Immune Therapy for T1D

Antoinette Moran, MDProfessor and Division Chief

Pediatric EndocrinologyUniversity of Minnesota

Disclosures

In the last 3 years Dr. Moran has

• Served on an DSMB for Novo Nordisk

• Served on advisory boards for Debiopharm, Vertex, Caladriusand Genentech

• Received research grant supplies only, investigator initiated, from Novo Nordisk and Lifescan

• Received industry research grant support pharma-initiated from Pfizer, Novartis

Objectives

1) Discuss the natural history of autoimmune diabetes

2) Understand that T1D can be predicted and has 3 expected and progressive stages that offer opportunities for specific intervention

3) Discuss various approaches to immune intervention to modify the course of T1D

STAGE 4

GeneticRisk

ImmuneActivation

ImmuneResponse

STAGE 1 STAGE 2 STAGE 3

Natural History of T1D

Normal Blood Sugar≥ 2 autoantibodies START OF T1D

Abnormal Blood Sugar≥ 2 autoantibodies

Clinical Diagnosis≥ 2 autoantibodies

Immune ResponseDevelopment of single

autoantibody

Starting PointIf you have a relative:

15x greater risk of developing T1D

Long-standingT1D

Immune ActivationBeta cells are attacked

The Stages to Type 1 Diabetes

Staging Presymptomatic Type 1 Diabetes: A Scientific Statement of JDRF, the Endocrine Society, and the American Diabetes AssociationDiabetes Care 2015;38:1964–1974

The Number of Autoantibodies Correlates with Risk of Progression to Clinical Disease

DAISY, DIPP and BABYDIAB

No Antibodies

1 Antibody

2 Antibody3 Antibodies

Pro

po

rtio

n W

ith

ou

t T1

D

Years

Not Diabetes

Diabetes

Predicting the Course of T1D

Stage MattersBut Needs to Be Interpreted Relative to Age

T1D Starts at Stage 1---Age Determines Progression Rate

Stage 1 risk of developing clinical (Stage 3) T1D within 10 yrs:• Adults: ~40%• Adolescents: 50-75%• Children under age 10: 85-95%

There is a particularly strong age effect once dysglycemia develops (Stage 2)

Age 5-9Age 10-14Age 15-19

Age ≥20

How are the Stages and Consideration of Age Useful?

• Provide a new standardized taxonomy for T1D

• Provide prognostic information for patients and families

• Aid design of clinical trials through risk profiles, subject stratification, and stage and age-specific clinical trial end points

• Eventually may promote precision medicine, tailoring optimal therapies to specific individuals at specific stages of the disease

Immune Therapy for T1D

• Progress in immunosuppression therapy over the last ~30 years has allowed long term success in organ transplantation

• This has opened the door for similar approaches to treating autoimmune diseases

Cellular Immunity is Central to T1D Pathophysiology

– T1D is associated with specific HLA types

– Every recent onset T1D case has insulitis (nPOD)

– Islet antigen reactive T cells found in humans with T1D

‒ A bone marrow donor with T1D can transfer T1D to the recipient

‒ Auto-immunity recurs after islet or pancreatic transplant

Autoimmune activation of T-cells follows a predictable path that offers sites for intervention

Signal 1

Signal 2Signal 3

ActivatedT-cells

Disease Modifying Therapy in New Onset T1D

₋ Anti-CD3 (Teplizumab)

₋ CTLA4 Ig (Abatacept)

₋ Anti-CD20 (Rituximab)

₋ Low dose ATG (thymoglobulin)

• Goal: prevent further loss of ß-cells (keep the patient in a perpetual honeymoon phase of T1D)

• We have been able to use immunomodulatory therapy to stop or slow progression of T1D for up to 1 year, but the response has not been durable.

• New agents and in particular new combinations of agents are being studied to try to halt the loss of beta cells in T1D.

Anti CD3 Reduces C-peptide Decline in New Onset T1D

Month

0 6 12 18 24

AU

C (

pm

ol/m

l/240m

in)

0

20

40

60

80

100

120

140

160

Drug

Control

• Single 14d course anti-CD3 in patients age 7-30

• Has shown efficacy in multiple new onset T1D clinical trials

• Excellent initial response, begins to wane after ~1 year

• Better response in children

• Currently being tested in TrialNet in Stage 2 diabetes; new trials will combine it with other agents

Herold et al, NEJM 2002

Co-Stimulation Modulation with AbataceptReduced C-peptide Decline in New Onset T1D

Lancet, 2011Orban, diabetes Care 37:1069-75, 2014

• 112 patients, age

6-45

• Monthly infusions

x 2yrs

• Minimal side

effects

• Now being studied

in Stage 1 TID

• Plan to combine

with rituximab

Rituximab Slowed C-peptide Decline in New Onset T1D

Pescovitz, N Engl J Med 2009; 26:2143-52

– 4 infusions over 3 wks

– 87 patients age 8-40

– Minimal side effects

Low-dose ATG +/- GCSF in new Onset T1D

‒ 89 subjects, age 12-45 years‒ 2 day infusion of ATG; GCSF q2 weeks x 6 doses‒ Modest cytokine release syndrome, some serum sickness

Immunotherapy to prevent progression from Stage 1 or 2 to clinical diabetes (Stage 3)

Oral insulin (2007-2017)• 560 antibody-positive participants received daily oral insulin (7.5-mg

fixed dose) or placebo

• Oral insulin was safe and well-tolerated

• In general, oral insulin did not prevent or delay onset of T1D

• In the subset of patients who started out with low insulin secretion, oral insulin delayed T1D onset by an average of 31 months.

Prevention Studies in Progress• CTLA-4 Ig (Abatacept)

• Anti-CD3 (Teplizumab)

• New studies are coming on board in the next year from TrialNet and industry

Manipulation of Cellular Immunity May Require Multiple Agents & Prolonged Therapy as in Transplant

Post transplant immunosuppression: induction and maintenance

Induction

• Short-term intense immuno-suppression right after transplant, when risk of rejection is highest

Lifelong Maintenance

• Use the lowest possible drug doses to maintain immunosuppression while minimizing complications

Special Concerns in Children

• There are age differences in both the disease process and the response to immunotherapy—adult data don’t necessarily predict pediatric data

• Young children are often excluded from studies of new drugs, even when they are the primary target population and the population most likely to benefit

• But there are special cautions in children:

₋ Exposure to immunosuppression may span decades₋ Uniquely susceptible to toxicities related to growth, development

and cognitive function₋ At increased risk for primary infections (eg EBV)₋ May interfere with vaccination ₋ Teen compliance issues

Summary: Immune Therapy in T1D To-Date

• Mostly single agent therapies have been tried• Short courses, hoped to cause permanent tolerance• Several work really well initially but the effect is not durable• Different responses in children and adults

So where do we go from here?– Drug combinations– Cellular therapies (studies in progress)– Lifelong therapy (induction and maintenance)– More focus on children (as allowed by the FDA)

Why Screen for T1D Autoantibodies?

• Significantly reduced risk for DKA at clinical diabetes onset (~ 5% vs ~35%)

• Potential participation in research to preserve ß-cells

– Even a small amount of residual ß-cell function reduces hypoglycemia and complications risk in established T1D

• Moves the field forward through better understanding of disease progression

Message: T1D Can Be Predicted With a Simple Blood Draw For Autoantibodies

Eligibility:

• Ages 1-20 with 1ST, 2ND or 3rd degree relative with T1D

• Ages 21-45 with a first degree relative with T1D

• Age 1-45 with autoantibodies

• Those under 18 without autoantibodies can be retested annually

TrialNet coordinators can obtain consent by phone and mail out screening kits that can be used free-of-charge at any lab

Screening: TrialNet Pathway to Prevention

Please tell your patients with T1D to consider having their relatives screened