Juvenile Diabetes Research Foundation International Research ...

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  • Dayton will mention Complications as he discusses this slide
  • Dayton keep?
  • Optional to keep – Dayton call confirm
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    Dexcom & Insulet examples
  • Various subpopulations meaning: small children, teenagers, adults with long standing diabetes.
    Possible health plan partners meaning: insurance companies we would be working with to identify the data they need to evaluate benefits over CGM over fingerstick (also address concerns of direct blood glucose measurement vs. interstatial), all w/focus towards approval and reimbursement of health plans.
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    Health Advances report talked about the translational research funding gap.
    What is this?
    How does it affect us?
    What are solutions to bridge this gap?
    This is a good slide showing the bench to bedside continuum (discovery to delivery; taking discoveries and inventions from the laboratory to the patient.) & evolving world of academic institutions and industry in the drug discovery and development process & and the importance of technology transfer
    Need to know enough about research to talk with donors and pique their interest, for more in-depth conversation call in troops (Dayton, Tom) since we do not have a pre-packaged set of products.
    Mission – (fundamental) to find a cure for diabetes and its complications through the support of research.
    NEW ADDITIONAL LANGUAGE – JDRF will proactively drive the discovery, development and delivery of therapeutics to improve the lives of people with diabetes today and ultimately find a cure.
    JDRF is evolving. Thinking & capabilities of research dept. are evolving
    Discovery, development and delivery of therapeutics – JDRF no longer just funding research.
    For years JDRF has been investing in basic exploratory reserarcgh primarily at academic institutions.
    JDRF needed to be involved along every step of the way
    JDRF launched IDDP – industry will develop product and deliver it to pts.
    Eg. APP – clinical trials, advocating coverage & educating clinicians.
    Exploratory Research – Path evaluation
    Up to 1 yr. ago 95% or research was Discovery Research – begin to look at where we can intervene in the pathway of the disease to see what we can do better. (causes & mechanisms of disease)
    Translational – academic lab and begin to translate into therapeutic
    Clinical Research - proof-of-concept trials (JDRF really investing in this area.) BIG GAP. Molecules are safe & have beneficial effect on diabetes. Goal – get industry interested in therapeutic in order to bring to market.
    Clinical Trials – Safety & efficacy trials.
    For the first time JDRF investing in Phase 3 clinical trials (anti-CD3)
    Industry partnership – if JDRF helps increase the value of a company or develop product, JDRF will get revenue stream that will then be invested in research.)
    Research Dept. Personnel changes – new skill set added to research dept to think of ourselves as a therapeutic development organization instead of the past view as a grant-making organization
    New staff has understanding of how to develop drugs and bring them to market. (currently interviewing for a clinical director that understands regulatory process of clinical trials.)
    Phase I, II, III – (define) safety, efficacy
    ANTI CD3 funded from initial stages of discovery through present clinical trials. (JDRF fortunate to have funded grants along the way, but did not drive these studies. THIS WILL NEVER HAPPEN AGAIN – JDRF will be proactively driving)
    Repositioning drugs currently on market for other indications to test for use in t1d.
    IDDP – there aren’t that many compaines developing producvtys for diabetes because it’s a hard dieseas to develop products for.
    Academic discoveries often stay in academia because they do not have the experience with getting companies interested in continued development of the product.
    JDRF filling gaps.
    As we become more sophisticated and portfolio becomes more involved, go-to org, it is going to take an increasing larger amount of money to enable JDRF to have this level of influence in the market. (need $$ and staff expertise)
    JDRF clout to be involved w/ other players in the commercial development of therapies.
    Hard to develop products for diabetes. GAP - Tech transfer – ideas transferred out of academic setting into a company. (WHAT DO YOU HAVE TO DO TO IMPROVE THE CHANCES OF GETTING IDEA OUT OF ACADEMIC SETTING AND PICKED UP BY INDUSTRY?)
    JDRF needs to do leg work to fill this gap.
  • Islet Replacement:
    • Industry partner differentiates Embryonic Stem Cells into insulin-producing cells.
    The biotechnology company Novocell, Inc. developed a way to convert human embryonic stem cells into insulin-producing cells. JDRF helped fund this work. Novocell advanced the field by differentiating the embryonic stem cells through discrete stages of development, and characterizing the cells at each stage. This work, while important, does not achieve the ultimate goal of creating insulin-secreting cells that could function as islets. Novocell noted that only a small fraction of the cells it produced secreted insulin, and the amount of insulin produced was too small to cure diabetes. In addition, the cells were not glucose-responsive, meaning they did not produce insulin in response to blood sugar. Still, the advance is an important step toward producing an unlimited source of insulin-secreting cells to treat diabetes. The results were published in the journal Nature Biotechnology. (October 2006)
    • Harvard scientists find that Natural Killer (NK) cells, knocked-out under current immunosuppressive protocols, may actually reduce the chance that transplanted tissue will be rejected
    JDRF-funded researchers at Harvard Medical School have made a surprising discovery about certain immune cells that could improve the outlook for islet replacement therapies. The scientists found that the cells, called Natural Killer (NK) cells, reduce the chance that transplanted tissue will be rejected. Knocking them out—as current immune-suppressing therapies do—may be a mistake. The researchers found that NK cells in the transplant recipient destroy cells in the implanted tissue that migrate to the recipient’s lymph nodes and stimulate a powerful immune response, resulting in rejection of the graft. The study was led by Xian Li, M.D., Ph.D., at Harvard Medical School and published in the Journal of Experimental Medicine. (August 2006)
    • Researchers at two JDRF islet transplant centers were able to reverse diabetes in monkeys by transplanting islet cells from pigs.
    Researchers at two JDRF islet transplant centers were able to reverse diabetes in monkeys by transplanting islet cells from pigs, providing encouragement to people with type 1 diabetes that therapies with an expandable supply of healthy islets may become available. The milestone studies, conducted at the University of Minnesota and the Emory University School of Medicine in Atlanta, were reported in the journal Nature Medicine. They showed that a combination of immunesuppressing drugs allowed the transplanted pig islets to avoid rejection and survive for several months. (February 2006)
    • JDRF-funded researchers in San Diego have discovered that non-secreting tissue in the pancreas can be transformed into insulin-producing cells.
    JDRF-funded researchers in San Diego have discovered that non-secreting tissue in the pancreas can be transformed into insulin-producing cells. The finding suggests a new approach to treating diabetes by coaxing primitive cells in the pancreatic tissue to behave like beta cells. If researchers can grow beta cells for use in humans, there could be an unlimited supply of islets for transplantation. The research, led by Fred Levine at the University of California, San Diego and the Burnham Institute, was reported in the journal Nature Medicine. (February 2006)
  • Regeneration of native islet cells
    JDRF-funded researchers at the University of Massachusetts have identified a protein in beta cells that regulates the production of insulin.
    The finding suggests that a drug or therapy that increases the activity of this protein could enable people with diabetes to boost their own insulin production and better manage type 1 diabetes. The protein, IRE1, operates in beta cells within the endoplasmic reticulum (ER), a large, intracellular membrane folded over many times on itself. Most proteins are assembled inside the ER before being transported to other sites within the cell to perform specific tasks. IRE1 helps regulate the process by which the insulin protein is folded into final form so it can function properly. The finding was made by Fumihiko Urano, M.D., Ph.D., and colleagues at the University of Massachusetts Medical School and published in the journal Cell Metabolism. (September 2006)
  • Restoring immune tolerance
    • Discovery that single protein can switch a key component of the immune system on or off depending on which molecule it teams with, sheds light on what is involved in keeping the immune system in check, paving the way for researchers to develop therapies for type 1 diabetes and other autoimmune afflictions such as arthritis and allergies
    A single protein can switch a key component of the immune system on or off depending on which molecule it teams with, JDRF-funded researchers have found. The protein, NFAT, pairs with other proteins to either spur immune cells into attack mode or direct them to stand down. The discovery sheds light on what is involved in keeping the immune system in check, paving the way for researchers to develop therapies for type 1 diabetes and other autoimmune afflictions such as arthritis and allergies. The finding was reported by Anjana Rao, Ph.D., and colleagues at the JDRF Center for Immunological Tolerance in Type 1 Diabetes at Harvard Medical School. Scientists at the University of Southern California, the University of Colorado, and the University of Washington were also involved in the research, which was published in the journal Cell. (July 2006)
    • Using natural compounds derived from a shrub and the venom of a sea anemone, JDRF-funded researchers at the University of California-Irvine thwarted the autoimmune attack causing type 1 diabetes in experiments with human cells and animals.
    Using natural compounds derived from a shrub and the venom of a sea anemone, JDRF-funded researchers at the University of California-Irvine thwarted the autoimmune attack causing type 1 diabetes in experiments with human cells and animals. In the research, the compounds blocked an ion channel in immune T cells that plays a critical role in allowing the cells to multiply and gear up for an immune attack. These results in human cells and animals suggest that the ion channel could be an important target for diabetes therapies. The study, led by George Chandy, M.D., Ph.D., and Christine Beeton, Ph.D., showed that the compounds selectively stop white blood cells called effector memory T lymphocytes, which play a major role in type 1 diabetes and autoimmune diseases such as arthritis. Other white blood cells are left free to fight disease and infection. The results were published in the Proceedings of the National Academy of Sciences. (November 2006)
  • Complications
    • JDRF-funded researchers have identified a potential mechanism that may shed light on why some people with diabetes lose the ability to recognize and correct hypoglycemia (low blood sugar).
    JDRF-funded researchers have identified a potential mechanism that may shed light on why some people with diabetes lose the ability to recognize and correct hypoglycemia (low blood sugar). Gaining a better understanding of why this happens could lead to the development of treatments for this very serious complication, which can cause a loss of consciousness, and even death. In the study, Dr. Rory McCrimmon and colleagues at the JDRF Yale Center for the Study of Hypoglycemia found that when a protein in the brain, urocortin I, is produced at abnormally high levels, it may contribute to the inability to produce a normal response to lows. The researchers demonstrated in rats that a key glucosesensing region of the brain loses sensitivity after being exposed to urocortin I. The discovery, reported in the Journal of Clinical Investigation, is an important step toward clinical strategies that will block urocortin I’s effect in the brain and allow diabetes patients to sense when blood sugar has dropped too low. (June 2006)
    • A JDRF-funded research project at Columbia University Medical Center that goes back 16 years has taken a major step toward translation into therapies to treat diabetic complications such as eye, nerve, kidney, and blood vessel damage.
    A JDRF-funded research project at Columbia University Medical Center that goes back 16 years has taken a major step toward translation into therapies to treat diabetic complications such as eye, nerve, kidney, and blood vessel damage. Two pharmaceutical companies, Pfizer, Inc., and TransTech Pharma, reached a licensing agreement to develop and commercialize drugs targeting a molecule called RAGE, which has been linked to diabetic retinopathy, nephropathy, neuropathy and heart disease—not to mention nondiabetic conditions such as Alzheimer’s disease and cancer. The agreement will help fund Phase III clinical trials to accelerate the pace of testing of RAGE in chronic disease, where it appears to play a key role. RAGE (Receptor for Advanced Glycation Endproducts) was first identified in 1990 by Ann Marie Schmidt, M.D., a JDRF-funded researcher and chief of the Division of Surgical Science at Columbia. (September 2006)
  • Metab olic Control
    • Grants Awarded in JDRF Artificial Pancreas Project
    In September 2006, JDRF announced grants exceeding $5.5 million in the first year alone to fund research assessing new diabetes technologies to accelerate their availability for patients. The funding will support a multi-site clinical trial to compare health outcomes of people who use continuous glucose sensors with those who do not, to quantify the benefits of these devices. The funding also will support a multi-site research consortium that will work collaboratively to research potential algorithms for a closed-loop system that links continuous glucose sensors and insulin pumps to automatically dispense
    insulin to patients with type 1 diabetes. (September 2006)
  • Juvenile Diabetes Research Foundation International Research ...

    1. 1. Juvenile Diabetes ResearchJuvenile Diabetes Research Foundation InternationalFoundation International Research Update Dayton Coles JDRF Central Pennsylvania ChapterJDRF Central Pennsylvania Chapter May 16, 2007May 16, 2007
    2. 2. What we’ll talk aboutWhat we’ll talk about  JDRF Research FundingJDRF Research Funding  Cure GoalsCure Goals  RegenerationRegeneration  Artificial PancreasArtificial Pancreas  JDRF’s Research Focus: TherapeuticsJDRF’s Research Focus: Therapeutics
    3. 3. My Connection to Type 1My Connection to Type 1
    4. 4. How Research Has Made aHow Research Has Made a DifferenceDifference  People with type 1 are living longer thanPeople with type 1 are living longer than ever beforeever before  The risk of complications is declining forThe risk of complications is declining for type 1type 1  Tight control of blood glucose is moreTight control of blood glucose is more achievable than everachievable than ever
    5. 5. JDRF Research FundingJDRF Research Funding  FY2005FY2005 $98 Million$98 Million  FY2006FY2006 $122 Million$122 Million  FY2007FY2007 $140 Million (estimate)$140 Million (estimate)
    6. 6. JDRF Funded ResearchJDRF Funded Research (FY06)(FY06)  AutoimmunityAutoimmunity $41 million$41 million  ComplicationsComplications $26 million$26 million  Islet ReplacementIslet Replacement  TransplantTransplant $21 million$21 million  Cell SourcesCell Sources $20 million$20 million  RegenerationRegeneration $8 million$8 million  MetabolicMetabolic ControlControl $6 million$6 million TOTAL:TOTAL: $122 million$122 million
    7. 7. JDRF’s Cure Goal PathwaysJDRF’s Cure Goal Pathways  Islet Cell ReplacementIslet Cell Replacement (Transplantation &(Transplantation & Source)Source)  Regeneration of Native Beta CellsRegeneration of Native Beta Cells  Restoring Immune ToleranceRestoring Immune Tolerance  ComplicationsComplications (Preventing & Treating)(Preventing & Treating)  Metabolic ControlMetabolic Control (Continuous Glucose(Continuous Glucose Monitoring, Artificial Pancreas)Monitoring, Artificial Pancreas)
    8. 8. Therapeutic StrategiesTherapeutic Strategies Defeat Autoimmunity Regenerate Beta cells Replace Restore Metabolic Control Restore Beta Cell Function
    9. 9. Replacing Beta CellsReplacing Beta Cells Precursors Beta cells Beta cells Neogenesis ReplicationIslets • Cadaver (ex-vivo expanded) • Stem cell-derived • Reprogrammed (liver, K cell) • Xeno (pig, fish) • Encapsulation • Pancreas-derived • Reprogrammed Defeat Autoimmunity Restore Metabolic Control Restore Beta Cell Function
    10. 10. Regeneration ofRegeneration of Native Beta CellsNative Beta Cells
    11. 11. Can beta cell regeneration occur inCan beta cell regeneration occur in patients with long standing diabetes?patients with long standing diabetes?  Many long-standing diabetes patients have detectable C-peptide  Research shows islets can expand under different circumstances, like pregnancy and significant weight gain  Animal experiments indicate life-long cell generation  Post-mortem exams have shown insulin-positive cells in islets in long-standing diabetes patients
    12. 12. Can beta cell regeneration occur inCan beta cell regeneration occur in patients with long standing diabetes?patients with long standing diabetes?  Beta cell regenerative capacity may remain clinically masked by  Poor glycemia control and/or other metabolic factors  Residual anti-beta cell specific autoimmunity  Increase by directing careful attention to:  Glycemia and lipid control  Efforts to control anti-beta cell autoimmunity  Delivering factors thought to promote beta cell proliferation or survival in vivo
    13. 13. NeogenesisNeogenesis ReplicationReplication Cell DeathCell Death Beta Cell MassBeta Cell Mass (New Beta Cell Generation from Precursors) (Cell Division) ExocrineExocrine DuctDuct Therapeutics: Metabolic Control Immune Tolerance Regeneration
    14. 14. Artificial Pancreas ProgramArtificial Pancreas Program
    15. 15. A1Cs Are High Even for Children withA1Cs Are High Even for Children with Highly Involved ParentsHighly Involved Parents A1C results for 563 respondents in CWD surveyA1C results for 563 respondents in CWD survey <6.5 6.6-7.0 7.1-8.0 8.1-9.0 >9.0 13%13% 15%15% 40%40% 24%24% 8%8% 73% are above the ADA recommended goal and 90% are above the recommended AACE goal - and these are among the most committed patients and families in the world.
    16. 16. Tremendous PotentialTremendous Potential Artificial pancreas technologies have the potential to revolutionize diabetes care  Prevent highs that lead to heart attacks, amputations, blindness  Prevent life threatening lows  Improve quality of life  Facilitate other cure goals (e.g., regeneration)
    17. 17. 17 Continuous Glucose MonitorContinuous Glucose Monitor Look at the Difference in 9 DaysLook at the Difference in 9 Days With CGM Use, 26% More Time in Normal Glucose RangeWith CGM Use, 26% More Time in Normal Glucose Range Diabetes Care 29:44-50.
    18. 18. Continuous Glucose Sensor Insulin Pump Control - Algorithm What is an ArtificialWhat is an Artificial Pancreas?Pancreas?
    19. 19. APP Project Goals  Accelerate the availability of a first generation artificial pancreas  Ensure the artificial pancreas and its components are available to the majority of people with type 1  Ensure devices from multiple companies are approved and reimbursed, encouraging investment in next generation technologies
    20. 20. APP/CGM Trials StatusAPP/CGM Trials Status Two tracks currently funded:Two tracks currently funded:  Track One: continuous glucose sensors  Track Two: artificial pancreas Will Examine:Will Examine:  Patient outcomes, e.g. HbA1c, hypoglycemia  Economic benefits, e.g. fewer hospitalizations  Quality of Life  Various subpopulations  Possible health plan partners
    21. 21. JDRF ApproachJDRF Approach  Patient focused, independent from industry  Commission independent, empirical research  Assess patient outcomes from use of artificial pancreas technologies  Answer regulator and payer questions  Engage with key decision makers  FDA – Critical Path Opportunity List  Center for Medicare and Medicaid Services  Congress  Private insurers  Physicians
    22. 22. Product Development Studies and Trials Coverage and Reimbursement Health Care System Acceptance Patient Acceptance and Use Steps to Widespread AvailabilitySteps to Widespread Availability
    23. 23. JDRF’s Research FocusJDRF’s Research Focus
    24. 24. “Proactively accelerate the discovery, development, and delivery of disease- modifying therapeutics to better treat and cure type 1 diabetes and its complications.” JDRF StrategyJDRF Strategy
    25. 25. From Discovery to TherapiesFrom Discovery to Therapies Exploratory Research Discovery Research Preclinical Research Clinical Research Clinical Trials Regulatory Launch/AccessClinical DevelopmentTranslational ResearchBasic Research Outcome Studies 3rd Party Coverage • Screening/ rationalScreening/ rational drug designdrug design • Lead optimizationLead optimization • Proof-of-conceptProof-of-concept in animal modelsin animal models • Safety studiesSafety studies • TargetTarget identification/videntification/v alidationalidation • PathwayPathway evaluationevaluation • Insights toInsights to diseasedisease processprocess • HumanHuman proof-of-proof-of- conceptconcept testingtesting • Safety and efficacy studiesSafety and efficacy studies • Phases I, II, IIIPhases I, II, III • AcademiaAcademia • AcademiaAcademia • IndustryIndustry (limited)(limited) • AcademiaAcademia (evolving)(evolving) • IndustryIndustry • IndustryIndustry • AcademiaAcademia (evolving)(evolving) • IndustryIndustry
    26. 26. Recent DevelopmentsRecent Developments  Islet Cell ReplacementIslet Cell Replacement  Industry partner differentiates Embryonic Stem Cells into insulin-producing cells  Harvard scientists find that Natural Killer (NK) cells, knocked-out under current immunosuppressive protocols, may actually reduce the chance that transplanted tissue will be rejected  JDRF-funded researchers in San Diego have discovered that non-secreting tissue in the pancreas can be transformed into insulin-producing cells.  Xenotransplantation: Trials launched and FDA discussions have been initiated  Cadaver Islet Transplantation: Grant activated
    27. 27. Recent DevelopmentsRecent Developments  Regeneration of Native Beta CellsRegeneration of Native Beta Cells  JDRF-funded researchers at the University of Massachusetts have identified a protein in beta cells that regulates the production of insulin.  New RFA launched on physiologic beta cell regeneration  Academic R&D grants under development with Broad, Harvard, Stanford, etc  GLP-1/Gastrin preclinical studies completed and trial has launched  Insulin-Making Protein identified in Beta Cells 
    28. 28. Recent DevelopmentsRecent Developments  Restoring Immune ToleranceRestoring Immune Tolerance  Discovery that single protein can switch a key component of the immune system on or off depending on which molecule it teams with, sheds light on what is involved in keeping the immune system in check, paving the way for researchers to develop therapies for type 1 diabetes and other autoimmune afflictions such as arthritis and allergies  Using natural compounds derived from a shrub and the venom of a sea anemone, JDRF-funded researchers at the University of California-Irvine thwarted the autoimmune attack causing type 1 diabetes in experiments with human cells and animals.  Rituxan trial launched, ATG trial to launch, IL1RA and AAT trials in development  Innate Immunity Program launched  Resource creation: Network for Pancreatic Organ donors with Diabetes to launch 
    29. 29. Recent DevelopmentsRecent Developments  ComplicationsComplications  JDRF-funded researchers have identified a potential mechanism that may shed light on why some people with diabetes lose the ability to recognize and correct hypoglycemia  A JDRF-funded research project at Columbia University Medical Center that goes back 16 years has taken a major step toward translation into therapies to treat diabetic complications.  Dr. Lloyd Aiello of the Joslin Diabetes Center has shown that the compound ruboxistaurin slowed the progress of retinopathy by inhibiting an enzyme in the body called protein kinase C beta (PKC beta), which is believed to contribute to the blood vessel damage that leads to the disease.  This is the first time a drug has been shown to protect against the complication in a human clinical trial. 
    30. 30. Recent DevelopmentsRecent Developments  Metabolic ControlMetabolic Control  JDRF CGM Clinical Trial launched with enrollment initiated January  Funded six site Artificial Pancreas Project Consortium  JDRF-FDA dialogue: Resulted in removal of Investigational Device Exemption – saving considerable time and resources “Critical Path” Initiative February meeting began to define pathway and approval metrics 
    31. 31. What You Can DoWhat You Can Do  Pay attentionPay attention  Time and TreasureTime and Treasure  Advocate – NIH funding and APPAdvocate – NIH funding and APP  Clinical TrialsClinical Trials  OtherOther
    32. 32. QuestionsQuestions

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