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Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop (2017)

Chapter: 2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities

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Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
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2

Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities

The previous Forum workshops discussed the need for more efficient discovery and development approaches to improve success rates in drug development for nervous system disorders. To provide context for the discussions in this third workshop, David Michelson gave a brief overview of the drug development pipeline for nervous system disorders. Figure 2-1 illustrates the path to a marketable drug, starting with target identification, then proceeding to lead identification and optimization and candidate selection, and finally to first-in-human trials, proof of concept, and confirmation studies.

The first step in this pathway, target identification and validation, is perhaps the most expensive because of the risk of failure and the low probability of success, said Stevin Zorn, president and chief executive officer of MindImmune Therapeutics, Inc. Steven Hyman added that the process of target validation requires understanding disease mechanisms, and traditionally this has been accomplished in animal models.

Zorn said there are currently no, and may never be, predictive animal models of complicated human diseases such as nervous system disorders. Instead, there are animals that model some type of biology to address very well-defined questions. The problem is that most of the animals used for modeling do not normally develop the nervous system disorders of interest, according to Steve Finkbeiner, director at the Gladstone Institutes. In the neurodegenerative disease area, for example, overexpression of certain genes has been used to try to force laboratory animals to mimic human pathology. However, by producing such non-physiologic phenotypes, the usefulness of the animals in predicting the response to perturbation may be lost.

Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
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Image
FIGURE 2-1 The path to a drug.
SOURCE: Presentation by Michelson, 2016.

Nonetheless, animal models remain critical to drug discovery, especially for lead optimization, said Michelson. They are a highly predictive means to assessing the safety, metabolism, and absorption characteristics of a compound, allowing deconstruction of a drug’s pharmacology in a way that cannot be done in humans. In addition, animal models enable investigators to test whether the pharmacology is associated with the expected biological change. Unfortunately, however, most animal models that have been developed for nervous system disorders or behavioral syndromes have been poor predictors of efficacy in humans. Therefore, better approaches and paradigms are needed to move forward in this area, said Michelson.

OVERVIEW OF CHALLENGES

Many workshop participants argued that the fundamental issue underlying clinical trial failures is scientific. Michelson noted that for many neurologic and neuropsychiatric diseases, a poor understanding of disease biology remains, making it difficult not only to choose the best tar-

Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
×

gets, but also to know when to intervene and how to move the biology effectively. Another preclinical challenge, mentioned by Rita Balice-Gordon, head of neuroscience research at Sanofi, is to understand the barriers between the periphery and the central nervous system (CNS), not only the blood‒brain barrier, but also barriers between blood and the retina, choroid plexus, and spinal cord.

A translational gap also occurs between identifying and validating a target and developing a clinical measure or biomarker that can predict a response and a disease, said Zorn. Frank Yocca, senior vice president of CNS research and development at BioXcel Corporation, said these problems are exacerbated because two separate teams are often working on discovery and biomarkers. Discovery always outpaces biomarker development, which often proceeds without fully understanding target engagement, dose, or patient selection parameters. A better approach, he said, would be to have discovery scientists work together with clinical scientists and clinical pharmacologists throughout the research and development process.

In this workshop, the challenges facing drug development were broken down into three groups: those related to preclinical issues, including target identification and validation; those that specifically relate to new approaches in animal models of disease; and those that relate to research infrastructure and resources.

Target Identification and Validation

The process of target and lead identification and validation, said Zorn, involves identifying a compound with a chemical structure that has the potential to modulate the target, and then optimizing it to have good drug characteristics, including good pharmacokinetics, a metabolic profile consistent with the therapeutic goals, no toxicity, and no off-target effects. As noted earlier, advances in genetics have led to the identification of a plethora of targets. However, because some diseases such as schizophrenia and Parkinson’s disease (PD) develop over many years, target identification is particularly challenging, said Niels Plath, vice president Synaptic Transmission at H. Lundbeck A/S.

Michelson defined target validation as the process of gathering evidence that perturbing the target in a particular way results in a change in some biological process relevant to the disease state. Targets can be validated by genetics, pathophysiology, human pharmacology, or animal models, he said. Moreover, the answer may not be a simple yes or no, but

Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
×

requires judgment about the strength and productivity of the data, and this judgment will vary among individuals and companies.

Validation is also about risk, said Michelson: How good is the evidence and how willing is the company to rely on it and go forward? As the limitations of animal models have been increasingly recognized, he said that the emphasis has shifted away from using animal models for the purposes of predicting efficacy targets, and toward validating those targets with human data.

Animal Models of Disease

The success of an assay requires the identification of a relevant phenotype in a model system, said Plath. He added that linking well-described, distinct biological phenomena to symptoms of a complex disease such as schizophrenia is a huge but necessary task. Indeed, the explanatory power of a model comes from working out the mechanistic basis for a phenotype, but requires rigor and discipline to not overgeneralize the results obtained using the model, said John Krystal, Robert L. McNeil professor of translational research and professor of psychiatry and neuroscience at Yale University. The first step toward building new models, said Zorn, is formulating the right clinical questions that need to be addressed by preclinical research. The subsequent challenge is determining how preclinical markers identified in these models can be translated into clinical endpoints, he added.

Many animal models are based on an increased understanding of human genetics; however, these genetic models present many challenges, said Steven McCarroll, director of genetics at the Stanley Center for Psychiatric Research at the Broad Institute of Massachusetts Institute of Technology and Harvard University. Among these challenges are the observations that individual genes and variants may have only small effects and may not be fully penetrant. In addition, large-effect variants often cause constellations of symptoms, which further complicate interpretation; strong-effect risk factors may not be shared across species. Several participants, including Guoping Feng, Poitras professor of neuroscience at the Massachusetts Institute of Technology, also noted that the genetic background of the animal can complicate interpretation of phenotypes.

For some nervous system disorders, existing animal models do not produce the key pathologic features or symptoms of the disease, and as a result may not be able to demonstrate whether a drug is going to be ef-

Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
×

fective, said Jan Egebjerg, vice president of neurodegeneration and biologics at H. Lundbeck A/S. For example, he noted that none of the transgenic PD animal models show PD symptomatology or the core pathology of the disease, that is, Lewy bodies composed of aggregated alphasynuclein. Moreover, for highly heterogeneous diseases such as schizophrenia, there will never be one single model, but several models for specific aspects or subtypes of the disease, said Plath.

Disease modeling is further complicated by the fact that there are aspects of the human nervous system that are not represented in virtually any other animal, said Doug Cole, managing partner at Flagship Ventures. He questioned the value of animal models as tools for validation, suggesting that the emphasis should be much more on human validation rather than trying to recapitulate the disease in animal models.

Research Infrastructure and Resources

Several research collaborations and partnerships were represented at the workshop, and a number of participants spoke of the need for improved infrastructure and resources, including a broader array of collaborative ventures, such as those that would integrate research and discovery with clinical testing efforts. Several participants, including Frances Jensen, professor and chair of neurology at the University of Pennsylvania Perelman School of Medicine, also commented on the inadequacy of workforce training for neuroscience research and the lack of trained clinicians working at the preclinical‒experimental medicine interface to better enable translation of preclinical findings to clinical studies.

OVERVIEW OF POTENTIAL OPPORTUNITIES

Several workshop participants identified a few innovative modeling paradigms that may mitigate the existing paucity of predictive animal models for nervous system disorders. These included not only cellular and computational models, but also nonhuman primate models that come closer to reflecting human disease than do rodents.1 Many participants also advocated for a greater focus on data emerging from human clinical

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1 The use of genetically modified or wild-type nonhuman primates in research involves ethical considerations that were beyond the scope of this workshop. For additional information about the use of primates in biomedical research, please see Belmonte et al. (2015).

Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
×

studies and human experimental medicine approaches, suggesting that these data have been poorly used to advance a fundamental understanding of human diseases. To realize the potential of these approaches, several participants called for increased integration of clinical and basic science efforts, in addition to more collaboration across stakeholder groups, and expanded sharing of data, resources, and tools to de-risk these efforts. The potential opportunities summarized here are discussed in greater detail throughout the proceedings.

A major theme throughout the workshop, articulated by Nita Farahany, professor of law and philosophy at the Duke University School of Law, was the need to ensure that ethical and regulatory issues are considered throughout the research process, beginning at the preclinical stage of research. This includes not only a focus on human protection, but also on ensuring that resources are allocated and used in a manner that maximizes the likelihood that research efforts will result in better treatments for patients, and that patients have a voice in determining how research is conducted. The following are some potential opportunities described by individual workshop participants.

Using Innovative Models

  • Modeling disease in human induced pluripotent stem (iPS) cells and complex three-dimensional organoids and spheroids derived from iPS cells offers the potential to characterize disease phenotypes at cellular, subcellular, molecular, genomic, epigenomic, transcriptomic, and proteomic levels, and then correlate these characteristics to disease phenotypes in patients (Finkbeiner).
  • Using new gene editing techniques such as CRISPR2 in nonhuman primates could enable the generation of primate models that more closely resemble humans than do existing animal models (Feng).
  • Computational modeling of brain circuits using quantitative systems pharmacology approaches enables the integration of data from various modalities, including iPS cells, organoids, animal models, and human clinical trials. Such integrative models have the potential to predict the outcome of investigational therapeu-

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2 Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology is a relatively inexpensive and user-friendly gene-editing system that allows investigators to alter the DNA of nearly any organism. For additional information on CRISPR technology, see Fellman et al. (2016) and Heidenreich and Zhang (2016).

Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
×

tics, potentially optimizing clinical trial design for enhanced probability of success (Geerts).

Developing More Sophisticated Human Clinical Studies

  • Reducing the burden of failure and increasing the probability of success will require more efficient studies that reliably predict clinical outcome, thus reducing the number of failed late-stage studies (Michelson).
  • Initiating research efforts by focusing on aspects of the human condition, whether genetic or clinical, and then linking findings back to what is known at a biological level through model systems may offer a more effective and efficient pathway to understanding human disease (Sherer).
  • Several workshop participants noted that moving to the clinic as quickly as possible may provide a more efficient route to identifying and validating novel therapeutics, given the failure of animal models to predict efficacy. However, other workshop participants commented that within a commercial organization, when competing against therapeutic areas that have more predictive biomarkers, generating some evidence in animal models will almost certainly be necessary.
  • When an adequate animal model of a disease is not available, it may be possible to model the impact of interventions using data from longitudinal human studies (Hoffman).
  • Integrating human observational assessments in biomarker studies might help researchers identify translatable biomarkers for validation (Zorn).
  • Deconstructing complex diseases into component mechanisms, which may have characteristic imaging and biochemical signatures, could accelerate translation across a range of nervous system disorders (Jensen).

Sharing Resources, Data, and Tools

  • Examining data using quantitative systems pharmacology approaches from failed clinical trials may provide valuable information to guide the planning of future studies (Geerts).
  • Sharing tools and outcomes from exploratory studies that target similar mechanisms will be essential to advance understanding
Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
×
  • of target engagement and the relevance of those targets to disease (Sherer).

  • Establishing a national repository of clinically annotated tissue would provide a valuable resource that researchers could use to characterize the progression of some diseases (Cole).
  • Creating prospective registries of patients, as well as preclinical and non-trial clinical studies, would enable investigators to conduct both preclinical studies and basic science studies that are confirmatory in nature (Kimmelman).
  • Applying more advanced statistics and multivariate analytical methods to animal studies would facilitate a better understanding of disease progression (Jensen).

Integrating Research Efforts and Promoting Collaborations

  • Closer collaboration between clinicians and researchers developing models is needed to ensure that phenotypes can be translated from nonhuman models to human systems (Andersen).
  • Building collaborative experimental medicine and preclinical research partnerships can shorten the cycle time required to identify, develop, and validate biomarkers. These biomarkers could help fill the translational gap between preclinical biological hypotheses and human outcome measures predictive of relevant disease components (Sherer).
  • Fostering the cross-training of scientists across academic and clinical departments of neuroscience, neurology, and psychiatry could lead to a more integrated understanding of the relationship between research and clinical domains, and could result in more relevant, translatable preclinical experimental designs (Jensen, Zorn).

Focusing on Gateway Indications

  • Applying novel preclinical, clinical, and computational models to orphan diseases, gateway indications (e.g., progressive supra-nuclear palsy as a gateway indication for Alzheimer’s disease), or monogenic diseases might provide the best opportunity for advancing CNS drug development (Feng, Jensen, Rubin, Yocca).
Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
×

Promoting Ethical and Effective Research Through Policies

  • Establishing policies at the top 10 academic medical centers that require investigators to publish studies within a 1- or 2-year period, as a condition of allowing them to recruit patients, would encourage greater circulation of information about clinical trials (Kimmelman).
  • Requiring that animal studies used to provide the evidence base for initiating a clinical trial include a prespecified hypothesis, power calculations, outcome measures, and sharing in a public database would increase the rigor and value of preclinical studies (Kimmelman).
  • Encouraging the Food and Drug Administration to require prospective registration of Phase I clinical trials would establish a public record and could be the first step to improving reporting and disseminating knowledge about the relative benefit and risk resulting from such studies (Kimmelman).
  • Instituting policies that encourage risk sharing, improve access to data, simplify clinical study requirements, invest in regulatory science, and extend patent protection could increase the probability of success for drug development (Martin).
Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
×

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Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
×
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Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
×
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Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
×
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Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
×
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Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
×
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Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
×
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Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
×
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Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
×
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Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
×
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Suggested Citation:"2 Drug Development for Nervous System Disorders: Overview of Challenges and Potential Opportunities." National Academies of Sciences, Engineering, and Medicine. 2017. Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24672.
×
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Next: 3 Case Studies: Therapeutic Development for Parkinson's Disease and Schizophrenia in the Absence of Predictive Animal Models of Disease »
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Compared with other disease areas, central nervous system (CNS) disorders have had the highest failure rate for new compounds in advanced clinical trials. Most CNS drugs fail because of efficacy, and the core issue underlying these problems is a poor understanding of disease biology. Concern about the poor productivity in neuroscience drug development has gained intensity over the past decade, amplified by a retraction in investment from the pharmaceutical industry. This retreat by industry has been fueled by the high failure rate of compounds in advanced clinical trials for nervous system disorders.

In response to the de-emphasis of CNS disorders in therapeutic development relative to other disease areas such as cancer, metabolism, and autoimmunity, the National Academies of Sciences, Engineering, and Medicine initiated a series of workshops in 2012 to address the challenges that have slowed drug development for nervous system disorders. Motivated by the notion that advances in genetics and other new technologies are beginning to bring forth new molecular targets and identify new biomarkers, the Academies hosted the third workshop in this series in September 2016. Participants discussed opportunities to accelerate early stages of drug development for nervous system disorders in the absence of animal models that reflect disease and predict efficacy. This publication summarizes the presentations and discussions from the workshop.

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