JOURNAL ANALYSIS

1. JOURNAL CLUB
MANISH MOHAN
JUNIOR RESIDENT

2. An Anti-CD3 Antibody,
Teplizumab, in Relatives at Risk
for Type 1 Diabetes

3. Contents
• Introduction
• Methods
• Results
• Discussion
• Critical appraisal

4. INTRODUCTION

5. Introduction
Type 1 diabetes
Autoimmune destruction of insulin-producing beta cells
(islets of Langerhans)
1- to 1.5 million 2 nd common diseases of
childhood

6. SCOTTISH STUDY
Diagnosed before the age of MEN WOMEN
10 yrs 14.2 17.7 life-years
20 yrs 11 13 life-years
In genetically susceptible persons
Type 1 diabetes progresses through asymptomatic stages before the
development of overt hyperglycemia.
stage 1-------- Autoantibodies
stage 2---------Metabolic responses to a glucose load are impaired

7. Cont…..
• Immune interventions
• Delay the decline in beta-cell function
• Teplizumab
(Fc receptor–nonbinding antiCD3 monoclonal antibodies)
Reduces the loss of beta-cell function
Even as long as 7 years after diagnosis
CD8+ T
lymphocytes

8. Teplizumab
Target – CD3
Type 1 diabetes mellitus
Renal allograft rejection
Psoriatic arthritis

9. Aim
• Whether interventions at stage 1 or 2 might alter the progression to
clinical type 1 diabetes ?
• Tested whether Teplizumab treatment would prevent or delay the
onset of clinical type 1 diabetes in high-risk persons.

10. Methods

11. Trial Participants
TrialNet Natural History Study
July 2011 through November 2018
Institutional-review-board approval was obtained at each participating
site
The participants, their parents, or both provided written informed
consent

12. ELIGIBILITY CRITERIA
• Nondiabetic relatives of patients with type 1 diabetes
• At least 8 years of age at the time of randomization
• Had two or more diabetes-related autoantibodies
Detected in 2 samples obtained within 6 months before randomization
• Evidence of dysglycemia during an oral glucose-tolerance test

13. Cont……
• FBS of 110 to 125 mg
• 2-hour PPBS level Of 140 -200 mg per deciliter
OR
• Intervening PPBS at 30, 60, or 90 minutes of greater than 200 mg /dl
on two occasions, within 52 days before enrollment

14. Cont….
• Protocol amended in 2014
• Enrollment of participants younger than 18 yrs age who had a single
abnormal oral glucose tolerance test result

15. EXCLUSION CRITERIA
Persons with other clinically
important medical histories
Abnormal laboratory chemical
values
Abnormal blood counts

16. TRIAL DESIGN
Phase 2 Randomized
Placebo-
controlled
Double-
blind trial

17. Cont………
• Treatment-group assignments were double masked
Participants
14-day outpatient course
Teplizumab Or Saline
Intravenously In A Clinical Research Center

18. TEPLIZUMAB DOSE
• 51 µg/meter square ------day 0
• 103 µg/meter square ------day 1
• 207 µg/meter square ------day 2
• 413 µg/meter square ------day3
• 826 µg/meter square ------days 4 through 13

19. End Points and Assessments
• The primary end point
• Elapsed time from randomization to the clinical diagnosis of diabetes
• GTT - 3 months and 6 months
- Every 6 months thereafter
• Random blood sugar - 3-month intervals
(RBS >200 mg/dl ---GTT)

20. Trial Oversight
Developed and conducted by Type 1 Diabetes TrialNet
Funded - National Institutes of Health and the Juvenile Diabetes Research
Foundation
MacroGenics -- holder of the investigational new drug application at the start
of the trial----Now - Provention Bio
An independent medical monitor (who was unaware of the treatment-group
assignments) reviewed all accruing safety data

21. Cont….
MacroGenics provided teplizumab and matching
placebo
Representatives from the National Institute of
Diabetes and Digestive and Kidney Diseases
participated in the design and conduct of the trial

22. Statistical Analysis
Cumulative incidence DM
Within each group over time after randomization
Kaplan–Meier analysis
Cumulative incidence b/w treatment groups
Hazard ratio

23. Cont…..
• Data on safety and efficacy
• Independent data and safety monitoring board
• Interim analysis conducted
• 18 cases of type 1 DM observed
• intention-to-treat principle

24. Results
Type 1 DM -42 participants
Median follow up duration- 745 days
93% completed (41) 88% completed (28)
44 – TEPLIZUMAB group 32 – placebo group
76 randomized
112 participants ( enrolled )

25. Base line features

26. Efficacy
• Annualized rate of diagnosis
• 14.9% / year – Teplizumab group
• 35.9% / year – placebo group
• Median time to diagnosis
• 48.4 month in teplizumab group
• 24.4 month in placebo group

27. Efficacy Cont……
• Type 1 diabetes incidence
• 3/44 ----Teplizumab group
• 14/32---Placebo group
• Overall Hazard Ratio – 0.41

28. Efficacy

29. Safety of Teplizumab

31. Cont ……
• TEPLIZUMAB
• Epstein Barr Virus re-activation
• Trial entry ----30 participants ( EBV antibody)
• There was quantifiable EBV DNA –8 participants ( Teplizumab Group)
• Subsided b/w day 43 and day 134

32. Changes in immune cell subsets
• Frequency of TIGIT + KLRG1 +EOMES+ CD 8+ T CELLS---T cell
unresponsiveness

33. Lymphocyte count

34. Subgroup Analysis

35. Cont……..

36. Discussion
• Single course Teplizumab
• Significantly slowed progression to type 1 diabetes mellitus
• Median delay – 2 years
• Conclusion of the trial-
• Percentage of diabetes free persons in Teplizumab group , was double than
that of saline group ( 57 % vs 28%)

37. Cont……
• HLA-DR3 absence
• Presence of HLA-DR4 better response
• Absence of antiZnT8
• Transient Lymphopenia
• Rash

38. Limitations
• cohort was relatively small
• The participants were relatives of patients with type 1 diabetes
• Non-hispanic white participants
• The drug was given for only one course
• Not fully assessed the potential development of antibodies to teplizumab

39. Conclusion
• 2-week course of teplizumab delayed the diagnosis of clinical type -1
diabetes mellitus in high risk participants

40. Critical Appraisal
• Only white race considered for this study
• Single dose study

41. Consort guidelines
• No Flow diagram of participants

42. THANK YOU