Improving and Accelerating Therapeutic Development for Nervous System Disorders Workshop Summary (2014) / Chapter Skim
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5 Opportunities to Improve and Accelerate the Drug Development Pipeline
5 Opportunities to Improve and Accelerate the Drug Development Pipeline
Pages 51-72
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From page 51... ...
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.
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From page 52... ...
After validation of the target succeeds, novel 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.
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From page 53... ...
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 inhibitors. He observed that fulfilling the promise of molecular medicine requires many educated guesses about the following: Drug formulation Patient selection (e.g., age, ratings at baseline, etc.)
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From page 54... ...
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 humans and examine outcomes at various levels (e.g., behavior, cortical activity, and brain imaging)
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From page 55... ...
Still, it is important to point out that the experimental medicine approach, particularly with regard to ketamine, 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 specific therapeutic mechanisms in an iterative process that could to lead to drug discovery efforts.
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From page 56... ...
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 validity, innovation, and value to patients in the selection of future tools and technologies.
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From page 57... ...
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.
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From page 58... ...
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)
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From page 59... ...
. 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.
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From page 60... ...
For example, if there were a rodent model of empathy, 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.
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From page 61... ...
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)
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From page 62... ...
Changing scientific approaches to the drug development pipeline to address current challenges in the field may be beneficial to the development of therapeutics for nervous system disorders. Several speakers stated 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 development pipeline by starting in humans first; and considering combination therapies for nervous system disorders.
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From page 63... ...
, the Massachusetts Neuroscience Consortium, and the Collaborative CNS Screening Initiative. In addition, establishing preclinical standards 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.
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From page 64... ...
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 collaborations with patient groups and regulators to de-risk novel targets.
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From page 65... ...
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 neuroscience research to establish a clinical network in which experimental medicine can be performed in an efficient way, said Austin.
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From page 66... ...
Each cooperative agreement is approximately $1–$1.5 million, primarily given to academic investigators; 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.
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From page 67... ...
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.
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From page 68... ...
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.
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From page 69... ...
The overall end goal is to improve the reproducibility of preclinical data, which could further researchers' understanding of what was or was not successful during preclinical 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.
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From page 70... ...
Reddy offered several suggestions that could accelerate the therapeutic development process by helping investment decisions: Improve delivery technologies for blood–brain barrier biologics. Expand access to a diverse set of human iPSC lines.
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From page 71... ...
Many participants highlighted the need for overarching changes to the current drug development pipeline through the transformation of conventional practices and technologies to ones that encourage innovation. 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.
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