Yes, We are Close to Preventing Diabetes!

Transcription

1 Yes, We are Close to Preventing Diabetes! Peter A. Gottlieb, MD Barbara Davis Center University of Colorado Health Sciences Center Denver, CO Practical Ways to Achieve Targets in Diabetes Care, Keystone, CO July 17, 2011

2 Presenter Disclosure Information Peter A. Gottlieb, MD Advisor: Genentech, Lilly, Tolerx, Sanofi Research Support: Bayhill Therapeutics, Inc. Diamyd, Macrogenics, Omni, Tolerx

3 Main Points Type 1 diabetes is an autoimmune disease. It is a predictable disease with different phases. Prevention and intervention strategies appropriate for each stage may change the course of type 1 diabetes.

4 T1D incidence is rising 3-5% per year Due to environmental cause(s) Incidence /100,000/ yr in children aged 0-14 Finland Sweden Colorado Germany REWERS

5 Finland Incidence Type 1 DM/100K Yrs yrs 5-9 yrs yrs Diabetes Care: 22:

6 HLA Concannon et al NEJM Insulin production & metabolism Locus Immunity β cell apoptosis protection Unknown function

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

8 Survival Distribution Function DPT-1 Time to Diabetes By Number of Antibodies P- Value< (Log Rank Test) Number at Risk n = Years Followed 8 STRATA:

9 Strategies to prevention and cure The balance of autoreactive T cells and regulatory T cells is important to disease development. Antigen presentation and innate immunity play a role in the disease process B lymphocytes, Macrophages and Dendritic Cells New trials based on these concepts may impact disease progression.

10 Strategies to prevention and cure The balance of autoreactive T cells and regulatory T cells is important to disease development. Antigen presentation and innate immunity play a role in the disease process B lymphocytes, Macrophages and Dendritic Cells New trials based on these concepts may impact disease progression.

11 Autoimmune Polyendocrine Syndromes and what they can tell us about disease pathways I From Eisenbarth and Gottlieb, N Engl J Med 2004;350:

12 APS and further insights about disease pathways II From Michels and Gottlieb, Nat Rev Endocrinol. 6(5):270-7., 2010.

13 Possible Approaches Cord Blood Stem Cells GCSF Recruitment of naïve cells with bias towards Treg Dendritic Cells loaded with Protective Cytokines or Antigens CD4+CD25+ Treg Depletion or Modulation of T effector cells e.g. Anti-CD3

14 Strategies to prevention and cure The balance of autoreactive T cells and regulatory T cells is important to disease development. Antigen presentation and innate immunity play a role in the disease process B lymphocytes, Macrophages and Dendritic Cells New trials based on these concepts may impact disease progression.

15 Macrophages are among the mononuclear cell infiltration of newly diagnosed pancreas islets CD68 macrophages infiltrate islets both in early and late insulitis Willcox, et al. 2008, Clinical and Experimental Immunology Macrophages were the 2nd most predominant infiltrating mononuclear cell in pancreatic biopsies of newly diagnosed subjects Itoh, et al. 1993, J. Clin. Invest. There are TNF- and IL-1 + macrophages and dendritic cells infiltrating islets of new-onset diabetics Uno, et al. 2007, Diabetologia Betsy Bradshaw, Brigham and Women s

16 Ex vivo monocytes from T1D subjects spontaneously secrete proinflammatory cytokines Monocytes from T1D subjects induce IL-17 in CD4 cells IL-17 secretion is dependent on IL-1, but not TNF

17 T1D subjects have a higher number of ex vivo IL-6 and IL-1 secreting PBMCs compared to control subjects T1D 1 T1D 2 T1D 3 T1D 4 HC 1 HC 2 HC 3 HC 4 Elispot of IL-1ß

18 Monocytes from T1D subjects induce a higher percentage of IL-17+ cells from memory CD4+ T cells than monocytes from healthy control subjects P < 0.01 P < 0.01 P < 0.01

19 The number of IL-17 secreting memory T cells can be reduced with IL-1 receptor antagonist

20 TLRs and their ligands Biochemical Journal (2009) 420, Himanshu Kumar, Taro Kawai and Shizuo Akira

21 Frequency (%) Frequency (%) Frequency (%) Frequency (%) Frequency (%) Frequency (%) 100 IL-1 Upregulation of TLR4 Induces Lower Frequencies of IL-1 Producing Monocytes from Patients with T1D LPS Poly(I:C) R848 p=0.01 p= Unactivated Activated Unactivated Activated 0 Unactivated Activated Unactivated Activated 0 Unactivated Activated Unactivated Activated Healthy (N=17) T1D (N=23) Healthy (N=12) T1D (N=16) Healthy (N=13) T1D (N=16) IL Unactivated Activated Unactivated Activated 0 Unactivated Activated Unactivated Activated 0 Unactivated Activated Unactivated Activated Healthy (N=17) T1D (N=24) Healthy (N=12) T1D (N=16) Healthy (N=13) T1D (N=16)

22 Monocytes Expressing IL-1 from the TrialNet Cohort Unactivated LPS Poly(I:C) R848

23 IL-1 Expressing Monocytes from the DAISY Cohort Unactivated LPS Poly(I:C) R848

24 Myeloid DCs Expressing IL-1 from the TrialNet Cohort Unactivated LPS Poly(I:C) R848

25 IL-1 Expressing Myeloid DCs from the DAISY Cohort Unactivated LPS Poly(I:C) R848

26 Summary Innate immune pathways are disordered in new onset and prediabetic individuals There appears to be a progression of polyactivation which begins with R848 and elevated levels of IL-1 in monocytes and myeloid DC s In later prediabetics, IL-1 levels are increased with all TLR ligands tested and unactivated monocytes, but not myeloid DC s also exhibit elevated IL-1 expression. This suggests that IL-1 may play an important role in disease pathogenesis and that innate immune pathways may be possible targets for immune intervention.

27 Anti-Inflammatory Approaches European trial of Anakinra (IL-1RA) TrialNet Canakinumab (ab to IL-1), fully enrolled last week, data next year this time. Omni AAT Recent onset 6-35 years old, adult group fully enrolled, peds to start in June, 2011 ITN AAT New onset, adult cohort fully enrolled, peds to start in June, 2011 TrialNet Prevention anti-il-1 in 1Ab+, IGT subjects

28 Ongoing and Other Possible Approaches Dietary interventions TRIGR cow s milk, FINDIA bovine insulin, NIP Omega 3 Fatty Acids, Vitamin D Pre-POINT - Oral Insulin in High Risk Subjects Probiotics with insulin peptide and IL-10? Insulin targeted to specific APC populations with or without antiinflammatory treatment (anti-il-1)

29 Strategies to prevention and cure The balance of autoreactive T cells and regulatory T cells is important to disease development. Antigen presentation and innate immunity play a role in the disease process B lymphocytes, Macrophages and Dendritic Cells New trials based on these concepts may impact disease progression.

30 Strategies to prevention and cure The balance of autoreactive T cells and regulatory T cells is important to disease development. Antigen presentation and innate immunity play a role in the disease process B lymphocytes, Macrophages and Dendritic Cells New trials based on these concepts may impact disease progression.

31

32 TrialNet Sites in North America North American Affiliates

33 Oral Tolerance: Mode of Action Oral Antigen Protective Cytokines Regulatory (Th2 / Th3) Lymphocytes Producing Protective Cytokines Inhibition of -Cell Autoimmunity and Prevention of Diabetes Insulin Producing -cells Autoimmune Lymphocytes

34 Survival Distribution Function DPT-1 Oral Study Time to Diabetes By Treatment Treated Control P- Value= (Log Rank Test) 0.2 Number at Risk Oral Insulin Oral Placebo Diabetes Care 2005; 28: Years Followed STRATA: Oral Insulin Oral Placebo

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

36 Proportion Free of Diabetes Insulin Effect Most Evident in Subjects with Baseline IAA 300 IAA >= 300 Oral Insulin Placebo Projected 10 year delay Log-rank P=0.01 Peto Pr. P=0.01 Hazard Rati o: 0.41 (0.21, 0.80) N=63 (Ins.) and 69 (Plac.) Years

37 Hazard Ratio Association of IAA Titer with Diabetes Risk By Study Arm: Increased effect with higher titer PLACEBO ORAL INSULIN Todd Mackenzie, Ph.D IAA at Baseline

38 Unknowns of Antigen Specific Therapy Magic bullet Approach Silver or otherwise Targets autoreactive cells deletion, anergy, distraction Generates protective cells - maybe Spares rest of immune system we hope so Minimal Toxicity so far Dose, adjuvant, timing and route may be critical to efficacy and we don t know enough about them

39 What do we know works in human T1D?

40 pmol/ml C-Peptide from 2-hr AUC Mean Over Time** * * Overall Rituximab: 0.68 (0.64, 0.72) Control: 0.56 (0.51, 0.61) p < * Ritux *p < Control Time in months Means and 95% CL **Adjusted for baseline C-peptide, age and sex

41 C-Peptide (nmol/l) C-Peptide from 2-hr AUC Mean Over Time Abatacept Placebo Aggregate p= Placebo N = 33 Abatacept N = 76 Placebo N = 32 Abatacept N = 72 Placebo N = 28 Abatacept N = 69 Placebo N = 30 Abatacept N = Time on Study (months) Means and 95% CI Adjusted for baseline C-peptide, age, gender, treatment assignment Orban et al, Lancet 2011; On-Line June 28

42 A single course of h (Ala-Ala) at dx of diabetes improves insulin secretion for over 2 years Drug ** ** ** Control 120 AUC (pmol/ml/240min) (p< **p<0.02) Month

43 T-cell Activation: Potential Targets Halloran N Engl J Med 2004, 351:

44 TrialNet Prevention Studies TrialNet Natural History Study miaa+, 1 other ab+, nl FPIR, nl OGTT GAD ab+, miaa-, nl FPIR, nl OGTT 1 ab+, dysglycemia OGTT 2 ab+, dysglycemia OGTT TrialNet Oral Insulin Study TrialNet GAD-Vaccine Study TrialNet Anti-IL-1 Prevention Study TrialNet Anti-CD3 Prevention Study

45 Summary Innate immune pathways are disordered and better understanding may lead to new therapies to prevent T1D Antigen specific therapies like oral insulin have slowed the disease process. Better delivery of these antigens + anti-inflammatory agents may improve efficacy. Therapies which target Signal One and Signal Two suggest new avenues to use in prediabetes to prevent disease. Multicenter trial networks and combination therapy targeting multiple pathways will help us find a cure for type 1 diabetes in the next decade.

46 Acknowledgements Gottlieb Lab Becky Wagner Lisa Fitzgerald-Miller Mylinh Dang Laurie Weiner Lisa Meyers Debbie Lehr Susan Barry Jenna Lungaro Whitney Kastelic Dominic Di Domenico BDC John Hutton Katie Keleman Howard Davidson Danny Zipris Ed Liu UCHSC Dan Waid David Wagner Ed Janoff Melissa Keays National Jewish Hospital John Cambier Shannon O Neill Mia Smith USCF Jeff Bluestone Amy Putnam BayHill Therapeutics Hideki Garren Joanne Quan Nanette Solvasen Yale University David Hafler UMass Sally Kent Brigham and Women s Hospital Elizabeth Bradshaw Virginia Mason Research Institute Ivana Duronivic-Bello Srinath Sanda Carla Greenbaum Columbia University Len Chess Hong Jiang Funding from NIDDK,NIAID, JDRF, ADA, Helmsley Foundation

47 Acknowledgements Laurie Weiner, Lisa Meyers, Debbie Lehr, Andrea Steck, Georgeanna Klingensmith, Peter Chase, Rob Slover, Ray Gutin, Mary Voelmle, Aaron Michels, Satish Garg, George Eisenbarth Natural History: Vicky Gage and Kendra Mason CTLA4-Ig: Whitney Kastelic Oral Insulin and PrePoint: Maria King T&B Cell: Rachael Jenison AbATE: Jenna Lungaro Alefacept: Jenna Lungaro ATG: Jenna Lungaro GAD: Sandy Barry DEFEND 1/2: Jenna Lungaro, Whitney Kastelic DELAY: Whitney Kastelic BHT: Sandy Barry AAT: Dominic Di Domenico Anti-CD3 Prevention Dominic Di Domenico Metabolic Control Study: Vicky Gage, Laurel Messer, Sally Sullivan ATG/GCSF: Jenna Lungaro And the Denver Type 1 Diabetes Referral Network

48 Sponsors NIDDK NIAID NICHD NCRR ADA JDRF

49 1-800-HALT-DM1 ( )