Benaroya Research Institute. Update on Type 1 Diabetes Trials. to Save Beta Cells. Carla Greenbaum MD. Seattle, WA

Transcription

1 Benaroya Research Institute Update on Type 1 Diabetes Trials Carla Greenbaum MD Seattle, WA to Save Beta Cells

2 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

3 Not much change for next 50 years! Human Insulin 1970 Home Glucose Monitoring 1980 Insulin pumps DCCT 1990 Marked changes in therapy 2000

4 DKA in type 1 diabetes in US 54% hospitalized at time of diagnosis 29.4% - DKA at diagnosis Related to $ but >20% from families with $$$ present in DKA No change in ~20 years Hospitalization for DKA <age 45: almost doubled from Rewers A, Pediatrics, May 2008; Maldonado, Diabetes Care, 2003

5 Where are We Today? Average A1c by Age, Age Intensive Rx Hvidoere DCCT EDIC N=195 N=175 N=1,295^ Sweden (80% of the nation) Los Angeles N=1664 < BDC Denver N= *^ * 8.6 > *11-18 yrs; ^the original 14 centers, unchanged compared to 1998 Barbara Davis Center Web Site: REWERS

6 T1D incidence is rising 3-5% per year 70 Incidence /100,000/ yr in children aged Finland Sweden Colorado Germany REWERS

7 Finland Type 1 Diabetes Incidence (32 years) Relative Percent Increase Age 1-4 Age 5-9 Age Diabetes Care: 22:

8 1970 Genetic studies: HLA region: Human Insulin Islet Cell Antibodies Home Glucose Monitoring Insulin pumps DCCT Pathology studies: Insulitis Insulin Autoantibodies GAD65 antibodies, IA-2 Marked changes in therapy Type 1 diabetes is an immune mediated disease

9 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

10 Autoimmune Diabetes Rheumatoid Arthritis; Lupus; Scleroderma; Polychondritis Multiple Sclerosis Inflammation Wound Repair and Tissue Reconstruction

11 Type 1 Diabetes Shared Genes Shared Mechanisms

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13 macrophage macrophage Killer T T Helper macrophage T Helpe r

14 Killer T Killer T T Helper

15 Killer T T Helper

16 Invader Attack Resolution Rapid memory response Killer T TIME

17 What goes wrong in autoimmunity? Failure of multiple Check Points

18 Invader is really self and the immune system makes a mistake and starts the whole immune response

19 T Regulatory cells loose the battle with T killer (effector) cells Killer T Killer T T Helper Killer T Killer T

20 Invader Attack Resolution Rapid memory response Killer T Killer T Killer T TIME

21 Why does autoimmunity effect only some cells? Type 1 diabetes Multiple Sclerosis Inflammatory Bowel Disease (Crohn s and Colitis) More susceptible to immune damage? Rheumatoid Arthritis Parts of these self mimic true invaders?

22 Why does the immune system make a mistake? Everyone has some cells that recognize self More survive More are activated More are made Likelihood of Autoimmunity

23 Why do T regulatory cells loose the battle? T regulatory cells no good AND/ OR T effector cells too strong

24 100 % Beta cell function 20% Clinical onset of disease Time

25 Save beta cells in those genetically at risk (Primary Prevention) 100 % Beta cell function 20% STOP progression to autoimmunity/beta Clinical onset of cell disease destructio Time

26 Save beta cells in antibody positive subjects (Secondary Prevention) 100 % Beta cell function 20% STOP clinical disease Time

27 Save beta cells after clinical disease (Tertiary Prevention-A) 100 % Beta cell function 20% STOP Clinical onset complications of disease Time

28 Save beta cells that are replaced after clinical disease (Tertiary Prevention-B) 100 % STOP complicati Beta cell function 20% Time

29 Three Key Requirements for Saving Beta cells at each stage 1. Know the natural history 2. Identify those at risk 3. Test therapies that balance risk/benefit

30 100 % Save Beta Cells in those Genetically at risk stop Autoimmunity 20% TRIGR Randomized trial to determine effect of Cow s milk in genetically at risk NIP study Hypothesis: Omega 3 fatty acids can prevent the initial autoimmune process.

31 Save beta cells after clinical disease (Tertiary Prevention-A) 100 % Beta cell function 20% Stop complications Clinical onset of disease Time

32 100 % Tertiary Prevention Studies: Diabetes Stop complications 20% Why preserve Beta cell function?

33 Diabetes Control and Complications Trial Does Intensive Diabetes Management (HbA1c <7%) reduce complications? YES, Absolutely 1993: marked reduction in retinopathy, nephropathy 2005: marked reduction in Cardiovascular disease

34 But, this is done at the risk of hypoglycemia DCCT: NEJM, 1993

35 DCCT: NEJM, 1993 UNLESS you still have beta cell function!!!!

36 Benefits of β-cell Preservation in DCCT Hypoglycemia with Coma/Seizure 62% Risk Reduction Rate per 100 pt years Ann Int Med 128: , 1998 Diabetes 53: , 2004 Conventional Intensive Intensive With insulin secretion No insulin secretion

37 DCCT Intensive Therapy Group Sustained 3+ Step Retinopathy Progression 12 Cumulative Incidence (%) Risk Reduction: 79% (CI: 9, 95) p < No insulin secretion With insulin secretion Year of Follow-up Diabetes 53: , 2004 TrialNet

38 Why preserve Beta cell function? Among DCCT subjects in the intensive treatment group: Prevents short term complications 62% less hypoglycemia Prevents long term complications 79% Risk reduction in retinopathy

39 Glucose Control impacts beta cell survival 100 % Beta cell function 20% Better diabetes control Time Poor diabetes control

40 Halloran N Engl J Med 2004, 351:

41 Monoclonal-Antibody Group Control Group Insulin Secretion Insulin Secretion Immune Toleranc e Network Herold K. et al., 2002 hokt3γ1(ala-ala) New England Journal of Medicine

42 Updated Data from Phase I/II Trial of Anti-CD3 in new onset T1DM AUC (pmol/ml/240min) * * * Anti-CD3 Comparison * p<0.02 Month Herold et al. Diabetes 2005; 54:1763-9

43 Ages 8-45 Diagnosed within past 3 months Randomized trial N=88 Outcome: Insulin secretion at 2 years Phase II trial: Rituximab M. Pescovitz, Indian STUDY COMPLETED IV rituximab x 4 doses IV placebo

44 And lower HbA1c with less insulin C-peptide Preservation of Insulin Secretion with Rituximab pmol/ml * * *p < * Overall p < Ritux Placebo Time in months

45 Antigen Therapy : GAD65-Alum 69 subjects, up to 18 months from diagnosis Ages GAD65-Alum Treatment and Insulin Secretion in Recent-Onset Type 1 Diabetes Ludvigsson et al NEJM 2008: 359

46 Ages 3-45 N=126 Phase II trial: GAD65-Alum D.Wherrett, Toronto RECRUITMENT DONE Outcome: Insulin secretion at 1 year RESULTS ~ 1 years GAD-Alum 3 sq injections 0,4,8 weeks GAD-Alum 2 sq injections 0, 4 weeks Placebo sq injection 8 weeks Placebo sq injections 0, 4, 8 weeks

47 Phase Ib trial: IL2+rapamycin Rabinovitch/Edmonton Greenbaum/BRI, Seattle Goland/Columbia University NYC Adults within 4 years of Type 1 diabetes diagnosis

48 Rationale: IL-2 combination with Rapamycin Besinger S.J. et. al. J. Immunol, 172: 5287, 2004 Tian L. et. al. Transplantation 77: 183, 2004 (induced) IL-2R IL-2 IL-2R(constitutive) CD4 + CD25 - Tcells RAPAMYCIN + FKBP P13K TOR Jak/STAT5 CD4 + CD25 + Treg cells No proliferation of CD4+ CD25 - T cells Survival /Proliferation of CD4+ CD25+ T reg cells

49 The Combination of IL-2 and Rapamycin Prevents Leukocytic Infiltration and Destruction of β -Cells in Syngeneic Islet Grafts in NOD Mice A Vehicle B Rapamycin C D IL-2 IL-2 + Rapamycin 200 μm

50 DirectNet Phase II trial: Metabolic Rest: closed loop pump and sensors B. Buckingham, Stanford Diagnosed within past week! Randomized trial N~66 NIDDK Primary Outcome: Insulin secretion at 1 year UCLA, Yale, Stanford NICHD

51 Effect of Intensive vs Conventional Therapy on β-cell Function Ann Int Med 128: , 1998 N = 303 With 1 5 y duration and C-Peptide pmol/ml Risk Reduction 57% (CI: 39, 71%) P < Intensive Conventional Palmer

52 100 % Save beta cells after diagnosis Anakinra (anti IL-1β) 20% Thymoglobulin MMF/DZB Peptidia Rituximab Insulin B chain Anti-CD3 multiple dose CTLA4-Ig Metabolic IL-2+Rapamycin GAD immunization

53 Save beta cells in antibody positive subjects (Secondary Prevention) 100 % stop clinical disease Beta cell function 20% Clinical onset of disease Time

54 Risk by the age of 20 years 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

55 Families with diabetes ~5% 15x Families without diabetes 100 Newly diagnosed patients with type 1 diabetes 0.3% 10 90

56 Save beta cells in antibody positive 100 % subjects (Secondary Prevention) 20% Previous large Studies ENDIT: Nicotinamide DPT-1: Parenteral Insulin DPT-1: Oral Insulin DIPP: Nasal Insulin

57 5 year risk estimates ICA+ relatives with low beta cell function or IGT ICA+ relatives <25% Low ICA+, IAA+ relatives 25-50% 35% Intermediate 60% >50% High

58 More antibodies = greater risk Survival Distribution Function n = ab 3 ab 1 ab 2 ab Years Followed 8

59 Abnormal Glucose Tolerance = VERY high risk Survival Distribution Function Control Treated Intervention Observation Years Followed New Engl J Med 2002; 346:

60 Anti-CD 3 in Prevention Herold Ab+ Abnormal Glucose Tolerance Ages 8-45 Very high risk Spring 2010?

61 1 ST Degree relatives (ages 1-45) 2 nd Degree relatives (ages 1-20) Blood draw ~4% positive Antibodies Very High Risk AntiCD3 (Spring 2010) Intermediate Risk Oral Insulin Low Risk Close monitoring GAD65-Alum (Winter 2010?)

62 Save beta cells in antibody positive subjects (Secondary Prevention) 100 % Oral Insulin Beta cell function 20% Clinical onset of disease Time

63 Oral Tolerance: Mode of Action Oral Antigen Protective Cytokines Regulatory Lymphocytes Inhibition of β-cell Autoimmunity and Prevention of Diabetes Insulin Producing β-cells Autoimmune Lymphocytes

64 Diabetes Prevention Trial type 1 diabetes ICA+ relatives with low beta cell function ICA % relatives ORAL INSULIN <25% Low ICA+, IAA+ relatives Intermediate >50% High

65 DPT-1 Oral Study Time to Diabetes By Treatment Survival Distribution Function NO BENEFIT Treated Control Years Followed Diabetes Care 2005; 28:

66 Yet, Marked Benefit in Subjects with high IAA Proportion Free of Diabetes 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.) Years Oral Insulin Placebo

67 Diabetes Prevention Trials Very High Risk AntiCD3 (Spring 2010) Intermediate Risk Oral Insulin GAD65-Alum (Winter 2010?) Low Risk Close monitoring 200,000 Relatives Needed

68 ~1,500,000 individuals with Type 1 diabetes in US

69 Health Providers

70 Health Providers Recommend getting involved in TrialNet Why be tested for risk? Early Detection Eligibility for prevention Providers Help research move forward

71 Participant and Parent Experience in DPT-1 trials DPT-1 Oral Trial DPT-1 Parenteral Trial >50% 5 yr risk 35-50% 5 yr risk oral insulin/placebo 95-96% parents stressed with news (resolved over time) OGTT every 6 months Random assignment Once yearly 4 days IV insulin and daily sq BID 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 % parents would recommend study to friends Bennett Johnson et al, Diabetes Care, Sept 2007; Pediatric Diabetes, 2009

72 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

73 Turku, Finland Malmo, Sweden Melbourne Bristol, UK Milan, Italy Munich, Germany

74 NIDDK NIAID NICHD NCRR

75 Paraphrased from Children with Diabetes Weekly Newsletter (April 14, 2010) 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?

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77 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

78 Business cards Actively enroll subjects Article in newsletter Bring research screening to your community Brochures, posters, flyers Web sites and toll-free phone number

79 Diabetes Clinical Research Program Dr. Sanda Dr. Bollyky Angela Dove Deborah Hefty Nicole Hilderman Kristen Kuhns Marli McCulloc h-olson Carynn Murphy Mary Ramey Marilyn Reeve Christine Webber Heather Vendettuoli