Can Type 1 Diabetes Be Prevented?

Della Matheson, RN, CDEResearch Coordinator, Type 1 Diabetes TrialNetUniversity of Miami, Diabetes Research Institute

Type 1 Diabetes Prevention in NOD MiceAAV murine IL-10AAV rat preproinsulin gene (vLP-1)Adenovirus expressing mIL-4Aerosol insulinAllogenic thymic macrophagesAlpha GalactosylceramideAlpha-interferon (rIFN-alpha)Alpha/beta T cell receptor thymocytes AminoguanidineAndrogensAnesthesiaAntioxidant MDL 29,311Antisense GAD mRNAAzathioprineAnti-B7-1Bacille Calmette Gue’rin (BCG)BaclofenBee venomBiolistic-mediated IL-4Blocking peptide of MHC class IIBone marrow transplantationCastrationAnti-CD3Anti-CD4CD4+CD25+regulatory T cellsAnti-CD8Anti-CD28 MAbCholera toxin B subunit-insulin proteinClass I derived self-I-A beta(g7) (54-76) peptideCold exposureAnti-complement receptorComplete Freund’s adjuvantAnti-CTLA-4Cyclic nucleotide phosphodiesterases (PDEs)CyclosporinCyclosporin ADC deficient in NF-kappaBDC from pancreatic lymph nodeDC with IL-4DeflazacortDeoxysperogualinDexamethasone/progesterone/growth hormone/estradiolDiazoxide1,25 dihydroxy Vitamin D3, KH10601,25 dihydroxycholecalciferol1,25 dihydroxyl Vitamin D3Elevated temperatureEmotionalityEncephalomyocarditis virus (ECMV)Essential fatty acid deficient dietsFK506FTY720 (myriocin)GAD 65 peptides in uteroAnti-GAD monoclonal antibodyGalactosylceramideGlucose (neonatal)Glutamic acid decarboxylase(intraperitoneal, intrathymic, intravenous, oral)Glutamic acid decarboxylase 65 Th2 cell cloneGlutamic acid decarboxylase peptides(intraperitoneal, intrathymic, intravenous, oral)

GonadectomyGuanidinoethyldisulphideHeat shock protein 65Heat shock protein peptide (p277)Hematopoietic stem cells encoding proinsulinHousing aloneHuman IGF-1I-A beta g7(54-76) peptideAnti-I-A monoclonal antibodiesAnti-ICAM-1IgG2a antibodiesImmobilizationInomideAnti-integrin alpha 4Insulin (intraperitoneal, oral, subcutaneous, nasal)Insulin B chain (plasmid)Insulin B chain/B chain amino acids 9-23 (intraperitoneal, oral, subcutaneous, nasal)Insulin-like growth factor I (IGF-I)Anti-intercellular adhesion molecule-1 (ICAM-1)Interferon-alpha (oral)Interferon-gammaAnti-interferon-gammaInterferon-gamma receptor/IgG1 fusion proteinInterleukin-1Interleukin-4Interleukin-4-Ig fusion proteinInterleukin-4-plasmidInterleukin-10Interleukin-10-plasmid DNAInterleukin-10-viralInterleukin 11-human Interleukin-12Intrathymic administration of mycobacterial heat shock protein 65 Intrathymic administration of mycobacterial heat shock peptide p277Islet cells-intrathymicL-Selectin (MEL-14)Lactate dehydogenase virus (LDH)Large multilamellar liposomeLazaroidAnti-leukocyte function associated antigen (LFA-1)Anti-LFA-1Linomide (quinoline-3-carboxamide)Lipopolysaccharide-activated B cellsLisofyllineLymphocyte choriomeningitis virus (LCMV)Anti-lymphocyte serumLymphoctyte vaccinationLymphocytic choriomeningitis virusAnti-L-selectinLymphotoxinLZ8MC1288 (20-epi-1,25-dihydroxyvitamin D3)MDL 29311Metabolically inactive insulin analogAnti-MHC class IAnti-MHC class IIMHC class II derived cyclic peptideMixed allogeneic chimerismMixed bone marrow chimerasMonosodium glutamateMurine hepatitis virus (MHV)

Mycobacterium aviumMycobacterium lepraeNatural antibodiesNatural polyreactive autoantibodiesNeuropeptide calcitonin gene-related peptideNicotinamideNicotineNinjin-to (Ren-Shen-Tang), a Kampo (Japanese traditional) formulationNKT cellsNY4.2 cellsOK432OvercrowdingPancreatectomyPentoxifyllinePertussigenPoly [I:C]Pregestimil dietPrenatal stressPreproinsulin DNAProbucolProlactinRampamycinRecombinant vaccinia virus expressing GADReg proteinReg proteinRolipramSaline (repeated injection)Schistosoma mansoniSemi-purified diet (e.g., AIN-76)Short term chronic stressSilicaSirolimus/tacrolimusSodium fusidateSoluble interferon-gamma receptorSomatostatinNon-specific pathogen free conditionsStreptococcal enterotoxinsStreptozotocinSulfatide (3’sulfogalactosylceramide)SuperantigensSuperoxide dismutase-desferrioxamineAnti-T cell receptorTGF-beta 1 somatic gene therapyTh1 clone specific for hsp60 peptideAnti-thy-1Thymectomy (neonatal)TolbutamideTolerogenic dendritic cells induced by vitamin D receptor ligandsTop of the rackTreatment combined with a 10% w/v sucrose-supplemented drinking water Tumor necrosis factor-alphaTX527 (19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3))Vitamin EAnti-VLA-4

Azathioprine & Steroids

Silverstein et al NEJM 1988;319:599-604

Canadian-European Cyclosporin Study Remissions

Skyler, Diabetes 1988; 37:1574-1582

Discovery of Insulin Auto-Antibodies

Natural History of Type 1 Diabetes

CELLULAR (T CELL) AUTOIMMUNITY

LOSS OF FIRST PHASE

INSULIN RESPONSE (IVGTT)

GLUCOSE INTOLERANCE(OGTT)

HUMORAL AUTOANTIBODIES(ICA, IAA, Anti-GAD65, IA2Ab, ZnT8 )

PUTATIVEENVIRONMENTAL

TRIGGER

CLINICALONSET

TIME

BET

A C

ELL

MA

SS

DIABETES

“PRE”-DIABETES

GENETICPREDISPOSITION

INSULITISBETA CELL INJURY

ADA Position Statement: 1990• Sufficient data exist to warrant intervention studies for prevention of T1D

• Intervention for prevention should be attempted only in the context of defined clinical trials

• Intervention studies are best accomplished by randomized controlled studies

• A registry of intervention studies should be maintained, and all planned studies should be reported to a coordinating body

• Screening of high risk populations is encouraged

• Risk assessment, counseling, and follow-up must be offered.

• Studies must be evaluated on the basis of potential risks vs. benefits; children should not be excluded, on the basis of age alone, from a therapeutic study that may benefit them by preventing diabetes

How Risk is Determined

• Step 1: Screening antibody testing • Step 2: Monitoring

OGTT HbA1c

HLA (DQA0102, DQB0602) Risk Score (age, BMI, C-

peptide)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

241511718405378147

22297140129725595

17049104522919261

1180774316313040

90525571187830

7439457914922

6198371663116

Number at Risk

Surv

ival

Dis

trib

utio

n Fu

nctio

n

P- Value< 0.001(Log Rank Test)

352419935148

0 1 2 3 4 5 6 7

Years Followed

STRATA: 0 1 2

8

01234

3 4

DPT-1 – Time to Diabetes By Number of Antibodies

n = 26799

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 1 2 3 4 5 6 7 8 9 10

Combined DPT-1 Parenteral & Oral Insulin Trials

576426536

Number at Risk

Surv

ival

Dis

trib

utio

n Fu

nctio

n

P- Value< 0.001(Log Rank Test)

Years Followed

IGT only

Normal Glucose Tolerance

CombinedIndeterminate only

STRATA: Comb IFG + (IGT or Indet) IGT OnlyIndet Only NGT

425120499

233516410

16199308

967220

Comb IFG+(IGTor Indet)IGT OnlyIndet OnlyNGT

323110

11

43

11

2

1

Indeterminate:BG > 200 mg/dl at 30, 60, or 90 min

DPT-1 Objective• To determine of antigen based

therapy (specifically insulin) could prevent or delay onset of T1D

• Parenteral Insulin In Subjects with High Risk: > 50% 5 year risk

• Oral Insulin In Subjects with Moderate Risk: 25-50% risk

The DPT·1 Funnel103,391 Relatives

Screened 97,635 Eligible Samples 97,273 Samples

Analyzed 3483 Samples ICA+

(3.58%) 711 Subjects

Randomized

DPT-1 Parenteral Study – Time to DiabetesBy Treatment

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0169170

144131

96101

6969

3940

1314 1

Number at Risk

Surv

ival

Dis

trib

utio

n Fu

nctio

n

P- Value= 0.796(Log Rank Test)

InterventionObservation

0 1 2 3 4 5 6 7

Years FollowedSTRATA: Intervention Observation

Control

Treated

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

186186

174170

146137

110102

8571

4037

2312

Number at RiskSurv

ival

Dis

trib

utio

n Fu

nctio

n

P- Value= 0.188(Log Rank Test)

Oral InsulinOral Placebo

0 1 2 3 4 5 6 7Years Followed

STRATA: Oral Insulin Oral Placebo

DPT-1 Oral Insulin Trial Time to Diabetes By Treatment

Control

Treated

DPT-1 Oral Study - Time to Diabetes - By TreatmentSubset: IAA Confirmed > 80 nU/ml

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Surv

ival

Dis

trib

utio

n Fu

nctio

n

0 1 2 3 4 5 6 7

Years Followed

130133

122121

10496

8669

6646

4032

2312

Number at Risk

P- Value= 0.015(Log Rank Test)

Oral InsulinOral Placebo

STRATA: Oral Insulin Oral Placebo

Control

Treated

Diabetes Care 2005; 28:1068-76

Projected 4.5 – 5 year delay

Insulin Effect Most Evident in Subjects with Baseline IAA ≥ 300

N=63 (Ins.) and 69 (Plac.)

IAA >= 300

Years

Pro

porti

on F

ree

of D

iabe

tes

0 1 2 3 4 5 6

0.0

0.2

0.4

0.6

0.8

1.0

Oral InsulinPlacebo

Log-rank P=0.01

Peto Pr. P=0.01

Hazard Ratio: 0.41 (0.21, 0.80)

Projected 10 year delay

endit

European Nicotinamide Diabetes

Intervention Trial

es

Perc

enta

ge d

evel

opin

g di

abet

es

Nicotinamide

Placebo

0

10

20

30

40

50

0 1 2 3 4 5Years since randomisation

PlaceboNicotinamide

275274

245260

232232

205208

184171

Overall Treatment Effect:Intention To Treat Analysis

N = 549

NIDDK NIAID NICHDNCRR

ADAJDRF

TrialNet Sites in North America14 Clinical Centers

+ 200 North American Affiliates

Melbourne, AustraliaMilan, Italy

Turku, Finland

Bristol, UK

TrialNet International Sites

Malmo, Swedem

Munich, Germany

+ 25 International Affiliates

Other NIH Funded Consortiums Immune Tolerance Network

TRIGR Study (Trial to Reduce IDDM in the Genetically At Risk)

breastfeeding/hydrolyzed formula vs standard formula; 2,160 babies to be followed x 10 years; results expected in 2017

TEDDY(Environmental Triggers and Determinants of Type 1 Diabetes) 7,801 babies: 788 first degree

relatives with genetic risk (10% risk), 7013 non- relatives with genetic risk (3%)

2836 families (11,626) sib pairs493 families (1479): trio’s

968 Controls

Natural History of Progression to Type 1 Diabetes

BETA

CEL

L M

ASS

C

Risk: Low(no antibodies)• Natural

History(Screening 113,000)

Genetic & Mechanistic Studies

Risk: LowTo Moderate(antibodies presentNormal OGTT)• Natural

History(Monitoring)

Risk:High(multiple antibodies&/or abnormalOGTT)

DiabetesDiagnosed

New Onset Studies:• MMF/DZB • AntiCD20• CTLA-4 Ig• GAD-alum• Anti-IL1β• Metabolic Control

(DirectNet) • Thymo (ITN)• IL-2/Rapa (ITN)• AntiCD3 (ITN)• Alefacept (ITN) not

yet completed

ANTI-CD3

ORAL INSULINNIP Pilot

CTLA-4IG

Helminths

Strategies for Interdicting Type 1 Diabetes

Immunosuppressive Agents: Inhibit or Prevent Activity of the Immune System:

Cyclosporin √ Anti-CD20 (Rituximab) √Azathiaprine √ CTLA-4Ig (Abatacept) √MMF/DZB Anti-CD3 (Teplizumab) √Thymoglobulin (ATG)IL2/Rapamycin Not yet reported:

Alefacept (anti-CD2)

ß cell

APC TH 0cell TH 2

Protective CytokinesIL-4, IL-4, IL10Beta cell survival

ß cell

APC TH 0cell TH 1

CytotoxicMØ

& T CellsDeath IL-1, TNF-ą, TN-ß, IFN-y

02, H202, NO

TH 2

How Immunosuppressive Agents Work

Destructive Cytokines

Other Strategies for Interdicting Type 1 Diabetes

Antigen-Specific Therapies • rhGAD65 with Alum (Diamyd)• Oral Insulin √

Probiotic TherapyHelminths (TSO)

ß cell

APCTH 0cell TH 1

Destructive CytokinesIFN-y, IL-2

CytotoxicMØ

& T CellsDeath IL-1, TNF-ą, TN-ß, IFN-y

02, H202, NO

TH2

Protective T cells

Choosing the Right Therapy

• The Benefit vs. Risk Ratio must be appropriate to the degree of risk for development of type 1 diabetes

• Must have proven efficacy

• Must be able to include children

Anti-CD3 (Teplizumab)

• High Risk: > 75% Risk for development of type 1 diabetes over the next 5 years

• 140-170 participants ; follow-up 4-6 years• 1:1 randomization; Teplizumab: Control• 14 Day Infusion (51mcg/m2 -826mcg/m2 day 4-

13)• Ages: 8-45 of 633 participants in studies using AntiCD3, 378 were children

Risk: AntiCD3• Lymphopenia (low WBC): 15%

with 2% graded as severe• Infections 49.5% with 48.6% mild

to moderate• Cytokine Release Syndrome:

5.7% with 85% mild moderate - chills, fever, headache, nausea, vomiting, achiness

• Rash 42-62%

hOKT3g1(Ala-Ala) in new onset Type 1 diabetes

Month

0 6 12 18 24

AU

C (p

mol

/ml/2

40m

in)

0

20

40

60

80

100

120

140

160

DrugControl

Month

0 5 10 15 20 25 30

Insu

lin d

ose

(U/k

g)

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

DrugControl

Month

0 5 10 15 20 25 30

Hem

oglo

bin

A1c

(%)

5

6

7

8

9

10

Drug Control

Insulin useHemoglobin A1cC-peptide

Therapies for Moderate Risk: CTLA 4Ig (Abatacept)

Moderate risk: >32% 5 year risk• 2 antibodies (but not mIAA)• Normal OGTT• Ages 6-45• 1:1 randomization, 206 participants• 14 infusions over 1 year (2 in the first

month, then 1 monthly)• Follow: primary outcome: abnormal GTT

secondary outcome: diabetes

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3462593/figure/F2/

CTLA-4Ig (Abatacept) Risks

Infusion and Hypersensitivity Reactions: 2% (47 of 2,514)

Infectious Adverse Events: 54% in Abatacept and 48% Control; most upper respiratory infections with no increase in neutropenia or EBV

Therapies for Moderate Risk: Oral Insulin

Oral Insulin: >32% 5 year risk• 2 antibodies, one of which is “insulin

autoantibody (mIAA)” • Normal Oral Glucose Tolerance Test• Ages 4-45• Risk – no adverse events or side effects

observed in DPT-1• 1 capsule per day (7.5mg) • 1:1 randomization

Antigen Based Therapy/Oral Tolerance: Mode of Action

Protective Cytokines

Insulin Producing-cells

Oral Antigen

Inhibition of -CellAutoimmunity and

Prevention of Diabetes

Autoimmune Lymphocytes

Regulatory (Th2 / Th3) Lymphocytes Producing

Protective Cytokines

Therapy for Low to Moderate Risk

Helminths: Trichuris suis ova(Porcine whipworm ova)

• Proof of principle established in inflammatory bowel disease and MS

•Oral bi-weekly administration

•Well tolerated• Use of therapeutic helminth

therapy based on the “Hygiene Hypothesis”

Hygiene Hypothesis

1910 = 65% helminthic infections; current = < 2%

1901 Paul Ehrlich dictum: “autotoxicus”: body’s immune system would never attack host tissue to cause disease20th Century brought an end to this theory with the identification of > 80autoimmune diseases.

Coronado Biosciences

Enhance expression Of Protective T Regulatory Cells

Coronado Biosciences 40

Patients and Methods

This was a randomized, double blind, placebo-controlled trial conducted at the University of Iowa and select private practices. Trichuris suis ova were obtained from the US Department of Agriculture. The trial included 54 patients with active colitis, defined by an Ulcerative Colitis Disease Activity Index of > or =4. Patients were recruited from physician participants and were randomly assigned to receive placebo or ova treatment. Patients received 2500 Trichuris suis ova or placebo orally at 2-week intervals for 12 weeks.

Results ASP 1002 significantly improved UCDAI versus placebo (stool frequency, presence of blood in the stool, mucosal appearance)

Conclusion Ova therapy seems safe and effective in patients with active colitis.

Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial

Summers, et.al., Gastroenterology 2005

Coronado Biosciences

Does not multiply in human host

Colonization is self-limited in humans

No systemic phase

No direct transmission

Ova stable

Benefits of Trichuris suis ova (TSO)

41

Side Effects limited to GI symptoms: nausea, upper abdominal cramping,Diarrhea, flatulence occurring during the first few weeks of treatment and then subsiding

Coronado Biosciences 42

Effect of Helminths on the Prevention of Insulin Dependent Diabetes Mellitus in Non-obese Mice

Cooke, et.al., Parasite Immunology 1999

Coronado Biosciences 43

Inhibition of Diabetes by Helminth Infection

Saunders, et.al, Infect. Immunol 2007

Can Type 1 Diabetes be Prevented?

CLINICALONSET

TIME

BET

A C

ELL

MA

SS

DIABETES

“PRE”-DIABETES

GENETICPREDISPOSITION

INSULITISBETA CELL INJURY

Helminths

ORAL INSULIN

CTLA-4IGANTI-CD3

Combination Therapies may need to be employed• primary prevention• anti-inflammatory agents• beta cell expansion therapies• antigen-specific therapies• immunosuppressive agents

New Onset Studies Underway:• UCSF, Phase 1 Study: Infusion of T

regulatory cells; 14 participants, ages 18-45

• Albert Einstein College of Medicine, Bronx NY, Phase 4: Exenatide; 20 patients, ages 12-18

• University Sao Paulo General Hospital, Phase 1:

High Dose Immunosuppression and AutologousHematopoeitic Stem Cells; 30 participants, ages 16-35

Why is Prevention Important?

Without prevention there is no Cure!!!!Evidence of reactivated autoimmunity after whole organ and islet cell transplantation

Get Involved – participate in Research www.clinicaltrials.govwww.diabetestrialnet.orgwww.immunetolerance.org

Debt of Gratitude