5

Role of Advocacy in Facilitating Translation of Basic Scientific Research

Important Points Highlighted by Individual Speakers

•   Patient advocacy organizations are uniquely positioned to help convene stakeholders involved in the biomedical research ecosystem to prioritize goals that improve patient outcomes.

•   Advocacy groups have identified innovative ways to work with academia and the private sector by encouraging them to embrace novel models for risk sharing.

•   Foundations partner with other organizations to promote networks that share and accelerate the identification of treatments for patients.

•   Advocacy groups are willing to bear more of the risk on innovative projects to advance early development and generate information that will attract larger funders for the next phase.

The ability to translate research results into outcomes for patients is urgently needed, and patient advocacy groups play a significant role in translating discoveries into patient treatments. Pat Furlong, founding president and chief executive officer of Parent Project Muscular Dystrophy (PPMD), examined the role of patient advocacy organizations within the broad biomedical and health care ecosystem. Todd Sherer, chief executive officer of The Michael J. Fox Foundation for Parkinson’s Research (MJFF), described some of the projects and strategies that MJFF has used



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5 Role of Advocacy in Facilitating Translation of Basic Scientific Research Important Points Highlighted by Individual Speakers • Patient advocacy organizations are uniquely positioned to help convene stakeholders involved in the biomedical research eco- system to prioritize goals that improve patient outcomes. • Advocacy groups have identified innovative ways to work with academia and the private sector by encouraging them to embrace novel models for risk sharing. • Foundations partner with other organizations to promote net- works that share and accelerate the identification of treatments for patients. • Advocacy groups are willing to bear more of the risk on inno- vative projects to advance early development and generate information that will attract larger funders for the next phase. The ability to translate research results into outcomes for patients is urgently needed, and patient advocacy groups play a significant role in translating discoveries into patient treatments. Pat Furlong, founding president and chief executive officer of Parent Project Muscular Dystrophy (PPMD), examined the role of patient advocacy organizations within the broad biomedical and health care ecosystem. Todd Sherer, chief execu- tive officer of The Michael J. Fox Foundation for Parkinson’s Research (MJFF), described some of the projects and strategies that MJFF has used 31

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32 EFFICIENCY AND EFFECTIVENESS OF GENOMIC SCIENCE TRANSLATION to accelerate the translation of novel ideas into improved therapies. Patients need cures today and cannot afford the time to wait, both speakers empha- sized; the ability to translate research results into treatments for patients is urgently needed. accelerating translation for those who need it now PPMD was founded in 1994 to help children who have a progressive, aggressive, and life-limiting disease. Duchenne muscular dystrophy (DMD) affects about 1 in 4,600 boys, causing them to lose muscle function gradu- ally over their lifetime of about 20 or 30 years; about 30 percent of patients also have learning or processing issues, even autism (Liew and Kang, 2013). DMD is an X chromosome–linked disease caused by mutations in a large gene, dystrophin, the product of which is a cytoskeletal protein that binds muscle membrane and helps to maintain muscle cell structure. About 30 per- cent of cases result from spontaneous mutations (Grimm et al., 2012). F ­ urlong recounted that in 1984, when her sons were diagnosed with the dis- ease, it was predicted that with the recent discovery of the gene responsible for DMD, a cure would be forthcoming in 18 months. Today, after 27 years and the deaths of both her sons, “we don’t have a treatment for Duchenne,” said Furlong. “It still remains the same: aggressive, progressive, and lethal.” The task of finding treatments is a difficult one. Mutations can occur throughout the 2.4 million base pairs and 79 exons of the gene, resulting in a wide variety of clinical presentations. At the same time, 50 foundations are involved in research on DMD in the United States alone, with annual expenditures on research on the disease being about $25 million. “It’s very duplicative,” said Furlong, “and this is happening continuously in the rare disease space” around the world. PPMD funds academic research, but it has found itself mired in dis- putes over overhead rates and technology transfer agreements. Working with the legal infrastructure of a university “wastes time—time that we don’t have,” Furlong said. This is an example of how research incentives need to be reevaluated. Academic institutions have actually turned down funding because PPMD’s board-directed cost policy could not be adjusted to provide additional funding for overhead expenses. As a result, the foun- dation has established its own lab to work on validating drug candidates so that it can reduce the risk on some of its investments. This lab offers validation for “any compound at any cost” because of support from PPMD. Not only do patients and families need therapies right now, but they are also struggling with the economic costs of participating in clinical ­ rials: t parents need to take time off from work, hire child care for their other children, and fund travel that might not be supported by trial sponsors.

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ROLE OF ADVOCACY 33 About 60 percent of DMD patients in the United States are on Medicaid, Furlong said. PPMD funds several initiatives aimed at finding treatments faster. It supports work in the drug repurposing space, because patients are in such need of therapies that their parents will often try to manage their sons’ medical care with information about potential effective therapies that they have learned on the Internet. “The families that I know will share data about their children freely and give it to anyone who can look at [those] data in a thoughtful way and begin to help us change what’s happening,” said Furlong. They believe that if they are fairly confident about the safety of a compound, it should be tested in trials. “The risk tolerance of this community and the rare disease community is quite high.” Furlong described the work of the Review of Approved Drugs for Duchenne (RADD) working group, which PPMD funds. A precompetitive ­ three-part collaboration among the Nationwide Children’s Hospital in ­ Columbus, Ohio, the Children’s National Medical Center in Washington, ­ DC, and the European initiative Translational Research in Europe–­ Assessment and Treatment of Neuromuscular Diseases (TREAT-NMD), RADD is designed to prioritize U.S. FDA–approved drugs for further test- ing. TREAT-NMD is a global network for the neuromuscular field that provides increased statistical power for research on rare diseases. Through RADD, published literature on pre­ linical models is annotated and entered c into searchable databases, and gene expression data from different models ­ and stages are compiled. One goal is to explain to parents which approaches are valid and which are not, Furlong said. The TREAT-NMD Advisory Committee for Therapeutics (TACT) is an international network that fosters collaboration among stakeholders with the goal of advancing research and therapeutic development, said Furlong. The TACT model is a comprehensive and integrated one that brings together experts from academia, regulatory agencies, industry, clini- cal practice, and basic science with parent advocates to discuss proposals in a confidential review setting and inform industry and academia about patient needs. The review process is more than that of a typical academic advisory committee, resulting in greatly increased coordination and cred- ibility among nonprofit organizations, industry, and funders. It also helps enable decisions about when projects are not meeting their milestones and should be concluded. To improve communication and development efficiency but reduce investment risk, PPMD has diversified its research investments. ­ uchenneConnect is a patient registry that now has 4,000 entries; personal D identifiers are removed from the data, and the information is curated and easily searched. DuchenneConnect is coordinated with clinicians’ offices to decrease the time that a physician would need to spend inputting data, and

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34 EFFICIENCY AND EFFECTIVENESS OF GENOMIC SCIENCE TRANSLATION it is also linked to TREAT-NMD to increase statistical power by including data for patients worldwide. Furlong insisted that every child with DMD and other rare diseases should be in a network “so that we can apply what we know and learn to fly the plane while it’s in the air.” The organization is also working with Public Library of Science (PLoS) ONE, because it believes that all information generated through its efforts should be fully accessible and not delayed for publication. Genomic studies are also under way to examine children who are out­ liers, that is, children who have been self-reported through social networking to be doing better or worse than expected, said Furlong. A task force is also looking at barriers to diagnosis across all pediatric dis- eases involving muscle weakness, and PPMD developed a website for this called childmuscleweakness.org. A parallel project is being performed by ­ S ­ omaLogic, a company based in Colorado looking at the protein signatures of the disease to accelerate the development of clinical products. Together, RADD, TACT, and their collaboration with Shire Pharma- ceuticals are designed to achieve tangible results in a faster time frame, said Furlong. PPMD’s strategic plan for research is to improve the quality of drug candidates entering clinical trials, decrease the time required to test drugs, and thereby buy time for this generation of boys. The foundation will also identify and support drug candidates with the greatest likelihood of success, more quickly recruit subjects for trials by identifying poten- tial subjects and supporting their participation, develop biomarkers and validate new functional endpoints, and encourage the use of centralized institutional review boards. The identification of markers in early disease would have the most impact for patients if the progression of the illness could be slowed by targeting these markers, Furlong said, but because the disease has so much clinical variability, there likely will not be one single drug to treat DMD. Patients today, not only those with DMD but many others with rare dis- eases, are waiting for cures, Furlong said. “We also have to think about today because it matters.” risk Sharing as a path to progress MJFF was founded in 2000 to deliver improved therapies and a cure for Parkinson’s disease through creative problem solving and the acceleration of novel research ideas through milestone-driven research. Sherer described some of the projects that MJFF has undertaken and some of the strategies that it uses to achieve these goals. MJFF is 100 percent focused on patients, said Sherer. It seeks to speed treatments that can slow, stop, or reverse the progression of Parkinson’s disease; create better treatments for the currently unaddressed or underaddressed symptoms of the disease; and accelerate the

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ROLE OF ADVOCACY 35 development of treatments to address or avoid the debilitating side effects of current drugs. MJFF has empowered its staff—nine employees with Ph.D.s and five project managers—with assessing opportunities, designing road maps, set- ting milestones, and collaborating with investigators to move projects for- ward, Sherer said. Foundation staff see all the projects so that if there are challenges with one project, the staff can determine if it is common across the disease. If needed, other experts may be consulted to find a solution to the challenge, Sherer said. The internal scientists at the foundation also work with investigators to set up milestones and to terminate projects if a particular approach is not working. In managing project risk, MJFF does not have an endowment, so each year it needs to return to its donors and justify what it has done. This means that the foundation needs to evolve as it learns from its fundraising and milestone histories to ensure that it is continuing to explore new and innovative areas. Also, as MJFF has grown, it has been able to take on more risk, said Sherer. Partnerships for Drug Development Foundations have influenced pharmaceutical companies by encourag- ing them to embrace novel models for risk sharing, said Sherer. However, development of these models takes time, flexibility, and perseverance. With regard to the need to change the way in which research tools are developed and to change strategies to make data accessible, “this is an area where the licensing and intellectual property [provisions] that universities have put into place are counterproductive and are overvaluing perhaps the commer- cial value of that asset,” Sherer said. “Restrictive-use licenses are limiting standardization and discouraging field-wide use.” Duplication of efforts is also wasting valuable resources, he noted. Finally, data availability is neces- sary, but it does not come for free. Data must be prepared, curated, stored, and distributed; and they have to be of sufficiently high quality to make these investments worthwhile, he said. Several examples of MJFF’s funding of projects in the early transla- tional pathway have resulted in clinical or pharmaceutical partnerships. The first one involved alpha-synuclein. In the late 1990s, genetic studies linked alpha-synuclein, a protein expressed in the brain, to Parkinson’s dis- ease. After foundation support of early validation work in animal studies ­ with a European company, the first clinical trial of an alpha-synuclein– based therapy started in 2012. MJFF has provided $2 million to this effort, and that investment led to almost $30 million of additional investment from venture capitalists. However, the translation process has been lengthy, consuming more than a decade. “Our goal is to try to take the risk on

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36 EFFICIENCY AND EFFECTIVENESS OF GENOMIC SCIENCE TRANSLATION innovative, novel ideas and help build data packages to get them to larger funders,” Sherer said. A second project involved the provision of a $5 million grant to a Vanderbilt University researcher. The funding allowed target validation, animal testing, and a drug discovery effort that has yielded a series of molecules targeting a neurotransmitter receptor for glutamate. In 2012, Vanderbilt University announced a major collaboration with Bristol-Myers Squibb to move the therapy forward into the clinic. In this case, MJFF will receive a portion of the licensing fee and will allocate it to direct further investments in its research, which is the first time that it has used this model, said Sherer. Sherer described another program that is developing a novel drug to reduce dyskinesia, or impairment of the ability to control voluntary move- ment, which may appear as a lack of coordination, a common side effect of treatment in patients with Parkinson’s disease. MJFF funded early target validation work and formed a partnership with a company developing molecules that interact as an antagonist to glutamate receptor 5. The com- pany recently completed a Phase II trial showing the efficacy and safety of the drug for use as a treatment for dyskinesia in patients with Parkinson’s disease, and both parties are working to find a pharmaceutical partner. MJFF will also take risks on technical approaches for therapeutic development. It formed a collaboration with Ceregene to conduct a series of clinical trials on a gene therapy approach focused on neurotropic factors, said Sherer. Results from this study are expected in 2013. Development of Research Tools In addition to these research projects, Sherer described the development of research tools to accelerate the translational process. The Parkinson’s Progression Markers Initiative is a large-scale natural history and bio- marker study for patients newly diagnosed with Parkinson’s disease. MJFF has invested $45 million to bridge the gap between industry, nonprofit organizations, and private individuals. Data are available through a website in real time, as are biological samples. Thirteen pharmaceutical partners are now helping to support the study and the use of the data, which are available to all researchers. MJFF is also investing in laboratory tools to accelerate the development of therapeutics for Parkinson’s disease outside of the traditional model of providing a grant to an academic laboratory. For example, through a col- laboration with The Jackson Laboratory, MJFF provides openly available animal models generated by any grantee. These models are thoroughly characterized and housed at The Jackson Laboratory. Similarly, it has sup- ported the development of research tools like viral vectors and antibodies ­

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ROLE OF ADVOCACY 37 and made them available as well. One advantage of this initiative is that people are using the same tools so that data can be compared across l ­aboratories, Sherer said. Finally, Sherer described the Fox Trial Finder, which matches ­ olunteers— v both those with Parkinson’s disease and controls—to clinical trials. Match- ing is based on demographic characteristics, medication history, diagnosis duration, and other attributes. Volunteers can connect directly—online and anonymously—with members of a trial team through secure messaging to learn more. Almost 12,000 people signed up for the trial finder in the course of a year. MJFF is working to extend the tool from English-speaking coun- tries to other countries. “The idea is to have volunteers at the ready as you launch new trials and studies,” Sherer said. A Drug Development Ecosystem Patient advocacy groups are part of a much larger ecosystem, which Furlong defined as a community of stakeholders (universities, companies, patient organizations, patients, and government agencies) that exist in con- junction with the nonliving components of their environment (e.g., regula- tions, economic factors, reimbursement potential), all of which interact as a system. PPMD seeks to fill in or strengthen the missing or weak pieces of the ecosystem, such as preclinical research, the clinical infrastructure, and education, and to accelerate interactions among the system’s components. It also seeks new paradigms that can deliver change more quickly than the existing system. PPMD has a patient advisory group that helps make decisions about which projects will be funded, and the groups tend to pursue projects that sound promising, even if those projects are risky. Engaging patients in deci- sion making helps them understand the process by which ideas are pursued and either accepted or rejected, said Furlong. The advisory group generates interesting ideas and discussion: patients “want to come to a table with people that they respect and feel that they have a definite interest in what they would like to accomplish,” Furlong indicated. The basic scientists “listen, and then they begin to think in a different realm, and sometimes new ideas are generated that make maybe a little more sense than the initial proposal. So it’s a way to engage the community,” said Furlong. Advocacy groups are changing, said Sharon Terry, Roundtable co-chair and president and chief executive officer of Genetic Alliance. Young parents do not necessarily sign up for a foundation and send in $50 per year. They join a Facebook group, find a local group at the library, or join affinity groups for other interests that their children share. People are aggregating themselves in ways that the disease groups have not yet prepared for, which will lead to the decline of groups that cling to old models, Terry said.

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38 EFFICIENCY AND EFFECTIVENESS OF GENOMIC SCIENCE TRANSLATION “Foundations can play an important role as a major player representing the patients in this ecosystem,” Sherer concluded. Foundations need to be part of the conversation on how the basic science research model needs to change to remind the community that the reason for funding bio­ edical m research is to help patients. He added that “we have highly motivated aca- demic researchers that volunteer their time, take lower indirect costs, share their tools, share their data, and are happy and excited in their careers to be a part of this effort. It’s [about] being part of something bigger than just their own projects.”