Immune Modulation of Type1 Diabetes

Transcription

1 Immune Modulation of Type1 Diabetes Jay S. Skyler, MD, MACP Division of Endocrinology, Diabetes, and Metabolism and Diabetes Research Institute University of Miami Miller School of Medicine

2 Ideal Therapeutic Goals in T1D Stop Immune Destruction Preservation of β-cell Mass β-cell Replacement or Regeneration

3 Natural History of Type 1 Diabetes PUTATIVE ENVIRONMENTAL TRIGGER BETA CELL MASS GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY CELLULAR (T CELL) AUTOIMMUNITY HUMORAL AUTOANTIBODIES (ICA, IAA, Anti-GAD 65, IA 2 Ab, ZnT8, etc.) LOSS OF FIRST PHASE INSULIN RESPONSE (IVGTT) PRE - DIABETES GLUCOSE INTOLERANCE (OGTT) DIABETES CLINICAL ONSET TIME

4 Potential Timing of Intervention Studies GENETICALLY AT-RISK MULTIPLE ANTIBODY POSITIVE BETA CELL MASS GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY LOSS OF FIRST PHASE INSULIN RESPONSE PRE - DIABETES DYSGLYCEMIA C-Peptide -cell function DIABETES TIME NEWLY-DIAGNOSED DIABETES

5 Prevention of Type 1 Diabetes

6 DPT-1 1 Parenteral Insulin Trial Time to Diabetes By Treatment 1.0 Survival Distribution Function P- Value= (Log Rank Test) Number at Risk Control Treated Intervention Observation STRATA: Years Followed Intervention Observation New Engl J Med 2002; 346:

7 DPT-1 1 Oral Study Time to Diabetes By Treatment Survival Distribution Function P- Value= (Log Rank Test) Number at Risk Treated Control Oral Insulin Oral STRATA: Years Followed Oral Insulin Oral Diabetes Care 2005; 28:

8 DPT-1 1 Oral Study - Time to Diabetes - By Treatment Subset: IAA Confirmed > 80 nu/ml Survival Distribution Function P- Value= (Log Rank Test) Number at Risk Projected year delay Treated Control Oral Insulin Oral STRATA: Years Followed Oral Insulin Oral Diabetes Care 2005; 28:

9 Insulin Effect Most Evident in Subjects with Baseline IAA Projected 10 year delay Oral Insulin Proportion Free of Diabetes Log-rank P=0.01 Peto Pr. P=0.01 Hazard Ratio: 0.41 (0.21, 0.80) Treated Control 0.0 N=63 (Ins.) and 69 (Plac.) Years Followed Ann NY Acad Sci 2009; 1150:

10 Overall Treatment Effect Intention To Treat Analysis Percentage developing diabetes es Nicotinamide Years since randomisation endit Nicotinamide Lancet 2003; 363:

11 DIPP - Diabetes-free Survival Index children Insulin Survival HR = 1.14 p = Number at Risk Insulin group group Time (years) Lancet 2008; 372:

12 Finnish TRIGR Cumulative Incidences of at Least One Autoantibody and of at Least Two Autoantibodies Knip M et al. N Engl J Med 2010;363:

13 Combined DPT-1 1 Parenteral & Oral Insulin Trials Indeterminate: BG > 200 mg/dl (11.1 mmol/l at 30, 60, or 90 min Survival Distribution Function P- Value< (Log Rank Test) Number at Risk IFG only Normal Glucose Tolerance Tolerance Indeterminate Indeterminate only only Combined IGT IGT only only Comb IFG+(IGTor Indet) IGT Only Indet Only NGT Years Followed STRATA: Comb IFG + (IGT or Indet) Indet Only IGT Only NGT

14 TrialNet Prevention Studies TrialNet Pathway to Prevention Study TrialNet Oral Insulin Study TrialNet Trichuris suis Ova Study TrialNet Abatacept Prevention Study TrialNet Anti-CD3 Prevention Study

15 Intervention in New Onset Type 1 Diabetes

16 Heat Shock Protein 60 Peptide - DiaPep-277 Change of C-peptide C levels from baseline Delta C C-peptide AUC (0-20 min) [nmol/l] Months * ** * 18 * * p < 0.05 DiaPep277 DiaPep277 administration Raz et al. Diab Metab Res Revs 2007; 23:292-8

17 Heat Shock Protein 60 Peptide - DiaPep-277 C-peptide AUC 0-20 by GST mitt Population PP Population Change from Baseline in C C-peptide AUC nmol/l/20min N = 175 N = 139 *p = *p = * N = 174 N = 151 * DiaPep 277 DiaPep 277 Relative treatment effect = 23.4% Relative treatment effect = 29.2% Pozzilli et al. ADA 2011

18 Heat Shock Protein 60 Peptide - DiaPep-277 Change in MMTT C-peptide C AUC Secretion mitt Population Change from Baseline in C C-peptide AUC nmol/l/120min Months DiaPep 277 Pozzilli et al. ADA 2011

19 Anti-CD3 Teplizumab 150 * * * AUC (pmol/ml/240min) Anti-CD3 Comparison Month * p < 0.02 Herold et al. N Engl J Med 2002;346: Herold et al. Diabetes 2005;54:1763-9

20 Anti-CD3 Otelixizumab nm/min Mean Change in C-peptide C from Entry p = p = 0.01 p = Anti-CD Time (months) Keymeulen et al. N Engl J Med 2005; 352:

21 Insulin Dose HbA 1c IU/kg/day n = 31 n = 33 n = 31 n = 28 n = 33 n = 33 n = 29 n = 31 n = 27 n = 32 n = 31 n = 32 n = 31 n = 33 p=0.004 p<0.001 p=0.001 p= Months ChAglyCD3 % p=0.761 p=0.984 p=0.990 p= Months Keymeulen et al. Diabetologia 2010; 53:

22 DEFEND 1 C peptide AUC (mean +/ SEM) over time Otelixizumab C peptide AUC, (nmol/l*min)/min Visit n Baseline Week 12 Month 6 Month Gottlieb et al. ADA 2011

23 Protégé Primary Endpoint All Subjects 25 Composite Responder Rates at Day 364 Intent to Treat Double Blind Subjects Percent of Subjects N Full 14 Day Regimen 1/3 14 Day Regimen 6 Day Regimen 0 Note: Subjects with missing values are counted as non-responders 1 HbA1c < 6.5% and Insulin Use < 0.5 U/kg/day Sherry et al. Lancet 2011; 378:

24 Protégé Teplizumab Study Full 14-Day Regimen 0.00 Median Change from Baseline *Wilcoxon rank-sum test p<0.05 for the change from baseline Visit / Study Day Number of Subjects Meeting Criteria: Sherry et al. Lancet 2011; 378:

25 Protégé Teplizumab Study Age Subgroups Children (8-11 Years) Only Median Change Drug Visit/Study Day Sherry et al. Lancet 2011; 378:

26 ABATE Teplizumab Study C-peptide AUC (pmol/ml/min) ** *** *** ** Time (Months) Drug Control Gitelman et al. ADA 2011

27 Responders in ABATE Distribution of % Decrease from Baseline in C-peptide C AUC Month Cumulative Frequency of Subjects Drug Control % Decrease from Baseline in C-peptide C AUC

28 Responders in ABATE Change from baseline C-peptide Months Responder Non-responder Control

29 DELAY Teplizumab Trial In(C-peptide AUC+1) Drug Months after entry Herold et al. ADA 2011

30 Geometric Mean C-Peptide C (pmol/ml) on 2-hour 2 MMTT MMF alone vs Control C-peptide pmol/ml Control MMF Control MMF Gottlieb et al. Diabetes Care 2010; 33: months

31 Geometric Mean C-Peptide C (pmol/ml) on 2-hour 2 MMTT MMF-DZB vs Control C-peptide pmol/ml Control Combo Control MMF-DZB Gottlieb et al. Diabetes Care 2010; 33: months

32 Anti-CD20 Rituximab * * Rituximab pmol/ml 0.6 * Means and 95% CL Adjusted for baseline C-peptide, C age, & sex Time (Months) Pescovitz et al. N Eng J Med 2009; 361: *p < 0.03

33 Anti-CD20 Rituximab Rituximab C-peptide (nmol/l) P = P = P = P = Plac. N = 28 Ritux. N = 51 Plac. N = 28 Ritux. N = 49 Plac. N = 27 Ritux. N = 49 Plac. N = 28 Ritux. N = 49 Plac. N = 21 Ritux. N = Time on Study (Months) Pescovitz et al, ADA 2010; submitted

34 Regression Line for Rituximab Trial 0.90 C-peptide (nmol/l) mos. Intercept Change 1st yr Rituximab Test (intercept)** p = 0.013** Time on Study (Months) ** test for difference in intercept by treatment group (one-sided) Adjusted for baseline C-peptide, C age, gender, treatment assignmentpescovitz et al, ADA 2010; submitted

35 Abatacept Abatacept C-Peptide (nmol/l) Aggregate p = Time on Study (months) Means and 95% CI Adjusted for baseline C-peptide, C age, gender, treatment assignment Orban et al. Lancet 2011; 378:412-9

36 Abatacept At 3 years C-peptide (nmol/l) Abatacept Abatacept N = 33 N = 76 N = 32 N = 72 N = 28 N = 69 N = 30 N = 73 N = 28 N = 69 N = 29 N = Means and 95% CI Adjusted for baseline C-peptide, C age, Time on Study (Months) gender, treatment assignment Orban for TrialNet, ADA 2012

37 Regression Line for Abatacept Trial C-peptide (nmol/l) 0.90 Intercept Change 1st yr Abatacept Single Time Population Estimates (Linear model) 9.5 mos. 95% CI: [3.44, 15.7] months 0.10 Global Test (6, 12, 18, 24, 30, 36 mos): p = Time on Study (Months) Adjusted for baseline C-peptide, C age, gender, treatment assignment Orban for TrialNet, ADA 2012

38 GAD-65 Vaccination 0.2 Diabetes Duration Prior to Treatment: Months pmol/ml/2 hour p = 0.01 p = 0.04 p = 0.05 p = 0.04 GAD-Alum Alum GAD-alum n = 11 n = Months in Study Ludvigsson et al. New Engl J Med 2008:359:

39 GAD-65 Vaccination C-Peptide (nmol/l) AIumx3 GAD-Alx2 Alx2 GAD-AIx3 AIx AIumx3 GAD-AIx2 AIx2 GAD-AIx3 AIx3 N=48 N=48 N=46 N=44 N=46 N=44 N=45 N=48 N=45 N=46 N=48 N= Means and 95% CI Adjusted for baseline C-peptide, C age, gender, treatment assignment Time on Study (months) Wherrett et al, Lancet 2011; 378:

40 GAD Antibody Titers Over Time AIumx3 GAD-AIx2 AIx2 AI x 1 GAD-AIx3 AIx3 GAD 65 (index units) p < p < AIx3 N=41 GAD-AIx2 AIx2 N=44 GAD-AIx3 AIx3 N=42 p < p < AIx3 N=49 GAD-AIx2 AIx2 N=48 GAD-AIx3 AIx3 N=45 p < p < AIx3 N=44 GAD-AIx2 AIx2 N=47 GAD-AIx3 AIx3 N= Time on Study (months) Wherrett et al, Lancet 2011; 378:

41 GAD-65 Vaccination Ludvigsson et al. New Engl J Med 2012:366:

42 GAD-65 Vaccination Ludvigsson et al. New Engl J Med 2012:366:

43 Etanercept in New-Onset T1D Etanercept Mastrandrea et al. Diabetes Care. 2009; 32: Epub 2009 Apr 14.

44 Canakinumab Trial 0.8 Canakinumab C-peptide (nmol/l) Canakinumab N = 21 N = 45 N = 22 N = 46 N = 20 N = 41 N = 21 N = Time on Study (months) Means and 95% CI Adjusted for baseline C-peptide, C age, gender, treatment assignment Moran for TrialNet, ADA 2012

45 AIDA Anakinra Trial Mean C-Peptide (minus Baseline Value) Anakinra p = 0.63 N = 25 N = 28 Anakinra p = 0.48 N = 25 N = 25 p = 0.58 N = 26 N = Time on Study (Months) Mandrup-Paulsen for AIDA Group, ADA 2012

46 Ongoing and Planned Studies Thymglobulin [T-lymphocyte depletion] Alefacept [apoptosis of memory-effector effector T-cells] T Sitagliptin + Lansoprazole [for β-cell proliferation] Diamyd-277 Alpha-1-anti anti-trypsintrypsin Thymoglobulin (low dose) + GCSF Ustekinumab anti-il12/23 Secukinumab anti-il17 Tocilizumab anti-il6 Proinsulin peptides

47 Cyclophosphamide, ATG, & AHBMT Couri et al. JAMA 2009; 301: Voltarelli et al. JAMA 2009; 302:624-5

48 Potential Combination Therapy Approach Anti-IL1β or Anti-TNF Anti-CD3 or Anti-CD20 or Co-Stimulation Blockade GAD Oral Insulin GCSF T-regs GAD GAD Exenatide or GLP-1 or HIP2b Time

49 Ideal Therapeutic Goals in T1D Stop Immune Destruction Preservation of β-cell Mass β-cell Replacement or Regeneration

50 NIDDK NIAID NICHD NCRR ADA JDRF DRIF

51 HALT-DM