dr dario tuccinardi university campus bio-medico of rome d ... · teplizumab might have increased...

Dr Dario Tuccinardi University Campus Bio-Medico of Rome

[email protected]

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

Topics to be discussed

Type 1 diabetes: a multifactorial disease

Incidence of type 1 diabetes in children aged

0-14 years by geographical region and over time

Diabetes Atlas 2012

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.





peptide secretion)


Future directions


Low risk HLA genotpye

0

10

20

30

40

50

60

70

80

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

Moderate risk HLA genotpye p= ns for all

comparisons

Year of

diagnosis

Spoletini M et al, IMDIAB Group, Plos One 2013

1980-1989 1990-1999 2000-2012

%





peptide secretion)


Future directions


Modified from Atkinson MA, Eisenbarth GS, Michels AW. Lancet 2013

1. Precipitating events

might occur

in utero

2. Genetic predisposition

probably the key driver

and/or linked to

immune abnormalities

3. Environment may

influence

entire natural history

5. Presence of 2 or more

islet autoAbs might represent

asymtomatic T1D

6. Increasing gluciose fluctuations

as individual approaches

symptomatic onset

7. Some patients produce

low concentrations of

C-peptide long after onset

8. Beta cell mass not

always absent in longstanding

patients

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)

Genetic

predisposition

No C-peptide

C-peptide

present

Overt

diabetes

Glucose

normal

Progressive loss

Insulin release Overt immunological

abnormalities

Normal

Insulin release

Beta

cell m

ass

Age (years)

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.

Bluestone JA, Herold K, Eisenbarth G, Nature 2010

Immune system balance is the key to

disease pathogenesis

Atkinson MA, Cold Spring Harb Perspect Med 2012

Type 1 diabetes risk stratification

by islet autoantibody properties




Preservation of beta cell function

(C-peptide secretion)


Future directions


Patients with nearly undetectable C- peptide

•Require more insulin for treatment

•Prone to have higher HbA1c 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

0

1

2

3

4

5

6

7

8

9

Undetectable Minimal Baseline-only Sustained

Stimulated C-Peptide

Retinopathy Albuminuria

Rate

s per

100 p

art

icip

ant-

years

Modified from Steffes WM et al, Diabetes Care 2003

Preserving beta cell function to reduce

late onset chronic complications (DCCT

legacy)

R2 = 0,8316

R2 = 0,9748

R2 = 0,9944

R2 = 0,9838

-5

-4,5

-4

-3,5

-3

-2,5

-2

-1,5

-1

-0,5

0

0 1 2 3 4 5 6

Time since diagnosis (years)

ln [m

ean fasting C

-p

ep

tid

e (nM

)]

≤5 years>5 and ≤10 years>10 and ≤18 years>18 years

Log-linear decline of fasting C-peptide over

5-years by age of onset of type 1 diabetes

Barker A, .... Pozzilli P. Diabetes Obes Metab. 2013

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...)


Continuation of the C-peptide survey ....

……

As consequence of the increase in obesity,

new phenotypes of type 1 diabetes are

diagnosed today associated with overweight

and obesity

Considerations

Trends Endocrinol Metab. 2007 Mar;18(2):52-7

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

Prevention of beta cell damage in

type 1 diabetes at diagnosis:

A GOAL TO REACH

WHEN ? Presence of sufficient residual beta cell function

(basal C-peptide 0.10-0.20 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

Prevention of beta cell loss:

When, why, with what


WM et al, Diabetes Care 2003

Prevention opportunities

Modified from Rewers and Gottlieb, Diabetes Care 2009

Dietary modifications

Antigen-specific vaccines

(TRIGR, BABY DIET, Pre-POINT)

Oral/intransal insulin

Nicotinamide

(DPT-1, ENDIT, DIPP)

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.

Prevention opportunities

Modified from Reimann M et al. Pharmacology & Therapeutics 2009

GAD65

HSP60

Anti CD3

CTLA-4

Anti CD20

IL-1 receptor

antagonist

Induction of immunomodulation in type 1 diabetes: WITH WHAT ? Red arrows depict inhibiting actions,

black arrows illustrate stimulatory

actions.

Anti-

inflammatory

B-cell direct Therapy

Antigen specific therapy

T-cell target Therapy

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)

208 C-peptide AUC (MMTT) No Constitutional symptoms

Abatacept

(CTLA4)

112 C-peptide AUC (MMTT) Yes ? Constitutional symptoms

IL-1 (Anakinra/Canakinu

mab)

82 C-peptide AUC (MMTT)

No Injection site reactions

Anti CD20 antibody (Rituximab)


Yes ? Fever, rash, hypotension,

nausea

Modified from Pozzilli P. Immunotherapy 2012

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

Italian coordinator centre: Univ. Campus Bio-Medico (Prof. Pozzilli)

Glutamic acid decarboxylase

N Engl J Med 2012;366:433-442

Ludvigsson J… Pozzilli P, N Engl J Med, 2012

C-Peptide and GAD65 autoantibody levels, according to study group

Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period.

p=0.10

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

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.

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.

Sherry N et al. Lancet 2011

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

Primary objective: Phase III randomized, double-blind study to determine

if otelixizumab reduces insulin requirement by inhibiting

beta cell loss in new-onset type 1 diabetes

Patient population: New-onset type 1 diabetes (within 90 days; N ≈ 240),

aged 12–45 years

Primary endpoint: Change in C-peptide

Secondary endpoints: Insulin use, HbA1c

Study commenced: May 2008

Study completed: December 2010

DEFEND-1: Durable Response Therapy Evaluation

For Early or New-Onset Type 1 Diabetes study

Otelixizumab (n ≈ 160)

Placebo (n ≈ 80)

New-onset

type 1 diabetes

(N ≈ 240)

Italian coordinating centre: Univ. Campus Bio-Medico (P Pozzilli)

Comparison of otelixizumab versus placebo for

C-peptide mean area under the curve

Otelixizumab

Placebo

Gottlieb et al. In preparation


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

Orban T, Lancet, 2011

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

HbA1c and insulin dose at diagnosis and during a 2 years follow-up period

p=0·0029

Orban T, Diabetes Care, 2014

C-peptide secretion from diagnosis up to 36 months:

follow-up 1 year after cessation of treatment.

P = 0.046

Orban T, Diabetes Care, 2014

HbA1c and insulin dose from diagnosis up to 36 months

follow-up 1 year after cessation of treatment.

Further observation will determine whether the beneficial

effect continues after cessation of Abatacept infusions.

Orban T. et al, 2014

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.


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

Mark D, N Engl J Med, 2009

Effects of Rituximab on C-peptide, HbA1c, insulin dose and CD19+ cell count

P=0,03 P=0,001

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

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

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)

208 C-peptide AUC (MMTT) No Constitutional symptoms

Abatacept

(CTLA4)

112 C-peptide AUC (MMTT) Yes Constitutional symptoms

IL-1 (Anakinra/Canakinumab)


No Injection site reactions

Anti CD20 antibody 87 C-peptide AUC (MMTT)

Yes Fever, rash, hypotension,

nausea

Modified from Pozzilli P. Immunotherapy 2012

Why immunointervention

did not stand at the hopes

that everyone was expecting ?

The latest studies are still negative …

Lancet Diabetes-Endocrinology 2013

• Pathogenesis of type 1 diabetes

• Preservation of beta cell function

(C-peptide secretion)

• Immunotherapy in type 1 diabetes

• Future directions


Combination therapy

Regeneration of beta cells occurs, however it appears that is not sufficient …

Which product can help to regenerate beta cells ?

Regeneration of beta cells

Diabetes Metab Res Rev. 2013

Control

autoimmunity Beta cell

regeneration

To protect new

beta cell mass

Cure

Hove KD et al. Diabetes Res Clin Pract 2010

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.

Singh PK et al. JCEM 2012

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.

Protection from autoimmunity

Cyclosporine (CyA) is an immunosuppressant agent consisting of 11 amino acids

Disease State Drug Oral Injectable

Organ Transplant Sandimmune 14-18 mg/kg/day, taper to 5-

10 mg/kg/day in 1-2 weeks

5-6 mg/kg/day

Neoral or a bioequivalent

generic

7-9 mg/kg/day, taper to 5-10

mg/kg/day in 1-2 weeks

Rheumatoid Arthritis Neoral or a bioequivalent

generic

2.5–4 mg/kg/day in two

divided doses

Psoriasis Neoral or a bioequivalent

generic

2.5–4 mg/kg/day in two

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 2.5-5 mg/kg/day

Usage and Dosages for Cyclosporine

Cyclosporine A had a 67.5% insulin-free remission among recent

onset type 1 patients, with 50% of patients sustaining the insulin-

free 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

Cyclosporine in Type 1 diabetes:

history (n= 692 treated patients)

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

“Insulin independence trial”:

the new trial in recent onset Type 1 diabetes

•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)

Primary Endpoint

•Age 10-35 years

•Fasting C-peptide ≥ 0.2nm/L (0.6 ng/mL)

•Diagnosis of diabetes within 6 months of study enrollment

Inclusion criteria

•CyA 7.5 mg/kg/day along with Lansoprazole

•Serum levels of CyA maintained between 150-200 ng/ml

From baseline to week 25

•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 75-100 ng/ml

At 26 weeks those patients who are insulin-independent

ClinicalTrials.gov Identifier: NCT01762644 Study coordinator for Europe: Prof. Paolo Pozzilli

dr dario tuccinardi university campus bio-medico of rome d ... · teplizumab might have increased...

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