Update on Type 1 Diabetes Trials to Save Beta Cells. DKA in type 1 diabetes in US. 33 yrs. Not much change for next 50 years!

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1 Benaroya Research Institute Carla Greenbaum MD Seattle, WA Update on ype 1 Diabetes rials to Save Beta Cells 1552 BC earliest written record of DM 1 st Breakthrough in undstanding: 1889 he 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 thapy Insulin pumps DCC DKA in type 1 diabetes in US 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 Rews A, Pediatrics, May 2008; Maldonado, Diabetes Care, 2003 Whe are We oday? Avage A1c by Age, Age Intensive Rx Hvidoe DCC EDIC N=195 N=175 N=1,295^ Sweden (80% of the nation) Los Angeles N=1664 < BDC Denv N=3910 1D incidence is rising 3-5% p year Incidence /100,000/ yr in children aged *^ * 8.6 > *11-18 yrs; ^the original 14 cents, unchanged compared to 1998 Barbara Davis Cent Web Site: REWERS REWERS

2 Finland ype 1 Diabetes Incidence (32 years) Relative Pcent Increase Human Insulin Home Glucose Monitoring Genetic studies: HLA region: Islet Cell Antibodies Pathology studies: Insulitis Insulin pumps Insulin Autoantibodies DCC 1990 GAD65 antibodies, IA-2 Diabetes Care: 22: Marked changes in thapy ype 1 diabetes is an immune mediated disease Alopecia areata Ankylosing spondylitis Addisons disease Hemolytic anemia Autoimmune Hepatitis hrombocytopenic purpura Behcets disease Pemphigus Crohns disease Dmatomyositis Lupus Graves disease Hashimotos hyroiditis Autoimmune Diabetes Multiple sclosis Myasthenia gravis Pnicious anemia Polyartitis Polychondritis Polymyositis Psoriasis Rheumatoid arthritis Sclodma Sjogren s syndroms Stiff man syndrome Giant cell Artitis Ulcative colitis Vasculitis Uveitis Vitiligo Autoimmune Diabetes Multiple Sclosis Inflammation Wound Repair and issue Reconstruction Rheumatoid Arthritis; Lupus; Sclodma; Polychondritis ype 1 Diabetes Shared Genes Shared Mechanisms

3 macrophage macrophage Kill Kill Kill Kill Kill Kill macrophage e r Kill Hel p Kill memory Invad Attack Resolution Rapid memory response Kill Kill Kill Kill Kill Kill Hel p memory memory Kill IME memory What goes wrong in autoimmunity? Failure of multiple Check Points Invad is really self and the immune system makes a mistake and starts the whole immune response

4 ulatory cells loose the battle with kill (effector) cells Invad Attack Resolution Rapid memory response Kill r Kill Kill eg ill Kill Kill Kill Hel p mem ory mem ory Kill IME Kill Kill mem ory Why does autoimmunity effect only some cells? ype 1 diabetes Inflammatory Bowel Disease (Crohn s and Colitis) More susceptible to immune damage? Multiple Sclosis Parts of these self mimic true invads? Rheumatoid Arthritis Why does the immune system make a mistake? Evyone has some cells that recognize self More survive More are activated GENESENVIRONMEN More are made Likelihood of Autoimmunity Why do regulatory cells loose the battle? regulatory cells no good AND/ OR effector cells too strong GENESENVIRONMEN Kill Clinical onset of disease ime

5 Save beta cells in those genetically at risk (Primary Prevention) Save beta cells in antibody positive subjects (Secondary Prevention) SOP progression to autoimmunity/beta Clinical onset of cell disease destructio SOP clinical disease ime ime Save beta cells aft clinical disease (tiary Prevention-A) Save beta cells that are replaced aft clinical disease (tiary Prevention-B) SOP complicati SOP Clinical onset complications of disease ime ime hree Key Requirements for Saving Beta cells at each stage 1. Know the natural history 2. Identify those at risk 3. est thapies that balance risk/benefit NIP study Save Beta Cells in those Genetically at risk stop Autoimmunity Hypothesis: Omega 3 fatty acids can prevent the initial autoimmune process. RIGR Randomized trial to detmine effect of Cow s milk in genetically at risk

6 Save beta cells aft clinical disease (tiary Prevention-A) tiary Prevention Studies: Diabetes Stop complications Stop complications Clinical onset of disease Why presve? ime Diabetes Control and Complications rial Does Intensive Diabetes Management (HbA1c <7%) reduce complications? YES, Absolutely 1993: marked reduction in retinopathy, nephropathy But, this is done at the risk of hypoglycemia DCC: NEJM, : marked reduction in Cardiovascular disease DCC: NEJM, 1993 Benefits of β-cell Presvation in DCC Hypoglycemia with Coma/Seizure 62% Risk Reduction UNLESS you still have beta cell function!!!! Rate p 100 pt years Ann Int Med 128: , 1998 Diabetes 53: , 2004 Conventional Intensive Intensive With insulin secretion No insulin secretion

7 Cumulative Incidence (%) DCC Intensive hapy Group Sustained 3+ Step Retinopathy Progression Risk Reduction: 79% (CI: 9, 95) p < No insulin secretion Year of Follow-up With insulin secretion Diabetes 53: , 2004 rialnet Why presve? Among DCC subjects in the intensive treatment group: Prevents short tm complications Prevents long tm complications 62% less hypoglycemia 79% Risk reduction in retinopathy Glucose Control impacts beta cell survival Bett diabetes control ime Poor diabetes control Halloran N Engl J Med 2004, 351: Monoclonal-Antibody Group Control Group Updated Data from Phase I/II rial of Anti-CD3 in new onset 1DM Insulin Secretion Immune olanc e Network Insulin Secretion Hold K. et al., 2002 hok3γ1(ala-ala) New England Journal of Medicine AUC (pmol/ml/240min) * * * Anti-CD3 Comparison * p<0.02 Month Hold et al. Diabetes 2005; 54:1763-9

8 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 SUDY COMPLEED Presvation of Insulin Secretion with Rituximab * C-peptide pmol/ml And low HbA1c with less insulin * *p < * Ovall p < Ritux Placebo IV rituximab x 4 doses IV placebo ime in months Antigen hapy : GAD65-Alum 69 subjects, up to 18 months from diagnosis Ages GAD65-Alum reatment and Insulin Secretion in Recent-Onset ype 1 Diabetes Ludvigsson et al NEJM 2008: 359 Phase II trial: GAD65-Alum D.Whrett, oronto Ages 3-45 N=126 Outcome: Insulin secretion at 1 year GAD-Alum 3 sq injections 0,4,8 weeks RECRUIMEN DONE RESULS ~ 1 years GAD-Alum 2 sq injections 0, 4 weeks Placebo sq injection 8 weeks Placebo sq injections 0, 4, 8 weeks Phase Ib trial: IL2+rapamycin Adults within 4 years of ype 1 diabetes diagnosis Rabinovitch/Edmonton Greenbaum/BRI, Seattle Goland/Columbia Univsity NYC Rationale: IL-2 combination with Rapamycin Besing S.J. et. al. J. Immunol, 172: 5287, 2004 ian L. et. al. ransplantation 77: 183, 2004 CD4 + CD25 - cells (induced) IL-2R RAPAMYCIN + FKBP P13K OR IL-2 IL-2R(constitutive) CD4 + CD25 + reg cells Jak/SA5 No prolifation of CD4+ CD25 - cells Survival / Prolifation of CD4+ CD25+ reg cells

9 he Combination of IL-2 and Rapamycin Prevents Leukocytic Infiltration and Destruction of β - Cells in Syngeneic Islet Grafts in NOD Mice A C Vehicle IL-2 B D Rapamycin IL-2 + Rapamycin 200 µm 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 UCLA, Yale, Stanford NICHD Effect of Intensive vs Conventional hapy on β-cell Function Ann Int Med 128: , 1998 Conventional N = 303 With 1 5 y duration and C-Peptide pmol/ml Risk Reduction 57% (CI: 39, 71%) P < Intensive Palm Save beta cells aft diagnosis Anakinra (anti IL-1β) hymoglobulin MMF/DZB Peptidia Insulin B chain Rituximab Anti-CD3 multiple dose CLA4-Ig Metabolic IL-2+Rapamycin GAD immunization Save beta cells in antibody positive subjects (Secondary Prevention) Risk by the age of 20 years stop clinical disease Clinical onset of disease ime

10 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 ENDI: Nicotinamide DP-1: Parental Insulin DP-1: Oral Insulin DIPP: Nasal Insulin 5 year risk estimates More antibodies = great risk ICA+ relatives <25% Low ICA+, IAA+ relatives 25-50% 35% Intmediate ICA+ relatives with low beta cell function or IG >50% 60% High Survival Distribution Function ab 2 ab 3 ab 4 ab n = Years Followed 8 Abnormal Glucose olance = VERY high risk 1.0 Anti-CD 3 in Prevention Hold 0.9 Survival Distribution Function Control reated Years Followed New Engl J Med 2002; 346: Intvention Obsvation Ab+ Abnormal Glucose olance Ages 8-45 Vy high risk Spring 2010?

11 1 S Degree relatives (ages 1-45) 2 nd Degree relatives (ages 1-20) Blood draw Vy High Risk AntiCD3 (Spring 2010) Intmediate Risk Oral Insulin GAD65-Alum (Wint 2010?) ~4% positive Antibodies Low Risk Close monitoring Save beta cells in antibody positive subjects (Secondary Prevention) ime Oral Insulin Clinical onset of disease Oral olance: Mode of Action Oral Antigen Protective Cytokines Diabetes Prevention rial type 1 diabetes ICA+ relatives with low beta cell function ulatory Lymphocytes Insulin Producing Autoimmune β-cells Lymphocytes Inhibition of β-cell Autoimmunity and Prevention of Diabetes <25% Low ICA+, IAA+ relatives ICA+ relatives 25-50% ORAL INSULIN Intmediate >50% High Survival Distribution Function DP-1 Oral Study ime to Diabetes By reatment Years Followed NO BENEFI reated Control 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.) Oral Insulin Placebo Diabetes Care 2005; 28: Years

12 Vy High Risk AntiCD3 (Spring 2010) Diabetes Prevention rials Intmediate Risk Oral Insulin GAD65-Alum (Wint 2010?) Low Risk Close monitoring ~1,500,000 individuals with ype 1 diabetes in US 200,000 Relatives Needed Health Provid s Health Provid s Recommend getting involved in rialnet Why be tested for risk? Early Detection Eligibility for prevention Provide rs research move forward Participant and Parent Expience in DP-1 trials DP-1 Oral rial 35-50% 5 yr risk OG evy 6 months DP-1 Parental rial >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 ov time) No placebo Relatively easy decision to participate 93% of parents best part of study : monitoring for development of 1DM Almost half found random assignment difficult % 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 aking control of your diabetes Pharmacies Media (radio, V, print) Social Networking

13 urku, Finland Malmo, Sweden Melbourne Bristol, UK Milan, Italy Munich, Gmany NIDDK NIAID NICHD NCRR Our son was diagnosed when he was 4 years old. He has been absolutely wondful about dealing with his diabetes NOHING 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 forev. 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 Newslett (April 14, 2010) ype 1 diabetes is an autoimmune disease Risk for ype 1 diabetes can be predicted Studies undway to save beta cells Prevention Prolong insulin secretion Let families know about clinical research Individuals WIH diabetes Relatives WIHOU diabetes Business cards Actively enroll subjects Article in newslett Bring research screening to your community Brochures, posts, flys Web sites and toll-free phone numb

14 Diabetes Clinical Research Program Dr. Sanda Dr. Bollyky Angela Dove Deborah Hefty Nicole Kristen Hildman Kuhns Marli McCulloc h-olson Carynn Mary Murphy Ramey Marilyn Reeve Christine Webb Heath Vendettuoli