Dr Dario Tuccinardi University Campus Bio-Medico of Rome

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1 Dr Dario Tuccinardi University Campus Bio-Medico of Rome

2 Topics to be discussed Epidemiology (increase in incidence) Genetics (more cases with moderate HLA risk alleles) Pathogenesis of type 1 diabetes Preservation of beta cell function (Cpeptide secretion) Immunotherapy in type 1 diabetes Future directions

3 Type 1 diabetes: a multifactorial disease

4 Incidence of type 1 diabetes in children aged 0-14 years by geographical region and over time During the last decades the incidence in Finland and Germany has risen, increasing yearly by 5% with a predominance in small children [Lancet 2008]. As this rapid development cannot be explained by genetic factors. Diabetes Atlas 2012

5 Topics to be discussed Epidemiology (increase in incidence) Genetics (more cases with moderate HLA risk alleles) Pathogenesis of type 1 diabetes Preservation of beta cell function (Cpeptide secretion) Immunotherapy in type 1 diabetes Future directions

6 Proportion of high, moderate and low risk genotypes of T1DM subjects with age of onset >15 years, subdivided according to year of diagnosis High risk HLA genotpye p= ns for all comparisons Moderate risk HLA genotpye Low risk HLA genotpye 60 % Spoletini M et al, IMDIAB Group, Plos One 2013 Year of diagnosis

7 Topics to be discussed Epidemiology (increase in incidence) Genetics (more cases with moderate HLA risk alleles) Pathogenesis of type 1 diabetes Preservation of beta cell function (Cpeptide secretion) Immunotherapy in type 1 diabetes Future directions

8 Beta cell mass The natural history of T1D: a 25 years old concept revisited A re-creation of the model of type 1 diabetes, originally proposed in 1986, is shown in red. Additions and conjectures based on recent knowledge gains are shown in blue. Modified from Atkinson MA, Eisenbarth GS, Michels AW. Lancet Precipitating events might occur in utero Genetic predisposition 2. Genetic predisposition probably the key driver and/or linked to 3. Environment may immune abnormalities influence entire natural history Progressive loss Insulin release Overt immunological abnormalities Normal Insulin release 5. Presence of 2 or more islet autoabs might represent asymtomatic T1D Overt diabetes 6. Increasing gluciose fluctuations as individual approaches symptomatic onset 7. Some patients produce low concentrations of C-peptide long after onset 4. Although overall loss of beta cell is potentially linear, it could show a relapsing or remitting pattern (Pozzilli P, Di Mario U, Diabetes Care 2001) Glucose normal C-peptide present No C-peptide 8. Beta cell mass not always absent in longstanding patients Age (years)

9 Immune system balance is the key to disease pathogenesis Bluestone JA, Herold K, Eisenbarth G, Nature 2010

10 Type 1 diabetes risk stratification by islet autoantibody properties Atkinson MA, Cold Spring Harb Perspect Med 2012

11 Topics to be discussed Epidemiology (increase in incidence) Genetics (more cases with moderate HLA risk alleles) Pathogenesis of type 1 diabetes Preservation of beta cell function (C-peptide secretion) Immunotherapy in type 1 diabetes Future directions

12 Patients with nearly undetectable C- peptide Require more insulin for treatment Prone to have higher HbA 1c levels Tend to develop complications later on Patients with higher C-peptide require less insulin for treatment lower HbA1c less frequent late complications Steffes MW et at, Diabetes Care 2003

13 Rates per 100 participant-years Preserving beta cell function to reduce late onset chronic complications (DCCT legacy) Retinopathy Albuminuria 0 Undetectable Minimal Baseline-only Sustained Stimulated C-Peptide Modified from Steffes WM et al, Diabetes Care 2003

14 ln [mean fasting C-peptide (nm)] Log-linear decline of fasting C-peptide over 5-years by age of onset of type 1 diabetes 0-0, Time since diagnosis (years) -1-1,5-2 5 years >5 and 10 years >10 and 18 years >18 years -2,5-3 R 2 = 0,9838-3,5-4 -4,5 R 2 = 0,9944 R 2 = 0,9748 R 2 = 0, Barker A,... Pozzilli P. Diabetes Obes Metab. 2013

15 Most Significant Findings C-peptide decline: Most from the second year Similar rate in all age group, although C-peptide values decline more in the very young group Not influenced by HbA1c at diagnosis Favoured by higher BMI at diagnosis - insulin resistance (data not presented:continuation of the C-peptide survey...) Barker A,... Pozzilli P. Diabetes Obes Metab. 2013

16 Continuation of the C-peptide survey...

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18 Considerations As consequence of the increase in obesity, new phenotypes of type 1 diabetes are diagnosed today associated with overweight and obesity Trends Endocrinol Metab Mar;18(2):52-7

19 Type 1 Diabetes: How & When to Intervene? Autoimmune disease, strong evidence for role of cellular immunity in destruction of beta-cells. Many components of the immune system participate. Many autoantigens involved, hierarchy not really clear. Difference in presentation, mainly age-associated: Genetic predisposition Length of non-symptomatic phase Autoantigens/autoantibodies involved Components of insulin resistance BMI The Mechanisms Leading to beta-cell Destruction are Potential Targets for Therapeutic Intervention.. 19

20 Prevention of beta cell damage in type 1 diabetes at diagnosis: A GOAL TO REACH

21 Prevention of beta cell loss: When, why, with what WHEN? Presence of sufficient residual beta cell function (basal C-peptide nm) and by at least two years from onset. WHY? Reduction in microangiopath when stimulated C- peptide >0.2 nm (DCCT data) WITH WHAT? Drugs which induce immune tolerance to beta cell antigens with a beneficial cost/benefit ratio Barker A,... Pozzilli P. Diabetes Obes Metab WM et al, Diabetes Care 2003

22 Prevention opportunities Dietary modifications Antigen-specific vaccines (TRIGR, BABY DIET, Pre-POINT) Oral/intransal insulin Nicotinamide (DPT-1, ENDIT, DIPP) Modified from Rewers and Gottlieb, Diabetes Care 2009

23 Prevention opportunities Is reasonable to believe that secondary prevention should be easier to achieve than tertiary prevention as there are more intact β-cells left. The mild therapeutic regimens used thus far have failed to halt β-cell deterioration Indeed. There is a reluctance to try more aggressive treatment as potential side effects are unacceptable in apparently healthy, non-diabetic subjects who are often at a young age.

24 Induction of immunomodulation in type 1 diabetes: WITH WHAT? Red arrows depict inhibiting actions, black arrows illustrate stimulatory actions. CTLA-4 T-cell target Therapy Anti CD3 IL-1 receptor antagonist Anti CD20 Antiinflammatory B-cell direct Therapy GAD65 HSP60 Antigen specific therapy Modified from Reimann M et al. Pharmacology & Therapeutics 2009

25 Immunotherapy N Main outcome Preservation of C-peptide secretion Adverse events GAD vaccine 334 Change in stimulated C- peptide (MMTT) No No GAD vaccine 145 C-peptide AUC (MMTT) No No Teplizumab (anticd3) 516 HbA1c <6.5% and insuline dose <0.5U/kg/day at 1 year Yes? Rash, leucopenia, cytokine release syndrome (rare) Otelixizumab (anticd3) Abatacept (CTLA4) 208 C-peptide AUC (MMTT) No Constitutional symptoms 112 C-peptide AUC (MMTT) Yes? Constitutional symptoms IL-1 (Anakinra/Canakinu mab) Anti CD20 antibody (Rituximab) 82 C-peptide AUC (MMTT) No Injection site reactions 87 C-peptide AUC (MMTT) Yes? Fever, rash, hypotension, nausea Modified from Pozzilli P. Immunotherapy 2012

26 Antigen specific immunotherapy with glutamic acid decarboxylase (GAD65) Glutamic acid decarboxylase (GAD) is a major target of the autoimmune response that occurs in type 1 diabetes mellitus In animal models of autoimmunity, treatment with a target antigen can modulate aggressive autoimmunity

27 Glutamic acid decarboxylase N Engl J Med 2012;366: Italian coordinator centre: Univ. Campus Bio-Medico (Prof. Pozzilli)

28 C-Peptide and GAD65 autoantibody levels, according to study group p=0.10 Treatment with GADalum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15- month period. Ludvigsson J Pozzilli P, N Engl J Med, 2012

29 Antigen based immunotherapy therapy using GAD-alum given subcutaneously in two or three doses over 4 to 12 weeks does not alter the course of loss of insulin secretion over one year in subjects with recently diagnosed T1DM. While antigen-based therapy is a highly desiderable treatment and is effective in animal models, traslation to human autoimmune disease remains a challenge. Diane K, Lancet, 2011

30 Non antigen specific immunotherapy with anti-cd3 monoclonal antibody (Teplizumab) It induces a complete and long remission when administered to diabetic animals. Capable of inducing peripheral immunological tolerance. Effect mediated by generation of TGF-beta dependent T cells.

31 Sherry N et al. Lancet 2011

32 Sherry N et al. Lancet 2011

33 Finding of exploratory analyses suggest that future studies of immunotherapeutic intervention with Teplizumab might have increased success in prevention of a decline in β-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children. Sherry N et al. Lancet 2011

34 DEFEND-1: Durable Response Therapy Evaluation For Early or New-Onset Type 1 Diabetes study Primary objective: New-onset type 1 diabetes (N 240) Phase III randomized, double-blind study to determine if otelixizumab reduces insulin requirement by inhibiting beta cell loss in new-onset type 1 diabetes Otelixizumab (n 160) Placebo (n 80) Patient population: New-onset type 1 diabetes (within 90 days; N 240), aged years Primary endpoint: Secondary endpoints: Change in C-peptide Insulin use, HbA1c Study commenced: May 2008 Study completed: December 2010 Italian coordinating centre: Univ. Campus Bio-Medico (P Pozzilli)

35 Comparison of otelixizumab versus placebo for C-peptide mean area under the curve Otelixizumab Placebo Gottlieb et al. In preparation

36 Non antigen specific immunotherapy with Anti-CD80 monoclonal antibody (extra cellular domain of CTLA-4 - Abatacept) Abatacept selectively binds to CD80 and CD86, thereby blocking the interaction with CD28 and interfering with the early phases of T-cell activation, proliferation, and survival It inhibits naive T-cell activation, thus having the potential to selectively inhibit T- cell response to specific antigens instead of broad immunosuppression Abatacept is mildly immunomodulatory, and it affects disease at early stages of pathogenesis. Studies in both animals and human beings have shown that interruption of the co-stimulatory second signal beneficially affects autoimmunity

37 C-peptide at diagnosis and during a 2 years follow-up period Patients aged 6 45 years recently diagnosed with T1D were randomly assigned (2:1) to receive abatacept (10 mg/kg, maximum 1000 mg per dose) or placebo infusions intravenously on days 1, 14, 28, and monthly for a total of 27 infusions over 2 years estimated 9 6 months' delay in C-peptide reduction with abatacept Orban T, Lancet, 2011

38 HbA1c and insulin dose at diagnosis and during a 2 years follow-up period p= Orban T, Lancet, 2011

39 C-peptide secretion from diagnosis up to 36 months: follow-up 1 year after cessation of treatment. P = Orban T, Diabetes Care, 2014

40 HbA1c and insulin dose from diagnosis up to 36 months follow-up 1 year after cessation of treatment. Orban T, Diabetes Care, 2014

41 Co-stimulation modulation with abatacept slowed decline of beta cell function over two years. The beneficial effect suggests that T-lymphocyte activation still occurs around the time of clinical diagnosis of T1DM. Yet, despite continued administration of abatacept over 24 months, the decline in beta cell function with abatacept was parallel to that with placebo after six months of treatment, causing us to speculate that T-lymphocyte activation may lessen with time. Further observation will determine whether the beneficial effect continues after cessation of Abatacept infusions. Orban T. et al, 2014

42 Non antigen specific immunotherapy with Anti-CD20 (B lymphocytes - Rituximab) Rituximab is a monoclonal antibody that is a chimeric murine/human monoclonal IgG1 kappa antibody It targets and deplets human CD20 expressing B cells Study in NOD mouse: a single cycle of treatment with a CD20 specific antibody temporarly depleted B cells and significantly delayed and/or reduced the onset of diabetes

43 Effects of Rituximab on C-peptide, HbA1c, insulin dose and CD19+ cell count P=0,03 P=0,001 Mark D, N Engl J Med, 2009

44 A four-dose course of Rituximab (Anti-CD20) partially preserved beta-cell function over a period of 1 year in patient with type 1 diabetes The finding that B lymphocytes contribute to the pathogenesis of type 1 diabetes may open a new pathway for exploration in the treatment of patients with this condition. Mark D, N Engl J Med, 2009

45 Immuno - therapy N Main outcome Preservation of C-petide secretion Adverse events GAD vaccine 334 Change in stimulated C- peptide (MMTT) No No GAD vaccine 145 C-peptide AUC (MMTT) No No Teplizumab (anticd3) 516 HbA1c <6.5% and insuline dose <0.5U/kg/day at 1 year Yes Rash, leucopenia, cytokine release syndrome (rare) Otelixizumab (anticd3) Abatacept (CTLA4) 208 C-peptide AUC (MMTT) No Constitutional symptoms 112 C-peptide AUC (MMTT) Yes Constitutional symptoms IL-1 (Anakinra/Canakinumab) 82 C-peptide AUC (MMTT) No Injection site reactions Anti CD20 antibody 87 C-peptide AUC (MMTT) Yes Fever, rash, hypotension, nausea Modified from Pozzilli P. Immunotherapy 2012

46 Why immunointervention did not stand at the hopes that everyone was expecting?

47 The latest studies are still negative Lancet Diabetes-Endocrinology 2013

48 Topics to be discussed Pathogenesis of type 1 diabetes Preservation of beta cell function (C-peptide secretion) Immunotherapy in type 1 diabetes Future directions

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50 Combination therapy

51 Regeneration of beta cells Regeneration of beta cells occurs, however it appears that is not sufficient Which product can help to regenerate beta cells?

52 Control autoimmunity Beta cell regeneration Cure To protect new beta cell mass Diabetes Metab Res Rev. 2013

53 Abstract We retrospectively studied whether treatment with esomeprazole improved HbA1c levels in T2D patients. We selected 21 patients who had been treated with esomeprazole for 11±3 months and 21 controls. HbA1c levels decreased in the esomeprazole-treated group. Our data indicate that proton pump inhibitors may improve glycaemic control in T2D patients. Hove KD et al. Diabetes Res Clin Pract 2010

54 31 patients were randomized to receive pantoprazole (n=16) or placebo (n=15) 12 weeks of pantoprazole therapy significantly increased plasma gastrin and insulin levels and improved beta cell function (p<0.05) along with a significant decrease in HbA1c. Singh PK et al. JCEM 2012

55 Protection from autoimmunity Cyclosporine (CyA) is an immunosuppressant agent consisting of 11 amino acids

56 Usage and Dosages for Cyclosporine Disease State Drug Oral Injectable Organ Transplant Sandimmune mg/kg/day, taper to 5-10 mg/kg/day in 1-2 weeks 5-6 mg/kg/day Neoral or a bioequivalent 7-9 mg/kg/day, taper to 5-10 generic mg/kg/day in 1-2 weeks Rheumatoid Arthritis Neoral or a bioequivalent mg/kg/day in two generic divided doses Psoriasis Neoral or a bioequivalent mg/kg/day in two generic divided doses Crohn's Disease Sandimmune 4 mg/kg/day Ulcerative Colitis Sandimmune 4 mg/kg/day Nephrotic Syndrome Brand not specified 3.5 mg/kg/day in two divided doses Multiple sclerosis Brand not specified 7.2 mg/kg/day Lupus Brand not specified 2.5 mg/kg/day Alopecia Areata Brand not specified 3-5 mg/kg/day Atopic Dermatitis Brand not specified 5 mg/kg/day Dermatomyositis Brand not specified 3-10 mg/kg/day Lichen Planus Brand not specified 6 mg/kg/day Myasthenia Gravis Brand not specified 5 mg/kg/day Polymyositis Brand not specified 2.5 mg/kg/day Psoriatic Arthritis Brand not specified 3.5 mg/kg/day Pulmonary Sarcoidosis Brand not specified 5-7 mg/kg/day Uveitis Brand not specified mg/kg/day

57 Cyclosporine in Type 1 diabetes: history (n= 692 treated patients) Cyclosporine A had a 67.5% insulin-free remission among recent onset type 1 patients, with 50% of patients sustaining the insulinfree state after 12 months (Bougneres PF et al. N Engl J Med 1988) Remissions are not typically sustained more than 2 years (De Filippo G et al. Diabetes 1996) Renal side effects were not seen in the many trials, including a published cohort of 285 patients with recent type 1 diabetes followed for up to 13 years after 20 months of therapy on cyclosporine (Assan R et al. Diabetes Metab Res Rev 2002) Cyclosporine was abandoned because it was not curative and not because of short term adverse effects

58 Effect of CyA treatment on T1DM remission rates (as reported by the Cyclosporine Diabetes French Study) Feutren G, Papoz L, Assan R, et al, Lancet 1986

59 Insulin independence trial : the new trial in recent onset Type 1 diabetes Primary Endpoint To demonstrate that subjects with type 1 diabetes with C-peptide levels of greater than or equal to 0.6 ng/ml (0.2 nmol/l) become insulin-free by 6 months of therapy with Cyclosporine A and Lansoprazole. Insulin independence is defined, at 6 months, as absence of insulin requirements for one week with fasting glucose below 126 mg/dl (6.9 mmol/l) Inclusion criteria Age years Fasting C-peptide 0.2nm/L (0.6 ng/ml) Diagnosis of diabetes within 6 months of study enrollment From baseline to week 25 CyA 7.5 mg/kg/day along with Lansoprazole Serum levels of CyA maintained between ng/ml At 26 weeks those patients who are insulin-independent CyA reduced to 3.5 mg/kg/day and continue their same dosage of Lansoprazole for an addition 25 weeks Serum levels of CyA maintained between ng/ml ClinicalTrials.gov Identifier: NCT Study coordinator for Europe: Prof. Paolo Pozzilli

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