5

Opportunities to Improve and Accelerate the Drug Development Pipeline

Key Points

•   The molecular medicine approach could be used for drug development by understanding the underlying pathophysiology of disease in order to identify and validate drug targets.

•   Using investigational drugs as clinical probes, to identify and/or verify a target in healthy human populations, could aid investigators in making go/no-go decisions.

•   Emerging tools and technologies based on scientific utility criteria that are relevant to the field today, such as diversity and competition, are needed.

•   Shifting the conventional paradigm of drug screening to one that requires more rigorous preclinical and clinical experiments could increase the likelihood of identifying successful targets and mechanisms.

•   Human phenotypes may better inform drug discovery; therefore, starting in humans first, then validating in animal models, may be more beneficial to drug development.

•   Due to the complexity and heterogeneity of patients, a greater emphasis on multipronged approaches using combination therapies, might result in an increased number of successful drugs.

•   Public–private partnerships and the extension of the precompetitive space among academia, industry, and government could help de-risk research.

•   Increasing standards and sharing of preclinical data might help to improve reproducibility, thereby strengthening the drug development pipeline.

•   Several factors could influence investment decisions that researchers might consider to increase the probability that their drug will be successful.

NOTE: The items in this list were addressed by individual speakers and participants and were identified and summarized for this report by the rapporteurs, not the workshop participants. This list is not meant to reflect a consensus among workshop participants.



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5 Opportunities to Improve and Accelerate the Drug Development Pipeline Key Points  The molecular medicine approach could be used for drug develop- ment by understanding the underlying pathophysiology of disease in order to identify and validate drug targets.  Using investigational drugs as clinical probes, to identify and/or verify a target in healthy human populations, could aid investigators in making go/no-go decisions.  Emerging tools and technologies based on scientific utility criteria that are relevant to the field today, such as diversity and competition, are needed.  Shifting the conventional paradigm of drug screening to one that re- quires more rigorous preclinical and clinical experiments could increase the likelihood of identifying successful targets and mechanisms.  Human phenotypes may better inform drug discovery; therefore, starting in humans first, then validating in animal models, may be more beneficial to drug development.  Due to the complexity and heterogeneity of patients, a greater em- phasis on multipronged approaches using combination therapies, might result in an increased number of successful drugs.  Public–private partnerships and the extension of the precompetitive space among academia, industry, and government could help de-risk research.  Increasing standards and sharing of preclinical data might help to improve reproducibility, thereby strengthening the drug development pipeline.  Several factors could influence investment decisions that researchers might consider to increase the probability that their drug will be successful. NOTE: The items in this list were addressed by individual speakers and participants and were identified and summarized for this report by the rapporteurs, not the workshop participants. This list is not meant to reflect a consensus among workshop participants. 51

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52 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS Novel approaches and infrastructure changes to the current drug de- velopment pipeline might improve the efficacy of research and support a more efficient process. Although there are several bottlenecks in the cur- rent pipeline, several participants discussed opportunities to facilitate drug development for nervous system disorders through methodological approaches, shifts in current processes, and changes to the infrastructural components in drug development. METHODOLOGICAL APPROACHES Due to the array of challenges the field is currently facing, several participants discussed the advantages of considering novel methodologi- cal approaches that address all stages of the development pipeline, in- cluding target identification and validation. According to Mark Bear, professor of neuroscience at the Massachusetts Institute of Technology, by examining the genetic basis of a disease first, a molecular medicine approach might provide insight into underlying pathophysiology to iden- tify and validate targets. John Krystal, Robert L. McNeil, Jr., Professor of Translational Research and chair of the department of psychiatry at Yale University School of Medicine, discussed the utility of the experi- mental medicine approach to improve translation between preclinical and clinical studies through an exploratory process of using drugs as clinical probes to identify and verify targets. Molecular Medicine Approach Bear began by outlining the promise of molecular medicine, an ap- proach that starts with a disease, proceeds to find its cause, and teases apart how the cause exerts pathophysiological effects by conducting basic research. This process results in a mechanistically inspired identifi- cation of a molecular target. After validation of the target succeeds, nov- el drugs aimed at the target can be tested first in animal models and then in clinical trials. The molecular medicine approach has successfully led to ongoing clinical trials for Fragile X syndrome, which is the most widespread single-gene cause of autism. The genetic cause, reported in 1991, was found to be a transcriptional silencing of the Fragile X Mental Retarda- tion 1 (FMR1) gene, resulting in absent expression of the FMR1 protein

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OPPORTUNITIES 53 (FMRP). By 1994, the first FMR1 knockout mouse was made. Eight years later, in 2002, research on basic neurobiology revealed that knock- out animals showed an abnormal type of synaptic plasticity marked by exaggerated function of the metabotropic glutamate receptor 5 (mGluR5). This key finding was validated in 2007 by the demonstration that numerous Fragile X phenotypes are corrected in FMR1 knockout mice by genetic reduction of mGluR5 protein production (Dölen et al., 2007). With the target validated, animal studies and clinical trials ensued with inhibitors of mGluR5. This line of investigation led to the mGluR theory of Fragile X, which holds that many of the syndrome’s psychiatric and neurological abnormalities are a downstream consequence of exaggerated mGluR5 activation (Bear et al., 2004). The normal FMRP is an mRNA-binding protein that functions at many synapses to repress local protein synthesis stimulated by mGluR5 (Bhakar et al., 2012). One part of the Fragile X story worth noting is that it was a “com- munity” effort: 40 distinct phenotypes were catalogued in knockout ani- mals, including flies, zebrafish, and mice, in at least 31 different publications (Bhakar et al., 2012). The lessons learned from the Fragile X story, according to Bear, are (1) defined genetic etiology led to valid animal models; (2) fundamental synaptic biology revealed signaling de- fects; (3) core pathophysiology is evolutionarily conserved; (4) disease- modifying treatments are feasible; (5) treatments can be successful after symptom onset; and (6) multiple mutations may converge on a common signaling pathway. Bear was careful to point out the risks incurred at every stage of the process, most notably in the design of clinical trials of mGluR5 inhibi- tors. He observed that fulfilling the promise of molecular medicine re- quires many educated guesses about the following:  Drug formulation  Patient selection (e.g., age, ratings at baseline, etc.)  Dose selection  Treatment duration  Number of subjects  Number of clinical sites  Choice of endpoints  Statistical analysis plan  Agreement with the U.S. Food and Drug Administration (FDA) on all of the above

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54 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS  Training of sites in Good Clinical Practice so that data are ac- ceptable to FDA Experimental Medicine Approach The most challenging step in the drug development process, Krystal said, is the translation of cellular or animal models to healthy human sub- jects and then to patients. Krystal noted that researchers cannot go direct- ly into the patient population without knowing whether the biology of the animal models applies to healthy humans. The drug development process is exploratory; it is an iterative process of testing specific mechanistic hypotheses across cellular and animal studies, healthy human subjects, and clinical trials, Krystal said. The experimental medicine approach, according to Krystal, involves the ability to evaluate the effects of a putative therapeutic agent in hu- mans and examine outcomes at various levels (e.g., behavior, cortical activity, and brain imaging). The goal is to produce therapeutic change in a pathophysiologic process, quickly, and in a laboratory setting. This ap- proach uses drugs as clinical probes in order to identify or verify a target and/or study mechanisms of disease. Similar to proof-of-concept clinical trials, this approach examines the ability of a drug to act on a pathologi- cal target and affect a biological endpoint as measured by a biomarker. In general, the experimental medicine approach relies on human studies rather than animal models (Insel, 2012b). The approach could be useful in several ways to advance and accel- erate drug development, said Krystal. First, for go/no-go decisions, using positron emission tomography (PET) imaging, researchers can determine whether a drug enters the brain and reaches the target. Second, the exper- imental medicine approach can increase or decrease confidence in a par- ticular drug, especially in Phase II. Proof-of-mechanism and proof-of- principle studies could be conducted using this approach to accelerate the development process for several reasons:  Studying healthy subjects in pathology models instead of pa- tients is cheaper and quicker.  Biology readouts can be based on short-term rather than long- term exposure (limited toxicology).  Human pharmacology studies might often be more tractable than studying the disorder because researchers can reduce heterogene-

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OPPORTUNITIES 55 ity and the impact of placebo response while probing specific mechanisms.  Experimental medicine approaches model pathology, which is often necessary to see a therapeutic drug effect. Krystal used this approach when deploying the drug ketamine to probe pathological mechanisms underlying schizophrenia. Krystal and colleagues demonstrated that ketamine, if given to healthy subjects, pro- duces both positive symptoms of schizophrenia—hallucinations and delusions—and negative symptoms—withdrawal, apathy, and lack of motivation (2005). The schizophrenia-like effects of ketamine are not altered by medications such as benzodiazepine, lorazepam, or two anti- psychotic drugs, haloperidol and olanzapine. Findings suggest that there are a variety of biological mechanisms underlying schizophrenia, and the ketamine model, in particular, is related to glutamate circuit dysfunction. Pharmacologic studies drive translation from animal to human to pa- tient, noted Krystal, and can be useful for asking specific questions that inform the drug development process. Still, it is important to point out that the experimental medicine approach, particularly with regard to ket- amine, is designed to probe specific mechanisms, not the full biology, of the disease. Krystal concluded that pharmacologic studies might be used in a thoughtful and hypothesis-based way to inform the testing of specif- ic therapeutic mechanisms in an iterative process that could to lead to drug discovery efforts. The molecular and experimental medicine approaches are just two ways to improve drug development by rethinking conventional method- ologies. Examining the pathophysiology of diseases and changes that occur from drug interactions in humans may improve translation from preclinical to clinical studies. In addition to the use of novel approaches, Krystal noted paradigm changes to the current drug development pipe- line are needed to facilitate a more efficient process. OVERARCHING CHANGES TO THE CURRENT PIPELINE The current drug development pipeline is characterized by a number of challenges that are impeding innovation and the development of novel therapeutics in the field, as discussed in Chapter 2. Jason Karlawish, pro- fessor in the department of medicine, medical ethics, and health policy at the University of Pennsylvania, discussed the need for new tools and

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56 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS technologies that fulfill specific criteria needed to answer research ques- tions and test hypotheses in the field. Nicholas Brandon, senior director of the Neuroscience Innovative Medicines Unit (iMED) at AstraZeneca, offered a new paradigm to screen drugs more effectively in order to in- crease the probability of advancing to clinical trials. Scott Small, profes- sor of neurology at Columbia University Medical Center, and Read Montague, director of the computational psychiatry unit at Virginia Tech and professor at University College London, highlighted the utility of adopting a top-down approach, or a reversal of the current pipeline direction. Finally, Christopher Austin, director of the National Center for Advancing Translational Science, discussed combinational strategies, emphasizing the use of more than one therapy to treat nervous system disorders. New Scientific Utility Criteria Karlawish said that the scientific community might opt for revised scientific utility criteria, namely, diversity, competition, degrees of valid- ity, innovation, and value to patients in the selection of future tools and technologies. Karlawish provided a historical overview of the use of the inbred mouse and discussed how new tools and technologies might be developed to reflect the current needs of the field. Karlawish opened by describing a current trend in translational failures: the inability of some drugs that show promise in preclinical animal models to translate into successful therapeutics. Another way to frame this problem is that the inbred mouse, which dominates drug discovery, has not had a commen- surate return on investment. This problem is not unique to the neurosci- ences, said Karlawish, and holds true in most other fields of medicine, especially cancer and infectious disease. For more than 70 years, the inbred mouse has dominated science. Karlawish noted that the inbred mouse, in particular, was chosen as “a matter of policy” due to its small size, easy maintenance, and low cost. During its initial use, the underlying scientific utility or “value” of the inbred mouse included efficiency, standardization, collaboration, and communication among laboratories, and its ability to produce high- volume data and increase fundamental knowledge. Today, roughly 60 percent of animals used for research protocols are mice (European Commission, 2010). Although inbred mice have substantially increased knowledge, the benefits of their use need to be weighed against potential

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OPPORTUNITIES 57 risks—namely, premature standardization, which can stall progress, said Karlawish. Heavy reliance on the inbred mouse might be precluding the use of a better tool or technology for generating new knowledge and treatments, noted Karlawish. The inbred mouse was not necessarily the wrong choice for the past 70 years, but rather, a choice that reflected scientific and society needs at the time, he continued. Although, there are several benefits to animal models, the inability for some drugs that show promise in preclinical studies to translate to clinical trials is still an issue. Com- monly used animal models, such as the inbred mouse, do not always ful- ly recapitulate human diseases, and therefore may limit the array of questions that can be answered (Bolker, 2012). Karlawish reiterated this point, stating that when the field is not sure where to go, it may be bene- ficial for researchers to be open to collegial competition and diversity. Researchers might consider utilizing other models that are also aligned with their specific research questions, taking into account environmental and other external factors (Bolker, 2012). New Paradigm for Drug Screening Brandon spoke about the need for a paradigm shift in screening nervous system drugs. As an example, Brandon used the conventional drug-screening paradigm for producing non-innovative, “me-too” com- pounds, which are pharmacologically similar to older drugs, but have reduced side effects (Rizzo et al., 2013). Conventional screens begin with high-throughput screening of large chemical libraries, resulting in identification of lead compounds for which in vivo screening and as- sessment of efficacy is conducted. Those steps are followed by demon- stration of efficacy relative to standard of care, determining side effects, and extended characterization. But this paradigm has been largely unsuc- cessful at finding novel targets and mechanisms because the targets stud- ied are generally not relevant to disease, Brandon noted. Brandon outlined components of a potential new drug-screening par- adigm that might produce greater success (see Table 5-1). Additional components include  target modulation to demonstrate a pharmacological effect, which is typically a behavioral effect, not necessarily related to efficacy, at doses that occupy the target;

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58 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS  evidence for efficacy potential using a relevant perturbation in a disease model;  modulation of physiology endpoints;  side-effect profiling; and  screening to identify drugs whose effects may translate across assays. Finally, Brandon suggested that understanding why drugs fail and then repeating the experiment may help in avoiding the abandonment of new drugs (Rizzo et al., 2013). Brandon’s experience with an inhibitor of phosphodiesterase 10A (PDE10A) exemplifies the limits of the conven- tional paradigm for drug screening. PDE10A is expressed primarily in medium spiny neurons of the striatum. Because PDE10A degrades cyclic TABLE 5-1 Paradigm Shifts Aimed at Improving Identification of Potential Therapeutics Paradigm Shifts Before After Target identification dependent on hu- Poor target identification man genome data Screens done quickly and without Thoughtful and relevant (e.g., iPSCs) thought Electrophysiological circuit-based end- Behavioral endpoints dominated points dominated Normal animals used Transgenics, lesion animal used Acute dosing Dosing regiments explored Target engagement obligatory (demon- Target engagement optional strate in vivo or ex vivo target occupancy in the brain) Mechanism unknown Mechanism explored Knowledge in patient population Biology of patient explored optional Walk away after failed Phase II trials Repeat experiments NOTE: iPSCs = induced pluripotent stem cells. SOURCE: Brandon presentation, April 8, 2013.

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OPPORTUNITIES 59 adenosine monophosphate (AMP), its inhibition results in a robust eleva- tion of AMP. The PDE10A inhibitor showed acute efficacy in animal models of schizophrenia and Huntington’s disease (Brandon et al., 2008; Giampà et al., 2010). Efficacy was shown in a stimulated locomotor as- say and in other assays used in conventional drug screening paradigms. Despite showing efficacy in multiple conventional screening assays, the drug failed to show efficacy in Phase II trials in schizophrenia. Had in- vestigators evaluated the drug’s potential according to Brandon’s sug- gested new paradigm, it might not have passed the screen. The drug showed target engagement and target modulation, but no evidence of reversal of positive symptoms, negative symptoms, or cognitive deficits in schizophrenia. It also did not show modulation of physiology end- points in positive symptoms, cognitive symptoms, and brain network activity. Failure in the new screening paradigm, in other words, may ex- plain why the drug did not work in human clinical trials. Brandon and colleagues, alongside the National Institute of Mental Health (NIMH), are considering more experiments to determine specific reasons for the failure and whether target occupancy in healthy volunteers and patients might be a critical component. The lesson Brandon learned from the failure of the PDE10A inhibi- tor clinical trial is that investigators cannot rely on the conventional par- adigm for drug screening. The PDE10A inhibitor showed promise in preclinical studies and Phase I trials, but failed in Phase II. Due to this experience, Brandon suggested a new drug screening paradigm with more rigorous components that could be beneficial to accelerate the drug development process (see Table 5-1). Brandon concluded that the field has misinterpreted animal data, oversold the same data, and has been re- luctant to do experiments in humans. To develop therapeutics, research- ers need to be willing to do the difficult experiments in both preclinical models and in an experimental medicine setting and accept some loss of speed (see Leaf, 2013). Reversing the Pipeline As previously highlighted in Chapter 2 by William Potter, senior advisor in the Office of the Director of NIMH, the current development pipeline moves from cellular/molecular mechanisms to animal models to control populations, and finally to the patient population. Several speakers noted that reversing the experimental pipeline by starting in

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60 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS humans for target identification and validation, then moving to ani- mal models for target engagement, may improve the drug development process. Imaging As previously discussed, Small suggested that translational imaging using a top-down approach, starting with humans and then validating findings using animal models, has the potential to accelerate the discov- ery of novel molecular targets (see Chapter 3). He emphasized the notion of regional vulnerability and the ability to identify underlying mecha- nisms using imaging, which could serve as future biomarkers for poten- tial therapeutics and assist with patient stratification. Computational Neuroscience Montague discussed the use of computational neuroscience to accel- erate development through reversal of the model organism pipeline by studying phenotypes of cognition (simple learning and conditioning be- haviors) in humans first and then validating those measures in animal studies. Montague defines “computational neuroscience” as the study of nervous system function by processing patterns of information with an emphasis on neurons and their connections. Understanding nervous sys- tem function in computational terms exposes the underpinnings of healthy and diseased conditions and suggests neurobiological mecha- nisms that can be important for drug discovery and development, said Montague. The use of model-based brain and behavioral responses may help to generate potential genetic targets. Montague asked, How do we validate rodent behavioral models as models of humans? For example, if there were a rodent model of empa- thy, what steps might be taken to ensure that it is in fact a model of what is observed in humans? Montague suggested that it might be beneficial to reverse the model organism pipeline and start in humans before moving into animal models for several reasons:  Cognitive phenotyping using model-based behavioral probes is beneficial when seeking mechanisms in comparison to subjective diagnostic categories.  Computational modeling can connect behavior and neural responses.

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OPPORTUNITIES 61  Complete “theories of cognition” are not necessary.  The use of model-based brain and behavioral responses may help generate potential genetic targets.  Conducting research in humans first to develop phenotypes that include computational model-based parameter extractions from their behavior may help to develop new ways to characterize and identify genetic variation and substrates that contribute to disease. Montague provided several examples in support of this view. Dopamine pathways play a central role in normal cognition—motivation, reward seeking and processing, working memory, and conditioned behavior— and disorders in these pathways are associated with addiction and schiz- ophrenia (Montague et al., 1996). Behavioral tasks can probe the under- lying mechanisms of normal and abnormal cognition and how dopamine systems are involved. For example, one behavioral task, of valuation and choice, asks subjects if they want $100 today or $117 in a week. The amounts and timeframe can be manipulated (e.g., $300 today or $330 next week) to determine the value of the future income relative to the present. Drug addicts will always choose the immediate reward, whereas healthy controls make choices based on the amount and timeframe. However, drug addicts were similar to healthy controls when there was a risky bet versus a “sure thing.” Montague said the study goal is to understand valuation and choice and catalogue human phenotypes. The phenotypes include computational model-based behavioral parameters and human imaging using functional magnetic resonance imaging (fMRI) when making decisions. Using this information, Montague noted that he could identify genes—particularly those that might be involved in the synthesis and distribution of dopamine or the construction of the system—that may be a part of process and input them into a model organism. Montague’s laboratory is now focused on computational modeling of fairness games (Kishida et al., 2010). One fairness game is the ultimatum game, in which one person is given $100 and asked to split it with a se- cond player. The second player can accept or reject the offer. If the se- cond player accepts the offer, the two split the money, whereas if the player rejects the amount, neither gets money. Montague’s research has shown that the second player rejects the offer 50 percent of the time if the first person only offers $20 of the $100 (an 80/20 split). The second player is incensed by the unfairness of the split and foregoes money for

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62 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS both players. This simple exchange, when extended to multiple rounds and different amounts of money, requires important cognitive functions such as (1) response to “fair” reciprocity (social norms); (2) depth of thought; (3) sensitivity to horizon (planning); (4) sensitivity to history of play (working memory); and (5) ability to learn and to model the other person. Using fairness and other types of complex decision-making games, Montague and coworkers examine the behaviors of healthy indi- viduals in comparison to people with psychiatric disorders to develop phenotypes of each group. Montague’s goal is to design behavioral probes of the dopamine system to make computational predictions about complex human decision making and behavior. Combination Therapy Austin highlighted the value of combinatorial strategies in drug de- velopment. Combinatorial strategies have become popular in diseases where the target cell mutates, such as in cancer and infectious disease. But the nervous system is adaptable in a more rapid way: it can adapt on a scale of microseconds. Therefore, it should not be a surprise that the nervous system is resistant to interventions, said Austin. When monotherapy does not work, perhaps the conclusion should be that the system adapted, rather than the more typical conclusion that the target was not valid. Combinatorial strategies should be considered in nervous system disorders for these reasons, reiterated Austin. Changing scientific approaches to the drug development pipeline to address current challenges in the field may be beneficial to the develop- ment of therapeutics for nervous system disorders. Several speakers stat- ed that changes to the current paradigm are needed to facilitate a more efficacious drug development pathway to include developing new tools and technologies that are based on scientific utility criteria desired from the field today; shifting the drug-screening process from conventional practice to one that produces innovative therapeutics; reversing the de- velopment pipeline by starting in humans first; and considering combina- tion therapies for nervous system disorders.

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OPPORTUNITIES 63 INFRASTRUCTURAL OPPORTUNITIES In addition to shifting current scientific practices, many participants noted a number of opportunities to improve and accelerate drug devel- opment through infrastructural changes. Potter said that public–private partnerships are a means to share resources and risk among several entities (i.e., academia, industry, and government). According to Chas Bountra, head of the Structural Genomics Consortium and professor of translational medicine at the University of Oxford, extending the precompetitive space to facilitate collaboration in preclinical and clinical research could de-risk the drug development process and decrease repeti- tive research among organizations. Walter Koroshetz, deputy director of the National Institute of Neurological Disorders and Stroke (NINDS), and Adrian Ivinson, director of the Harvard NeuroDiscovery Center at Harvard University, discussed several initiatives are currently under way, including opportunities sponsored by the National Institutes of Health (NIH), the Massachusetts Neuroscience Consortium, and the Collabora- tive CNS Screening Initiative. In addition, establishing preclinical stand- ards and a repository to share and mine data, such as “www.preclinical trials.gov,” may improve reproducibility, said Paul Aisen, director of the Alzheimer’s Disease Cooperative Study and professor in the department of Neurosciences at the University of California, San Diego. Develop Public–Private Partnerships to De-Risk Research Collaboration and the ability to share risk and costs among entities are two reasons why public–private partnerships are important for suc- cessful drug development, especially with current resource constraints. In addition to pharmaceutical companies stepping back from the drug dis- covery process, venture capital (VC) typically does not take risks beyond 7 years. There is a need to spread the risk among discovery, preclinical proof of concept through Phase I and Phase II trials, a participant noted. Bountra commented that industry is good at processes that require scale and infrastructure (e.g., high-throughput screening, lead optimization, manufacturing); target discovery is the main challenge. Academia and industry could work together to help develop targets that can be convert- ed to drugs. Potter agreed and stated that the current drug development model does not allow the field to translate molecular science into new therapeutics, and the idea of sharing risk across several groups (e.g.,

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64 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS stakeholders, advocacy groups, government, industry, and academia) would help investments from industry to focus on compounds that are more likely to succeed. Lawrence Goldstein commented that rather than trying to de-risk, the field could try to identify key bottlenecks in the sys- tem that allow risk tolerance and a degree of uncertainty. Bountra is among a group of researchers spearheading a public– private partnership aimed at overcoming the many challenges facing drug development for nervous system disorders (Norman et al., 2011). The partnership consists of academic researchers, regulators, and several pharmaceutical companies. The goals are to de-risk drug development, increase efficiency, and accelerate new knowledge. The group hopes to achieve these goals by  focusing on epigenetic targets;  making novel reagents freely available;  evaluating drugs in human primary cells;  publishing all data immediately; and  pushing the precompetitive boundary to Phase IIa when evaluat- ing novel targets in patients. Bountra elaborated that he and his colleagues are creating a public– private partnership in which resources are shared, which in turn will help de-risk the drug development process to Phase II. Bountra concluded that pioneering drug discovery can be challenging for any single organization and suggested that advances might occur through pooled funds from both the public and private sectors, improved access to reagents, and collabo- rations with patient groups and regulators to de-risk novel targets. After a public–private partnership advances the preclinical space forward toward Phase IIa, industry could be better situated to generate new drugs with greater accuracy and less risk, Bountra said. Kazumi Shiosaki, managing director at MPM Capital, agreed with Kiran Reddy, principal at Third Rock Ventures, that there is a need for public–private partnerships to help alleviate the risk for neuroscience venture investments. VC firms are continuing to invest in the preclinical stages of drug development and are optimistic about emerging therapeutic approaches and technologies in the field. Shiosaki described how VC firms such as MPM work to reduce the time between their investment and a pharmaceutical company acquisition liquidity event by using various types of structured acquisitions to share risks and rewards. In a structured acquisition, large pharmaceutical companies make the

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OPPORTUNITIES 65 bulk of their payments for the startup (known as “earn-outs”) contingent on the success of clinical trials or commercial activities. More recently, when there are drugs in development, the acquisition is made using an “option to acquire” agreement for the pharmaceutical company to acquire the startup if programs advance successfully. The pharmaceutical company pays an option fee that brings in non-dilutive capital to advance the drug project. The startup and the pharmaceutical company need to have a clear agreement and definition of the milestones that trigger the option. Several participants suggested there is an increasing trend for lead generation and other steps in preclinical testing to be done by organizations other than drug companies (e.g., government, academia, and biotechnology companies). Potter noted that some drug companies choose to minimize risk by devoting their resources to drugs that are farther along the development pathway. Consequently, NIH has become more actively involved in supporting preclinical drug development. Through its National Center for Advancing Translational Science (NCATS), NIH supports new programs in preclinical development, one of which is the NIH molecular libraries program.1 The program consists of a network of national laboratories whose aim is to generate novel small molecule probes by performing high-throughput screening, secondary screens, and medicinal chemistry. In addition, NIMH is supporting the Fast-Fail Trials (FAST) initiative2 in the discovery of psychiatric medications by providing a rapid means for researchers to test new or repurposed compounds for their potential therapeutic use. NCATS is working with other NIH institutes involved in neurosci- ence research to establish a clinical network in which experimental medicine can be performed in an efficient way, said Austin. Koroshetz reiterated that smaller and medium-sized institutes that want to partici- pate in translational research could benefit from leveraging what is ex- pected to be larger and more stable resources from NCATS. The initiative is designed to forge a network of centers that have harmonized information (both non-disease-specific and disease-specific). To help investigators understand FDA requirements and to facilitate communica- tion, NCATS is engaged in conversations with FDA about having FDA staff members serve as consultants to new investigators. A few partici- pants noted that by supporting public–private partnerships, government 1 See http://mli.nih.gov/mli. 2 See http://www.nimh.nih.gov/research-priorities/research-initiatives/fast-fast-fail- trials.html.

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66 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS partners, such as NIH, might improve and accelerate drug development through a focus on understanding disease mechanisms and the underly- ing biology. Extend the Precompetitive Space In addition to public–private partnerships, collaboration in the precompetitive space is important to identify and validate novel targets while reducing the replication of studies. Bountra suggested that by ex- tending the precompetitive boundary to Phase II, academic and govern- ment investigators would be included in research that establishes proof of clinical mechanism of a drug in humans before industry makes a huge investment. Sharing the risk and cost among all sectors could help ad- vance drugs along the development pipeline (Bunnage, 2011). Several initiatives are under way to encourage collaboration in the precompeti- tive space to facilitate drug development. Efforts by the National Institute of Neurological Disorders and Stroke Koroshetz provided several examples of the institute’s portfolio of grants, contracts, and cooperative agreements that provide researchers with resources needed to build confidence throughout the drug development process, adding knowledge to the precompetitive space. The oldest program, which has been under way for 10 years, consists of cooperative agreements designed to give 5 years of dedicated funding for conducting preclinical research leading to an investigational new drug (IND) submission.3 Today, the program is milestone-driven and includes criteria for go/no-go decisions. If investigators do not hit milestones in pursuit of an IND, funding can be halted. Each cooperative agreement is approximately $1–$1.5 million, primarily given to academic investiga- tors; however, small businesses and industry partnerships with academia are eligible to apply, said Koroshetz. A new program, Blueprint Neurotherapeutics,4 is designed to fund preclinical research covering the “valley of death,” so named because it is a gap in the drug development pipeline where NIH funding typically ends and pharmaceutical industry development begins. Blueprint Neurotherapeutics is dedicated to advancing promising compounds from 3 See http://www.ninds.nih.gov/research/translational. 4 See http://neuroscienceblueprint.nih.gov/bpdrugs/project_pipeline_fig.pdf.

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OPPORTUNITIES 67 lead optimization to candidate selection, preclinical safety, and Phase I clinical testing. Each project is led by a team composed of a principal investigator, industry consultants, and NIH staff. The team plans a research strategy and oversees implementation, which is often out- sourced to contract research organizations that are better equipped to conduct testing in which most academic investigators typically do not specialize, said Koroshetz. Another new program is NeuroNext,5 which consists of a network of 25 sites around the country that conduct Phase II clinical trials. The network has its own data coordinating center and clinical coordinating center. Investigators are encouraged to share preclinical data that justify going forward with Phase II clinical trials. The funding under NeuroNext can be used to test therapies and develop biomarkers. The program is established for academics or members of industry who have a Cooperative Research and Development Agreement (CRADA) with NIH. All 25 sites use the same institutional review board (IRB), which allows for rapid implementation. The first study funded by NeuroNext— a biomarker for spinal muscular atrophy—was initiated in just 54 days. A NeuroNext network for stroke is to be established in 2014. According to Koroshetz, NINDS also has several resources that are instrumental to translational research. One is a cell bank of iPSCs from patients with neurological disorders as well as controls. Another resource is a Small Business Innovation Research (SBIR) program for which there is 3 percent of dedicated funding set aside to help small business commercialize neuroscience diagnostics or therapeutics.6 Koroshetz concluded with some ideas about how NINDS might enhance translational and clinical programs. In addition to encouraging better animal models and more rigorous design of preclinical trials, Koroshetz suggested development of better biomarkers, improvement of translational knowledge at the level of grantees and NINDS staff, and integration of knowledge across nervous system disorders with overlapping mechanisms, such as abnormal protein deposition, which applies to Alzheimer’s and Parkinson’s disease, and amyotrophic lateral sclerosis. Koroshetz suggested that government efforts to support translational research might lead to new and innovative therapeutics and accelerate the drug development process for nervous system disorders. During the discussion, one participant noted that there is some concern 5 See http://www.neuronext.org. 6 See http://www.ninds.nih.gov/funding/small-business.

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68 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS that congressionally directed money is not yielding return investment for the taxpayer. The participant proposed that a model be developed that would advance drug discovery and encourage early collaboration between taxpayer funding and pharmaceutical companies. Koroshetz stated that there is an experiment going on in Europe in which companies and the government are trying to partner to address this same issue. Massachusetts Neuroscience Consortium and Collaborative CNS Screening Initiative The Massachusetts Neuroscience Consortium7 is another opportunity for entities to collaborate in the precompetitive space. It is a new initia- tive designed to accelerate preclinical research, introduce academic in- vestigators to the challenges of targeted research and drug discovery, and forge industry–academic partnerships, said Ivinson. Consortium projects are centered on target identification and validation. Because the focus is on the precompetitive space, there is no impact on ownership of intellec- tual property. The funding available is approximately $250,000 per pro- ject. The projects are milestone-driven, with accompanying checkpoints and clearly defined timeframes. The data generated are shared among members and then published. The consortium is sponsored by the state of Massachusetts, and the program is administered through the Massachu- setts Life Sciences Center. Another new precompetitive program is the Collaborative CNS Screening Initiative. Under this initiative, university and industry part- ners pool their anonymous active compounds into a shared library. The eligible compounds have to exhibit potential in primary screens and have to be validated through secondary assays. The partner that discovers novel activity for the compound is then put in touch with the original sponsor of the compound to share results and ideas. The initiative began with academic partners, but will include industry partners as well. The funding comes from three foundations—the Alzheimer’s Drug Discovery Foundation, the Beyond Batten Disease Foundation, and the National Multiple Sclerosis Society. 7 See http://www.masslifesciences.com/neuroscience.html.

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OPPORTUNITIES 69 Improve Reproducibility by Increasing Preclinical Study Standards and Sharing Public–private partnerships and collaboration in the precompetitive space create opportunities to identify areas of improvement in the field. Two points that several participants highlighted were the need to increase statistical and research standards of preclinical studies and the creation of a central portal to share preclinical data. The overall end goal is to improve the reproducibility of preclinical data, which could further rese- archers’ understanding of what was or was not successful during pre- clinical trials before investing their time and resources into similar targets or drugs. Statistical Standards for Preclinical Studies According to several participants, more statistical rigor is needed for preclinical studies. The number of successful animal studies is high due in part to the widespread practice of a 0.05 statistical cutoff for positive findings. Aisen suggested that this cutoff is appropriate only if there is a single variable; however, the overwhelming majority of studies have numerous variables, making it easier to detect positive results at this cut- off point. This, in turn, may have an influence on the lack of negative data that are published in the field. From an investment standpoint, Shiosaki noted that consultants are used to guide companies in under- standing the science and the risks when performing due diligence to as- sess the quality and interpretation of the data that have been submitted for startup funding. If needed, the data are replicated through contract research organizations (CROs). Central Repository for Preclinical Data Sharing Aisen asserted a need for researchers to be required to register animal studies in advance in the same way that clinical trials are registered. Aisen suggested that such a registry could include study design, drugs, route of administration, dose, duration, primary outcome measure, and statistical plan. These features could be captured in a centralized website akin to www.clinicaltrials.gov (e.g., “www. preclinicaltrials.gov”) that would serve as a portal for sharing of experimental designs and results. A partici- pant noted that there are several issues related to data sharing, particularly related to imaging technologies that lack standardization. Data that are

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70 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS readily available, analyzable, and reproducible may be beneficial to the field. VENTURE CAPITAL PERSPECTIVE ON OPPORTUNITIES TO IMPROVE DRUG DEVELOPMENT VC firms are primary engines of drug development innovation, con- sidering that VC firms, according to Reddy’s analysis, backed 12 of 14 Fast Track drug approvals by FDA in 2011. During that year, the U.S. VC industry invested $28 billion in all industries; approximately $7–$8 billion was invested in the life sciences, including biotechnology, medi- cal devices, and medical equipment sectors. When VC firms invest in preclinical stage projects, they have a high success rate in terms of return on investment and usually “exit” through large company acquisition or initial public offerings (IPOs). There is a misconception that VC firms are looking at 2- to 3-year investment horizons, when the actual figure is approximately 5 to 7 years, said Reddy. Reddy offered several suggestions that could accelerate the therapeu- tic development process by helping investment decisions:  Improve delivery technologies for blood–brain barrier biologics.  Expand access to a diverse set of human iPSC lines.  Promote more safe, well-controlled, “human lab” testing (i.e., iPSCs).  Build mechanisms to encourage replication of important preclin- ical findings and publishing of negative results.  Define objective biomarkers for behaviors (e.g., electroencepha- logram, fMRI, diffusion tensor imaging, omics platforms, etc.).  Obtain straightforward phenotypic/genotypic information of het- erogeneous patient populations.  Create patient registries that enable rapid and cost-efficient development.  Provide approvals or “conditional” approvals based on surrogate endpoints with Phase IV requirements.  Extend patent terms for nervous system indications associated with long development time lines (i.e., disease modifying/ preventative therapies).

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OPPORTUNITIES 71 Workshop speakers and participants discussed multiple opportunities and approaches that might improve and accelerate drug development for nervous system disorders. Novel methodological approaches, such as molecular and experimental medicine approaches, could facilitate the translation from preclinical to clinical more effectively than current methods. Many participants highlighted the need for overarching chang- es to the current drug development pipeline through the transformation of conventional practices and technologies to ones that encourage innova- tion. Capitalizing on infrastructural opportunities such as public–private partnerships, collaboration in the precompetitive space, and preclinical data sharing could alleviate the risk associated with drug development and limit unnecessary research. Finally, from a VC perspective, a num- ber of strategies could aid in investment decisions for nervous system disorders (e.g., objective biomarkers, patient registries, technologies for blood–brain barrier biologics).

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