6

Perspectives on Next Steps

The end of the workshop provided an opportunity for session chairs to engage participants in discussing opportunities for improving and accelerating drug discovery as discussed in their respective sessions (see Box 6-1)1; session chairs’ comments are summarized in this chapter.

Current Therapeutic Development Practices

David Michelson, vice president of clinical neuroscience and ophthalmology at Merck Research Laboratories, observed several key themes throughout the first session and identified next steps to aid in drug discovery. Michelson said several participants indicated that companies do not have confidence in choosing nervous system disorder targets and as a result choose to work in areas where the science is further along. Many times, this leads to a restriction of the focus of research to the disease areas that are best understood, which often are not within the neurosciences. To build confidence in the next stage of research and the investments made, many participants who spoke agreed there is a need to de-risk across steps in the development time line. Some researchers continue to prematurely proceed to clinical trials, without sufficient preclini-

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1The topics highlighted in this chapter are based on the summary remarks made by each session chair during the final workshop session and at the end of his or her respective session. Additional comments by participants related to the closing remarks are also included. As noted in Chapter 1, comments included here should not be construed as reflecting any group consensus or endorsement by the Institute of Medicine or the Forum on Neuroscience and Nervous System Disorders.



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6 Perspectives on Next Steps The end of the workshop provided an opportunity for session chairs to engage participants in discussing opportunities for improving and ac- celerating drug discovery as discussed in their respective sessions (see Box 6-1)1; session chairs’ comments are summarized in this chapter. Current Therapeutic Development Practices David Michelson, vice president of clinical neuroscience and oph- thalmology at Merck Research Laboratories, observed several key themes throughout the first session and identified next steps to aid in drug discovery. Michelson said several participants indicated that com- panies do not have confidence in choosing nervous system disorder tar- gets and as a result choose to work in areas where the science is further along. Many times, this leads to a restriction of the focus of research to the disease areas that are best understood, which often are not within the neurosciences. To build confidence in the next stage of research and the investments made, many participants who spoke agreed there is a need to de-risk across steps in the development time line. Some researchers con- tinue to prematurely proceed to clinical trials, without sufficient preclini- 1 The topics highlighted in this chapter are based on the summary remarks made by each session chair during the final workshop session and at the end of his or her respec- tive session. Additional comments by participants related to the closing remarks are also included. As noted in Chapter 1, comments included here should not be construed as reflecting any group consensus or endorsement by the Institute of Medicine or the Forum on Neuroscience and Nervous System Disorders. 73

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74 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS cal data, resulting in high clinical failure rates (Leaf, 2013). When com- panies are at the point of making larger investments and commitments, the probability of success should high, said Michelson. Several participants noted that the use of multiple models may be beneficial to discover and validate targets; there is no simple “yes” or “no” as to whether a specific animal model will be useful, but little is gained by continuing to pursue a target when data suggest it may be fu- tile. Increasing reagents for novel targets in laboratories and establishing better biomarkers by considering the patient group in which the mecha- nism of the disease is likely to be homogeneous (patient stratification) could also help de-risk research programs. A few participants reiterated BOX 6-1 Potential Opportunities to Accelerate Therapeutic Development  Utilize combinations of animal and cell-based models to further un- derstand underlying biological mechanisms of diseases and improve target identification.  Improve biomarkers for nervous system disorders.  Consider target invalidation in addition to validation.  Extend the precompetitive space to identify and validate novel targets and eliminate replication of studies.  Increase the availability of new and emerging tools and technologies (e.g., induced pluripotent stem cells [iPSCs], humanized animal models, neuroimaging, experimental medicine, computational neuroscience).  Identify and use mechanisms (e.g., iPSCs, assays, clinical probes) to assist and accelerate go/no-go decisions.  Reverse the experimental pipeline starting in humans for target identi- fication and validation, then move to animal models for target en- gagement.  Increase preclinical study standards and improve reproducibility.  Share preclinical positive and negative data.  Develop a www.preclinicaltrials.gov portal for sharing of experimental designs and results.  Continue to establish public–private partnerships focused on target identification and validation to de-risk research. NOTE: The items in this list were addressed by individual speakers and par- ticipants and were identified and summarized for this report by the rappor- teurs, not the workshop participants. This list is not meant to reflect a consensus among workshop participants.

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PERSPECTIVES ON NEXT STEPS 75 the need for public–private partnerships to de-risk investments as well as pushing the precompetitive boundaries to Phase IIa by evaluating novel targets in patients. Another concept mentioned by several participants is that large pharmaceutical companies are not the only places where drug discovery and development can occur. Biotechnology companies and federal agencies, for example, might also be resources to consider. Regarding next steps, Michelson posed the following three questions: 1. What areas are the ripest for work? 2. What are the gaps, and how can they be addressed? 3. What are the steps in the drug discovery process that can be de- risked and provide confidence across the development pipeline? Michelson noted that the focus should not be to accelerate the drug dis- covery process, but rather to make it better and more efficient. The Regulatory Pathway William Potter, senior advisor in the Office of the Director of the Na- tional Institute of Mental Health, highlighted how many basic scientists are unfamiliar with Food and Drug Administration approval procedures and resources at NCATS that may potentially resolve these issues. FDA, in its current case-by-case approach, views flexibility as a benefit and helps academic researchers better understand the guidance documents that may alleviate common mistakes and misconceptions. Echoing com- ments made by several participants, Potter asked, Where are the opportu- nities for increasing the probability of success? This is an area in which the neuroscience field has been struggling, he noted. Beyond these con- cerns, Potter stated, the fundamental question is, How can we create a better fit between preclinical assays and experimental human models? Is the field at a point where it can depend on one method, and can this be tested? New and Emerging Tools and Technologies There was an overall sense at that workshop that the cell is the smallest common denominator, as opposed to the gene or protein, said

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76 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS session chair Rajesh Ranganathan, director of the Office of Translational Research at NINDS. Several participants noted that human phenotypes may better inform the translational space than animal models, and, if possible, measuring the same variables in humans and animals might be beneficial. Many participants who spoke agreed that creating a database, such as “www.preclinicaltrials.gov,” as a repository to share data could further the understanding of nervous system disorders and provide a mechanism for researchers to share discoveries. Ranganathan reflected on the Human Genome Project and asked whether there is a fundamental technology that could change the neuro- science space, and if so, should investment be increased in this specific area? Specifically, for neuroscience, said Ranganathan, target engage- ment is critical. Ensuring that there is target engagement, taking meas- urements that are pharmacodynamically related to the target, and testing where it truly matters are important, he added. Developing a better learn- ing curve in clinical trials is needed to eliminate the common responses of “it did not work and we do not know why” or “it’s the patient, not the drug.” Ranganathan concluded by saying that the field should push to race ahead with a broad-based platform of investment to facilitate drug discovery. Opportunities in Nervous System Disorders Magali Haas, chief science and technology officer at One Mind for Research, observed that in the course of the workshop, the focus had been on the ability to predict outcomes and determine which steps are or are not informative in the development pipeline, rather than moving to- ward first-in-human trials from cellular models. During the session, par- ticipants discussed an array of topics, including the use of human data for target identification; the willingness of researchers to conduct rigorous experiments both in preclinical models and in an experimental medicine setting; and opportunities to accelerate the pathway to first-in-human trials when the severity of the disease warrants it. However, participants mainly focused their discussions on the investment portfolio in the neu- roscience field and where there are opportunities for nonprofits, NIH, and pharmaceutical companies to reconsider their portfolios. There is a large investment in iPSC lines because of the potential to conduct func- tional pharmacology from a cell derived from a patient or normal indi- vidual. Although there was not much discussion about where the next

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PERSPECTIVES ON NEXT STEPS 77 generation of genetic data, biomarkers, or phenotypes will fit into large- scale human trials, Haas noted that many participants and speakers agreed that this will happen through large-scale public–private partnerships. Sev- eral participants advocated for information technology platforms for shar- ing reliable data, such as a neuroscience community portal (which is currently under development), “neuromine,” or “www.preclinicaltrials. gov” as suggested by a workshop speaker. In addition, Haas noted that there is a strong need to consider the use of new tools such as proteomics, transcriptomics, and computational modeling approaches. Optimizing Therapeutic Development Collaboration and the precompetitive space were two key themes in the workshop discussions, noted Daniel Burch, vice president and global therapeutic area head for central nervous system diseases at Pharmaceu- tical Product Development, Inc. (PPDi). Several participants identified a number of potential areas for collaboration, including target identifica- tion and validation, animal assays, and de-risking aspects of research. In addition, many participants highlighted the importance of extending the precompetitive space and establishing small-scale collaborative models. Burch stated that there is inefficiency within the translational space; re- searchers and groups are reinventing the wheel when it is unnecessary. The development of platforms to explore certain mechanisms might be beneficial, he added. SUMMARY Given the challenges surrounding current therapeutic development practices for nervous system disorders, this workshop sought to explore opportunities that could potentially make the pathway from discovery to approval more effective and efficient. Rather than focusing on accelerat- ing the process from cellular models to first-in-human trials, workshop discussion focused on predicting outcomes and determining next steps in the development pipeline. Speakers and participants highlighted several limitations related to de-risking research, target validation and engage- ment, the regulatory process, inefficient research, and reproducibility. Although clinical outcomes cannot be predicted and additional research is needed, new and emerging tools and technologies, such as iPSCs, are

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78 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS avenues that could potentially improve the drug development process, according to several participants. Patient stratification, target identifica- tion based on human data, systematic evaluations of failed clinical trials, and improved guidance on regulatory issues were just a few potential solutions that participants considered. Finally, several speakers and par- ticipants advocated for open data sharing among researchers and a cen- tralized database for all preclinical trials to increase collaborative efforts and decrease replication in the field.