Accelerating Progression to Type 1 Diabetes Prevention - JDRF Initiative

1. Progression to Type NoneJessica Dunne, Ph.D.Director, ResearchJDRF

2. Jessica Dunne, Ph.D. Joined JDRF in September 2008, Lead for Prevention program since its inception in July 2012 14 yrs in immunology/inflammation/vaccine research including in the pharma and biotech sectors Sister-in-law (mis)diagnosed as adult 3 years ago. Hello… Accelerating Progress

3. JDRF – what motivates us? Accelerating life-changing breakthroughs to cure, prevent and treat type 1 diabetes and its complications A world without type 1 diabetes Vision Mission

4. TYPE 1 DIABETES Overview Accelerating Progress

6. THE PLAN Accelerating Progress Across the Pipeline Moving scientific discoveries from the laboratory to the real world (Clinical Trials) Ensuring treatments are affordable and accessible Identifying new approaches to cure, prevent and treat T1D and its complications Creating FDA approval pathways for new T1D treatments Expanding access to the latest T1D therapies through education Delivering treatmentsto people with T1D Accelerating Progress

7. Jdrf’s capabilities RESEARCH PARTNERSHIPS IMPROVED OUTCOMES INTERNATIONAL REACH (foundations)

8. T1D is on the rise • Number of US youth <20 years with T1D projected to increase 3.3-fold by 2050 Diabetes Care 35 (12), 2515 (2012)

9. What is the risk for developing type 1 diabetes among family members compared to the rest of the population? no difference 3X greater risk 15X greater risk

10. Staging and Screening

11. T1D Disease Progression Starting Point Genetic Risk The path to T1D starts here Everyone who is diagnosed with T1D has the gene(s) associated with T1D General population risk is 1 in 300 Family members are at 15x greater risk to develop T1D Relative risk is 1 in 20 1 300 1 20

12. T1D Disease Progression Progression by Population: • Essentially everyone with 2 or more autoantibodies will continue to progress towards clinical symptoms • T1D starts when you develop two or more autoantibodies Genetic Risk Immune Activation Starting Point If you have a relative: 15x greater risk of developing T1D Immune Response Immune Activation Beta cells are attacked Immune Response Development of single autoantibody Type 1 Diabetes

13. T1D develops in predictable stages • For people with 2 or more autoantibodies, the risk of developing symptomatic T1D is: • 51% within the next 5 years • 75% within the next 10 years • Almost 100% within the next 20 years JAMA 309 (23), 2473-2479 (2013) Diabetes Care 38 (10), 1964-1974 (2015)

14. Why Screen if No Preventative Therapy Currently Exists? • Significantly reduced risk for DKA in TEDDY antibody positive individuals • Up to 36% DKA at diagnosis in general population • As low as 4-5% in with screening and monitoring (unpublished) • Reduction of DKA can result in better long-term glucose control and lower HbA1c • Prevention trials launched and launching • Moving the field forward through better understanding of disease progression

15. Childhood population-based risk screening: Age 3 and 4 years may be an optimal age in Germany Incidence of islet autoantibodies in cases with multiple Abs amongst unselected FDRs 25 20 • IsletAAbseroconversion • (case per 1,000 person-years) 15 10 5 95% CI 0 0 2 4 6 8 10 12 14 16 18 Age (year) 2/3 of multiples islet autoantibodies occur before age 4 years (JAMA). ~ 90% of youth T1D is after age 3 years Ziegler, Diabetologia 2012

16. Screening can identify people at risk

17. T1D Disease Progression Importance of staging • Accelerate the clinical development of therapies by providing a common framework for • Regulators, funders, academia and industry • Identification of T1D in it’s earliest stages can lead to a decreased risk of diagnosis in DKA • Staging diabetes allows us to treat T1D early to delay progression and ultimately prevent stage 3 (symptomatic T1D) • Treating high blood pressure, allows us to treat the disease early and ultimately prevent a heart attack or stroke

18. The Plan for a World without T1D Does someone in your family have T1D? • Risk of T1D in relatives of individuals with T1D • Identical Twin: 30-70% • Multiple Affected First Degree Relatives: 20-50% • Sibling: 8% (but if HLA risk genes identical:30-70%) • Offspring • Father: 5% • Mother: 3% • If no Family Hx- General Population: 0.4% (but if HLA risk genes: 4%) (Only 10-15% of newly diagnosed cases of T1D have a relative with T1D)

19. TrialNet Disease Intervention P2P Pathway to Prevention Determine where you are on the path No cost 1st and 2nd degree relatives Screens for autoantibodies Based on results Look to enroll in clinical trial to preserve beta cell function Or monitor for disease progression Scott & Adam Pathway to Prevention Participants Keilyn Pathway to Prevention Participant Brooke, Emily & Ava Pathway to Prevention Participants

20. TrialNet Disease Intervention P2P Pathway to Prevention Eligibility Requirements Anyone between age 1 and 45 with a sibling, child or parent with type 1 Anyone between age 1 and 20 with a sibling, child, parent, cousin, uncle, aunt, niece, nephew, grandparent or half-sibling with T1D Those under 18 who do not have autoantibodies can be retested every year Tracy Rodriguez TrialNet Coordinator, UCSF

21. Big Data

22. CONFIDENTIAL JDRF-IBM Watson Partner for T1D Modeling

23. CONFIDENTIAL pre-TEDDY Cohorts Will Provide Initial Data DAISY 1993 – 2004 Colorado, USA •Children at increased genetic risk for T1D followed from birth DEW-IT 2002 - Washington, USA • Cohort of children screened for HLA risk using newborn dried blood spot and followed for Ab surveillance DIPP 1994 – 2009 Finland • Children at increased genetic risk for T1D followed from birth to age 15 years DiPiS2000 – 2004 Sweden • Children with genetic risk for T1D followed from birth for 15 years

24. CONFIDENTIAL Announcement has Generated Significant Interest

25. Microbiome

26. What is the gut microbiome? • We have 10x more bactetrial cells in our bodies than human cells • We are walking ecosystems! • These microbes are integrated into our biology: they help us digest food, shape our immune system, alter our metabolism and evidence is even starting to show that they affect the nervous system, influencing our mood and behavior.

27. Gut microbiome is altered in T1D Detection of 2+ autoantibodies Symptom onset • Gut microbiome is associated with immunity • It develops differently in those who progress to symptomatic T1D • There could be a connection between the microbiome and T1D Cell Host & Microbe 17, 260-273 (2015)

28. Gut Microbiome in T1D Key Messages • Our guts are made up of trillions of microbes that play important roles in our biology • Through modern day practices, we may have altered our gut microbiomes in such a way to alter biological processes. • The rate of T1D has been increasing worldwide and may be linked to changes in the microbiome • If we could reset the microbiome at an early age, we may be able to prevent or delay the onset of T1D in some individuals. 30

29. Virus and disease etiology

30. Enteroviruses RATIONALE: • Enterovirus detected in new onset T1D pancreas (nPOD-V, DiViD); Islet cell damage in fatal enterovirus infections; Genetic association (IFIH1) • Viral infections precede onset of T1D autoimmunity in some cases GAPS & POTENTIAL CHALLENGES: • Need to confirm number of causative serotypes • Industry commitment to vaccine development • Go/no-go data

31. Enterovirus infection is linked to T1D • Enterovirus infections before autoantibodies are detected (ie, before stage 1) are more common in people who later develop T1D • There are many factors involved and researchers are working to understand them better Stage 1: detection of 2+ autoantibodies Diabetes 60, 276 (2011)

32. nPOD Viral Group Type 1 Diabetes Enterovirus Vaccine: JDRF’s Role • Funding additional epidemiological studies to strengthen the case for vaccine development • Funding studies to detect viruses in pancreas in T1D and explore role for chronic viral infection in T1D (nPOD-V) • Build the business/regulatory case

33. The Plan for a World without T1D The goals of nPOD are to: • Maintain a network of procuring and characterizing, in a collaborative manner, pancreata and related tissues (spleen, lymph node, pancreatic lymph node, peripheral blood) from cadaveric organ donors with type 1 diabetes as well as those whom are islet autoantibody positive. • Utilizing these tissues, investigators will work together to address key immunological, histological, viral, and metabolic questions related to how type 1 diabetes develops • To find out more information about nPOD, please visit www.jdrfnpod.org

34. The Plan for a World without T1D Vision Plan Capabilities Your Support

35. The Plan for a World without T1D For more information about preventing T1D • www.jdrf.org • www.pathway2prevention.org • www.jdrfnpod.org • www.askhealth.org

36. Summary • Prevention is important • And getting more important as T1D incidence increases • Tools are now available that enable prevention • Staging paradigm shows a predictable course for T1D • Screening efforts are identifying people at risk • NewT1D biomarkers are providing better screening tools • Therapeutic approaches are being discovered • Emerging from investigation of potential triggers including microbiome alteration and viral infection • Emerging from JDRF efforts in Immune Therapies, b Cell Survival Therapies and Metabolic Control • JDRF is not in this alone • Partnering adds additional dollars, expertise and perspectives

37. What is the risk for developing type 1 diabetes among family members compared to the rest of the population? no difference 3X greater risk 15X greater risk

38. e: jdunne@jdrf.org o: (212) 479-7595 m: (917) 574-8056 New York, NY The Plan for a World without T1D Jessica Dunne, Ph.D. Director, Discovery Research