers from models without systemically validating the data? o Phenotyping: Several participants noted that the current model of drug development does not facilitate translation of discovery research directly into clinical trials for new thera- peutics. One speaker highlighted that the field has lost track of clinical phenotyping and endotyping even though failures

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6 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS of clinical trials are almost always predictable due to the known heterogeneity of the population affected by nervous system disorders. o Resources: Several participants discussed resource constraints in the field and how organizations such as the National Insti- tutes of Health and venture capital companies are critical in supporting the early discovery process since pharmaceutical companies may now be less likely to take on that task. o Target identification: A large number of participants suggested that better target identification could significantly improve drug development. The need for target identifica- tion strategies based on human data via patient stratification, rather than animal models, was discussed. One participant discussed a novel approach to target identification in schizo- phrenia by translating genes of interest into molecular mech- anisms of illness through RNA sequencing. o Target validation: In addition to target identification, many participants noted the importance of target validation. Several suggested that rapid target invalidation is equally important. A few participants noted that target engagement is critical and measuring exposure pharmacodynamically is important. In addition, many participants highlighted the need for a greater number of validated biomarkers and translational endpoints to determine clinical efficacy. Opportunities  New tools, technologies, and approaches: Many participants noted that emerging tools and technologies (e.g., induced plu- ripotent stem cells [iPSCs], humanized animal models, computa- tional neuroscience) may be important to further understand mechanisms of diseases, and help to identify and validate drug targets. For example, iPSCs may be better than animal models for target identification. Humanized animal models may help improve understanding of nervous system disorders and identify mechanisms of disease by engrafting human tissue stem cells in- to mice, a few participants noted. Computational neuroscience in conjunction with neuroimaging might aid in understanding underlying neurobiological mechanisms of diseases. However,

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INTRODUCTION AND OVERVIEW 7 several participants cautioned that these novel assays do not fully mimic or recapitulate human diseases and disorders. These same participants therefore suggested that earlier human trials in the drug discovery pathway remain critical and validating targets us- ing multiple models could provide more accurate information about the target than using a single model.  Humans as the starting point: Several participants noted that an initial focus on human phenotypes rather than animal models might better inform the drug discovery process. Some partici- pants suggested going directly into the patient population to validate targets. However, several participants noted that it might be faster to go into a control populations rather than patients because controls are easier to recruit. A few participants pro- posed reversing the pipeline and using humans for target identification and then animal models for target validation while others suggested that both identification and validation could be accomplished in humans.  Patient stratification: Several participants discussed the need for improved patient stratification for improved target identifica- tion, due to the high heterogeneity of patients with a nervous sys- tem disorder. Through clinical phenotyping and identification of common genetic variants, small clinical trials of homogeneous populations could be useful, such as those with rare diseases, to establish proof of concept and further understand disease patho- genesis (Fishman, 2013; Leaf, 2013).  Combination therapies: Because of heterogeneity and com- plexity of pathophysiology, several participants expressed the view that a single drug is not likely to be as effective for any given disorder compared to combination therapies. Rather than taking a singular approach, many participants suggested that starting drug development assuming that multiple drugs in com- bination will be needed to help patients, a multipronged ap- proach, could potentially improve and accelerate drug development.  Increasing and sharing standards for preclinical studies: Many participants stated that the current drug development paradigm might need to change, particularly for preclinical studies. It was noted that it might be beneficial for preclinical studies to have rigorous standards, similar to clinical trials, to ensure sound research design and credible statistical analyses. This, in turn, could improve the reproducibility of preclinical studies, which is

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8 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS a major challenge for the field, according to many participants. Several participants also agreed that the publication of negative studies is important along with the development of a mechanism to share preclinical experimental design and results in an accessible repository similar to www.clinicaltrials.gov (e.g., “www.preclinicaltrials.gov”).  Regulatory pathways: Many participants expressed lack of familiarity with current regulatory processes and sought clarifi- cation from speakers. Requirements for obtaining approval of an IND application include safety pharmacology, extensive toxicity testing, and testing for absorption, distribution, metabolism, and excretion. Although a number of participants indicated a need for more specific application guidelines, Food and Drug Administra- tion speakers emphasized that, in order to maintain flexibility in their approaches, applications are handled on a case-by-case basis. Several participants noted the value of pre-IND meetings to discuss specific questions prior to submission of applications.  Precompetitive space: Participants discussed opportunities for the scientific community (academia, industry, and government) to come together in the precompetitive space to discuss challenges and opportunities to move the field forward as a whole. Many participants noted that no one group will be able to solve the challenges associated with developing therapeutics. Many participants discussed the importance of “de-risking” re- search throughout the drug discovery process. By sharing risk across sectors, resources could be saved, attracting companies to reinvest in nervous system disorder drug discovery.  Public–private partnerships: Many participants noted that, as discovery research advances and becomes increasingly resource intensive and challenging, researchers could gain confidence and increase the probability of success through greater collaboration. Several speakers described the establishment of new preclinical public–private partnerships, especially for target validation.