Update on Type 1 Diabetes Trials to Save Beta Cells

Benaroya Research Institute Carla Greenbaum MD Seattle, WA Update on Type 1 Diabetes Trials to Save Beta Cells 1552 BC earliest written record of DM 1 st Breakthrough in understanding: 1889 The problem is within the pancreas Cure for diabetes insulin: 1922 insulin 33 yrs Not much change for next 50 years! Human Insulin Home Glucose Monitoring 1980 Marked changes in therapy Insulin pumps DCCT CGMS 1970 1990 2000 2010 DKA in type 1 diabetes in US (Rewers A, Pediatrics, May 2008) 54% hospitalized at time of diagnosis 29.4% - DKA at diagnosis Related to $, but > from families with $$$ present in DKA No change in ~20 years Hospitalization for DKA <age 45: almost doubled from 1980 2003 (Maldonado, Diabetes Care, 2003) Where are We Today? Average A1c by Age, 2005-0606 T1D incidence is rising 3-5% per year Age Intensive Rx Hvidoere DCCT EDIC N=195 N=175 N=1,295^ Sweden (80% of the nation) Los Angeles N=1664 <6 7.5 8.0 7.8 6-12 7.9 7.8 8.2 13-18 8.1 8.4 8.6*^ 8.4 8.4* 8.6 BDC Denver N=3910 >18 7.1 7.9 8.0 7.8 *11-1818 yrs; ^the original 14 centers, unchanged compared to 1998 Barbara Davis Center Web Site: REWERS Incidence /100,000/ yr 70 in children aged 0-14 60 50 40 30 20 10 0 1950 1960 1970 1980 1990 2000 Finland Sweden Colorado Germany REWERS

Finland Type 1 Diabetes Incidence 1965-19961996 (32 years) Relative Percent Increase 350 Human Insulin Home Glucose Monitoring Insulin pumps 1970 1980 Genetic studies: HLA region: 73-75 Islet Cell Antibodies Pathology studies: Insulitis Insulin Autoantibodies 300 250 DCCT 1990 GAD65 antibodies, IA-2 200 150 100 50 0 Age 1-4 Age 5-9 Age 10-14 Diabetes Care: 22:1066-1070 CGM Marked changes in therapy 2000 2010 Znt8Ab Type 1 diabetes is an immune mediated disease Alopecia areata Ankylosing spondylitis Addisons disease Hemolytic anemia Autoimmune Hepatitis Thrombocytopenic purpura Behcets disease Pemphigus Crohns disease Dermatomyositis Lupus Graves disease Hashimotos Thyroiditis Autoimmune Diabetes Multiple sclerosis Myasthenia gravis Pernicious anemia Polyarteritis Polychondritis Polymyositis Psoriasis Rheumatoid arthritis Scleroderma Sjogren s syndroms Stiff man syndrome Giant cell Arteritis Ulcerative colitis Vasculitis Uveitis Vitiligo Autoimmune Diabetes Multiple Sclerosis Inflammation Wound Repair and Tissue Reconstruction Rheumatoid Arthritis; Lupus; Scleroderma; Polychondritis Type 1 Diabetes Shared Genes Shared Mechanisms

macrophage macrophage T Helper T Helper macrophage T Helpe r Invader Attack Resolution Rapid memory response T Helper TIME What goes wrong in autoimmunity? Failure of multiple Check Points Invader is really self and the immune system makes a mistake and starts the whole immune response

T Regulatory cells loose the battle with T killer (effector) cells Invader Attack Resolution Rapid memory response T Helper TIME Why does autoimmunity effect only some cells? Why does the immune system make a mistake? Everyone has some cells that recognize self Type 1 diabetes Multiple Sclerosis More survive Inflammatory Bowel Disease (Crohn s and Colitis) More susceptible to immune damage? Parts of these self mimic true invaders? Rheumatoid Arthritis More are made More are activated Likelihood of Autoimmunity Why do T regulatory cells loose the battle? T regulatory cells no good AND/ OR T effector cells too strong Clinical onset of disease

Save beta cells in those genetically at risk (Primary Prevention) Save beta cells in antibody positive subjects (Secondary Prevention) STOP progression to autoimmunity/beta Clinical onset of cell disease destructio STOP clinical disease Save beta cells after clinical disease (Tertiary Prevention-A) Save beta cells that are replaced after clinical disease (Tertiary Prevention-B) STOP complicati STOP Clinical onset complications of disease How long until NO detectable C-peptide? Persistence of Fasting C-peptide in Antibody Positive Youth % Preserved 100 90 80 70 60 50 40 30 20 10 DCCT: <0.07 pm DCCT NHANES 5 th : 0.33 pm NHANES 50 th : 0.63 pm NHANES 5th NHANES 50th 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Duration of Diabetes (Months) By 2 years: ~80% with C-peptide Even by 4 years.~50% still with 29 C-peptide N = 120 348 271 186 243 179 125 114 72 60 52 42 52 45 58 55 44 38 43 36 35 34 37 27 32 37 32 23 29 20 20 30 18 261

Three Key Requirements for Saving Beta cells at each stage Clinical onset of disease? 1. Know the natural history 2. Identify those at risk 3. Test therapies that balance risk/benefit Primary Prevention Studies 230 babies: First degree relative with T1DM: high risk genes When not breast feeding take hydrolyzed formula or regulator formula Role of the GUT and microbiome Hydrolyzed protein Hydrolyzed protein Pre-Point Point Study TRIGR study 9/109 diabetes 7/113 diabetes NIP study Knip et al, NEJM, 2010 TRIGR PILOT Full Study results to come No Difference Save beta cells after clinical disease (Tertiary Prevention-A) Tertiary Prevention Studies: Diabetes Stop complications Stop complications Clinical onset of disease Why preserve?

Diabetes Control and Complications Trial Does Intensive Diabetes Management (GOAL HbA1c <7%) reduce complications? YES But, this is done at the risk of hypoglycemia DCCT: NEJM, 1993 1993: marked reduction in retinopathy, nephropathy 2005: Marked reduction in cardiovascular disease DCCT: NEJM, 1993 Benefits of β-cell Preservation in DCCT Hypoglycemia with Coma/Seizure 62% Risk Reduction UNLESS you still have beta cell function!!!! Rate per 100 pt years 18 16 14 12 10 8 6 4 2 0 Ann Int Med 128:517-523, 1998 Diabetes 53:250-264, 2004 Conventional Intensive Intensive With insulin secretion No insulin secretion Cumulative Incidence (%) DCCT Intensive Therapy Group Sustained 3+ Step Retinopathy Progression 12 10 8 6 4 2 0 Risk Reduction: 79% (CI: 9, 95) p < 0. 012 No insulin secretion Year of Follow-up With insulin secretion 0 1 2 3 4 5 6 7 8 Diabetes 53: 550-264, 2004 TrialNet Why preserve? Among DCCT subjects in the intensive treatment group: Prevents short term complications Prevents long term complications 62% less hypoglycemia 79% Risk reduction in retinopathy

Glucose Control impacts beta cell survival Better diabetes control Poor diabetes control Halloran N Engl J Med 2004, 351: 2715-29 Preservation of Beta Cell Function by Monoclonal-Antibody Group Anti-CD3 Immune Tolerance Network (Macrogenics: Protege Studies) Anti T cell therapy Insulin Secretion Insulin Secretion Control Group 9/12 stable or increase 2/12 stable or increase [hokt3γ1(ala-ala)] Herold, KC et al, New England Journal of Medicine, 2002 C-peptide Preservation of Insulin Secretion with Rituximab * * pmol/ml Anti B cell therapy 0.4 0.5 0.6 0.7 0.8 *p < 0.020 0 3 6 12 in months * Overall p < 0.001 Ritux Placebo Antigen based therapy GAD65-Alum Alum Treatment 69 subjects, up to 18 months from diagnosis; Ages 10-1818 And lower HbA1c with less insulin 47 Diamyd: DiaPrevent Study Ludvigsson et al NEJM 2008 GAD65 Study 48

Selected Trials to report results 2011 Abatacept CTLA4-Ig Phase II(NIH TrialNet) Diamyd GAD-alum Phase III(Diaprevent) Phase III(European) Phase II(NIH TrialNet) DiaPep277 HSP peptide Phase III IL-2 + Rapamycin Phase I(NIH, ITN) Prochymal Mesenchymal stem Phase II Teplizumab Anti-CD3 Phase II/III(Protégé) Phase II (Protégé encoure) Phase II (NIH ITN, AbATE) Otelixizumab Anti-CD3 Phase III(Defend-1) 49 Selected new onset Trials underway Meticulous Glucose Control (TN and DirecNet) Anti-inflammatory Anakinra (Europe) Canakinumab (TrialNet) Alpha-1 antitrypsin (ITN) Proton pump inhibitor + DPP IV inhibitor (Sanford) Cord blood (UF, Gainesville) Thymoglobulin (ITN) Naturally processed peptides (DVDC, UK) 50 DirectNet Phase II trial: Metabolic Rest: closed loop pump and sensors B. Buckingham, Stanford Diagnosed within past week! Randomized trial NIDDK N~66 Primary Outcome: Insulin secretion at 1 year Effect of Intensive vs Conventional Therapy on β-cell Function Ann Int Med 128: 517-523, 1998 Conventional N = 303 With 1 5 y duration and C-Peptide 0.2 0.5 pmol/ml Risk Reduction 57% (CI: 39, 71%) P < 0.0001 Intensive UCLA, Yale, Stanford NICHD Palmer Save beta cells in antibody positive subjects (Secondary Prevention) Risk by the age of 20 years stop clinical disease Clinical onset of disease Risk group Autoimmunity T1 DM Population 1:30 1:300 Maternal offspring 1:15 1:50 Paternal offspring Siblings HLA-DR3/4,DQB1*0302 1:5 1:15 Monozygotic twins 1:1 (?) 1:3

Families with diabetes 10 ~5% 15x 100 Newly diagnosed patients with type 1 diabetes 90 Families without diabetes 0.3% Save beta cells in antibody positive subjects (Secondary Prevention) Previous large Studies ENDIT: Nicotinamide DPT-1: Parenteral Insulin DPT-1: Oral Insulin DIPP: Nasal Insulin 5 year risk estimates More antibodies = greater risk ICA+ relatives <25% Low ICA+, IAA+ relatives 25-50% 35% Intermediate ICA+ relatives with low beta cell function or IGT >50% 60% High Survival Distribution Function 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 n = 26799 4 ab 1 2 3 4 5 6 7 Years Followed 3 ab 1 ab 2 ab 8 QUESTION #1 Question There is no way to know who is going to get type 1 diabetes True or False We CAN determine an individual s risk for diabetes This is done by a combination of genetics (family history), antibody testing, and testing of insulin secretion and glucose.

Risk in Family members Number of antibodies increased risk Low insulin secretion increased risk Abnormal glucose increased risk Free tests available Question Who should get tested? a. My daughter has type 1 diabetes, my other children should be tested a. I should get tested. My cousin has type 1 diabetes a. I am an adult with type 1 diabetes. My kids are all grown they don t need to be tested. Answer : Who should get tested? X a. My daughter has type 1 diabetes, my other children should be tested. Your other children and you and her dad and aunts, uncles, cousins, nieces and nephews. X b. I should get tested. My cousin has type 1 diabetes c. I am an adult with type 1 diabetes. My kids are all grown they don t need to be tested. No, half of all type 1 diabetes occurs in adults. If you have a family member up to age 45, they should be tested (including grandkids!) Which family members should be screened? MOM (under age 45) Sisters and Brothers (under age 45) Nieces and Nephews (< age 20) DAD (under age 45) Children (< age 45) Grandchildren (< age 20) Half-sibling < age 20 Aunts and Uncles (< age 20) Cousins < age 20 1 ST 2 nd ST Degree relatives (ages 1-45) nd Degree relatives (ages 1-20) Blood draw ~4% positive Antibodies 1 ST 2 nd ST Degree relatives (ages 1-45) nd Degree relatives (ages 1-20) Blood draw ~4% positive Antibodies Very High Risk AntiCD3 Intermediate Risk Oral Insulin Low Risk Close monitoring Very High Risk Intermediate Risk Oral Insulin Low Risk GAD65-Alum GAD65-Alum

Save beta cells in antibody positive subjects (Secondary Prevention) Oral Insulin Oral Tolerance: Mode of Action Protective Cytokines Oral Antigen Clinical onset of disease Regulatory Lymphocytes Inhibition of β-cell Autoimmunity and Prevention of Diabetes Insulin Producing β-cells Autoimmune Lymphocytes Diabetes Prevention Trial type 1 diabetes <25% Low ICA+, IAA+ relatives ICA+ relatives 25-50% ORAL INSULIN Intermediate ICA+ relatives with low beta cell function >50% High Survival Distribution Function 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 DPT-1 Oral Study to Diabetes By Treatment 0 1 2 3 4 5 6 7 Diabetes Care 2005; 28:1068-76 Years Followed NO BENEFIT Treated Control Yet, Marked Benefit in Subjects with high IAA Proportion Free of Diabetes 0.0 0.2 0.4 0.6 0.8 1.0 Log-rank P=0.01 Peto Pr. P=0.01 IAA >= 300 Hazard Ratio: 0.41 (0.21, 0.80) N=63 (Ins.) and 69 (Plac.) Oral Insulin Placebo 1 ST 2 nd ST Degree relatives (ages 1-45) nd Degree relatives (ages 1-20) Blood draw Very High Risk AntiCD3 Intermediate Risk ~4% positive Antibodies Low Risk 0 1 2 3 4 5 6 Years

Survival Distribution Function Abnormal Glucose Tolerance = VERY high risk 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Control Treated 0 1 2 3 4 5 6 Years Followed New Engl J Med 2002; 346:1685-91 Intervention Observation Updated Data from Phase I/II Trial of Anti-CD3 in new onset T1DM AUC (pmol/ml/240min) 150 100 50 0 * * * 0 6 12 18 24 Anti-CD3 Comparison * p<0.02 Month Herold et al. Diabetes 2005; 54:1763-9 Very High Risk AntiCD3 Diabetes Prevention Trials Intermediate Risk Oral Insulin GAD65-Alum Low Risk Close monitoring ~1,500,000 individuals with Type 1 diabetes in US 200,000 Relatives Needed Health Providers Health Providers Recommend getting involved in TrialNet Why be tested for risk? Early Detection Eligibility for prevention Providers Help research move forward

Participant and Parent Experience in DPT-1 trials DPT-1 Oral Trial 35-50% 5 yr risk OGTT every 6 months DPT-1 Parenteral Trial >50% 5 yr risk oral insulin/placebo Once yearly 4 days IV Random assignment insulin and daily sq BID 95-96% parents stressed with news (resolved over time) No placebo Relatively easy decision to participate 93% of parents best part of study : monitoring for development of T1DM Almost half found random assignment difficult 96-97 % parents would recommend study to friends Bennett Johnson et al, Diabetes Care, Sept 2007; Pediatric Diabetes, 2009 Diabetes Support Groups JDRF events (walks, parties) ADA events (camps, walks, expo) Children with Diabetes Taking control of your diabetes Pharmacies Media (radio, TV, print) Social Networking Turku, Finland Malmo, Sweden Melbourne Bristol, UK Milan, Italy Munich, Germany NIDDK NIAID NICHD NCRR Our son was diagnosed when he was 4 years old. He has been absolutely wonderful about dealing with his diabetes NOTHING stops this child Before we left his Endo appointment this past Wednesday, he says, Mom, what does cure mean? I explained that it means when scientists find out how to stop a disease or problem and then it is gone forever. He looks at me with this silly expression on his face and says, Well, do you think that you can tell my doctor to speed things up a little? Paraphrased from Children with Diabetes Weekly Newsletter (April 14, 2010)

Type 1 diabetes is an autoimmune disease Risk for Type 1 diabetes can be predicted Studies underway to save beta cells Prevention Prolong insulin secretion Let families know about clinical research Individuals WITH diabetes Relatives WITHOUT diabetes Diabetes Clinical Research Team Srinath Sanda MD Jennifer Bollyky MD Angela Dove Jani Klein Deborah Emily Hefty Batts Mary Ramey Kristen Kuhns Marli McCulloch -Olson Marilyn Christine Heather Rebecca Reeve Webber Vendettuoli Walker Brochures, posters, flyers Business cards Actively enroll subjects Article in newsletter Web sites and toll-free phone number Bring research screening to your community www.benaroyaresearch.org 800-888-4187