1. Progression to Type None Jessica Dunne, Ph.D. Director, Research JDRF

2. Hello… 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.
Accelerating Progress

3. JDRF – what motivates us?
Vision
A world without type 1 diabetes
Mission
Accelerating life-changing breakthroughs to
cure, prevent and treat
type 1 diabetes and its complications
Today, JDRF is engaged in more activities across the globe than ever before. But our vision remains that of our founders – a world without type 1 diabetes.
JDRF remains relentless in our pursuit of a cure. At the same time, we are committed to keeping people with T1D healthy until we have that cure.
The goal of a cure for T1D and its complications is also captured in our mission statement, which also reflects JDRF’s goals of accelerating life changing breakthrough to prevent and treat the disease.

4. TYPE 1 DIABETES
Overview
Accelerating Progress

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

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

8. T1D is on the rise
Number of US youth <20 years with T1D projected to increase 3.3-fold by 2050
T1D is on the rise
We don’t know exactly why T1D develops, or why the incidence is increasing, though it’s likely that environmental impacts (largely unknown) are involved
We need effective risk detection and prevention to stop this trend
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 20 1
300

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
Blood sugar
Normal
Abnormal
Symptoms No
Yes
Autoantibodies 2+
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
We do know that T1D begins well before symptoms develop and we have learned a lot about the earliest stages of T1D
Stage 1: normal blood sugar, no symptoms
Stage 2: abnormal blood sugar, no symptoms
Stage 3: abnormal blood sugar, symptoms become apparent
These stages are characterized by the presence of two or more autoantibodies
Autoantibodies are antibodies against one’s own proteins
Four major different autoantibodies are associated with T1D and can appear years or even decades before symptoms of T1D appear
The number of autoantibodies is a strong predictor of developing the disease -- someone who tests positive for multiple autoantibodies is more likely to be diagnosed with T1D down the road
By screening for the presence of autoantibodies, we can detect and monitor T1D
JAMA 309 (23), (2013)
Diabetes Care 38 (10), (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
95% CI 10 5 15 20 25 6 4 2 14 12 8 16 18
(case per 1,000 person-years)
Islet AAb seroconversion
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
Screening for autoantibodies can help to identify T1D in its earliest stages
This enables us to:
avoid episodes of diabetic ketoacidosis (DKA) and subsequent hospital stays
develop/investigate interventions to change the course of the disease or to stop disease progression by preserving beta cell production
Autoantibody screening for T1D is currently recommended in first-degree family members of a person with T1D by the ADA Standards in Medical Care of Diabetes 2017
JDRF supports screening and monitoring programs worldwide
Autoantibodies are currently the best biomarkers we have for T1D

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. 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)
The Plan for a World without 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. JDRF-IBM Watson Partner for T1D Modeling
CONFIDENTIAL

23. pre-TEDDY Cohorts Will Provide Initial Data
DAISY 1993 – 2004 Colorado, USA
•Children at increased genetic risk for T1D followed from birth
DEW-IT 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
DiPiS 2000 – 2004 Sweden
• Children with genetic risk for T1D followed from birth for 15 years
CONFIDENTIAL

24. Announcement has Generated Significant Interest
CONFIDENTIAL

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
The human gut hosts a community of trillions of microbes that play important roles in our biology, called a microbiome
Through modern day practices, we may have altered our gut microbiomes in a way that likely affects biological processes
Recent publications and unpublished observations confirm that alterations in gut microbiomes have a role in T1D
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
JDRF has catalyzed this field in T1D and published a review article on the topic through the JDRF Microbiome Consortium (Clin Exp Immunol 177; 2014)
We are trying to better understand the complex interactions between the gut microbiome and the human body in order to develop rational approaches to prevent or delay the development of T1D
The microbiome may also serve as a biomarker to assess T1D susceptibility and progression or to evaluate the efficacy of interventions
Cell Host & Microbe 17, (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.
This slides is a summary of the key messages to communicate about the JDRF prevention R&D program that were reviewed in this presentation. 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
Business case
Regulatory environment
Reimbursement
Long term safety Overcoming fear of vaccination (lawsuits)

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
Enterovirus infections before autoantibodies are present (ie, before Stage 1) have been linked to development of T1D
If we could protect against enterovirus infection, we may be able to prevent or delay the onset of T1D in some individuals
It would be very difficult to prove directly that enterovirus infection causes T1D in people but we can look for evidence to support this link in order to encourage development of a vaccine against enteroviruses that could prevent or delay onset of symptomatic T1D
JDRF is funding studies to:
Detect viruses in the pancreas in people with T1D
Explore role for chronic viral infection in T1D
Identify which viruses are involved in T1D
Evaluate how the timing of viral infection relates to the development of T1D
Understand how viruses affect the immune system and the pancreas
Stage 1: detection of 2+ autoantibodies
Diabetes 60, 276 (2011)

32. 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
nPOD Viral Group

33. 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
The Plan for a World without T1D

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

35. For more information about preventing T1D
The Plan for a World without T1D

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. Jessica Dunne, Ph.D. The Plan for a World without T1De:
o: (212)
m: (917)
New York, NY
Director, Discovery Research
The Plan for a World without T1D