CME INDIA Presentation by Dr. N. K. Singh, MD, FICP, FACP, F-RSSDI, Director – Diabetes and Heart Research Centre, Dhanbad, Jharkhand, India. Editor, www.cmeindia.in.
Dr. Sujoy Ghosh, DM, Endo, Kolkata shares:
“On November 17, 2022, the U.S. Food and Drug Administration approved Tzield (teplizumab-mzwv) injection to delay the onset of stage 3 type 1 diabetes in adults and paediatric patients 8 years and older who currently have stage 2 type 1 diabetes.”
| This approval of a first-in-class therapy adds an important new treatment option for certain at-risk patients. |
| The drug’s potential to delay clinical diagnosis of type 1 diabetes may provide patients with months to years without the burdens of disease. |
– John Sharretts, M.D., director of the Division of Diabetes, Lipid Disorders, and Obesity in the FDA’s Centre for Drug Evaluation and Research.
A New Era in Better Diabetes Management
- Teplizumab is simply “the foot in the door.”
- The prevention trial showed that the median time the onset of type 1 diabetes was delayed was two years.
- “Some people ask, ‘If you’re still going to get diabetes, what’s the big deal?’”
“But if you’re an eight-year-old child, and the diagnosis of type 1 diabetes, the time at which you need to take insulin and follow a prescribed diet and monitor your blood sugar is delayed for two more years, that’s huge.”
– Kevan Herold, MD, C.N.H. Long Professor of Immunobiology and of Medicine (Endocrinology), Yale School of Medicine.
In childhood, a few years can make a substantial difference in terms of maturity—a high schooler, for instance, may be better equipped to handle the burden of a challenging chronic disease than a middle schooler. The delay also reduces the amount of exposure a patient has to the high blood sugars responsible for a wide range of complications.
How Tzield works?
| Tzield binds to certain immune system cells and delays progression to stage 3 type 1 diabetes. |
| Tzield may deactivate the immune cells that attack insulin-producing cells, while increasing the proportion of cells that help moderate the immune response. |
| Tzield is administered by intravenous infusion once daily for 14 consecutive days. |
How Tzield’s safety and efficacy were evaluated?
- It was evaluated in a randomized, double-blind, event-driven, placebo-controlled trial with 76 patients with stage 2 type 1 diabetes.
- Patients randomly received Tzield or a placebo once daily via intravenous infusion for 14 days.
- The primary measure of efficacy:
- Time from randomization to development of stage 3 type 1 diabetes diagnosis.
- Over a median follow-up of 51 months, 45% of the 44 patients who received Tzield were later diagnosed with stage 3 type 1 diabetes, compared to 72% of the 32 patients who received a placebo.
- The mid-range time from randomization to stage 3 type 1 diabetes diagnosis was 50 months for the patients who received Tzield and 25 months for those who received a placebo. This represents a statistically significant delay in the development of stage 3 type 1 diabetes.
Adverse Effects
- The most common side effects of Tzield include decreased levels of certain white blood cells, rash and headache.
The use of Tzield comes with warnings and precautions
- Premedicating and monitoring for symptoms of Cytokine Release Syndrome.
- Risk of serious infections.
- Decreased levels of lymphocytes.
- Risk of hypersensitivity reactions.
- The need to administer all age-appropriate vaccinations prior to starting Tzield; as well as avoiding concurrent use of live, inactivated and mRNA vaccines with Tzield.
CME INDIA Discussion
Dr. N K Singh:
- This was in news. In couple of years, what is stage 3 of type 1 DM?
Dr. Meena Chhabra, Diabetologist, Delhi:
- Stage 1 of type 1 diabetes is antibodies are positive.
- Stage 2 there is dysglycemia but no symptoms.
- Stage three when there is symptomatic hyperglycaemia.
- If you screen siblings of type 1 and they have antibody positivity particularly more than one antibody then they may progress to dysglycemia.
As per JDRF, which is the largest non-profit funder of type 1 diabetes (T1D) research (Ref-2)
- These staging criteria help us predict and plan for progression to a type 1 diabetes diagnosis.
- When multiple autoantibodies are detected, the lifetime risk for developing type 1 diabetes approaches 100%, with 44% progressing to a diagnosis within 5 years and 70% within 10 years.
- We know that the immune system mediated destruction of the insulin-producing beta cells in the pancreas begins long before insulin is required.
- In fact, current clinical guidelines provide for pre-symptomatic staging of type 1 diabetes. This staging can be used to predict the risk of type 1 diabetes over time based on the number of autoantibodies and blood glucose levels.
The diagnostic criteria for the stages of type 1 diabetes
| Stage 1: Multiple islet autoantibodies present, no impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). |
| Stage 2: Multiple islet autoantibodies present, IGT (2-hour plasma glucose 140-199 mg/dL) and/or IFG (100-125 mg/dL) and/or A1C of 5.7-6.4 or ≥10% increase in A1C. |
| Stage 3: Clinical type 1 diabetes diagnosed by standard criteria. |
How can diabetes care and education specialists use this knowledge in their practice setting?
- Recommend screening to family members of people with type 1 diabetes.
- Provide individuals with information about the other screening options available in India.
- Teach people that screening alone is not enough. Search about associations who provide advice about screening and monitoring for individuals and families.
- Educate people who test positive for autoantibodies about the symptoms of type 1 diabetes.
Dr. Basab Ghosh, Diabetologist, Agartala:
- U.S. FDA approved Tzield (teplizumab-mzwv) injection to delay the onset of stage 3 type 1 diabetes in adults and paediatric patients >8 years who currently have stage 2 type 1 diabetes.
- Not approved for T1DM treatment module.
- It should not be misused, where effect could be detrimental!
- Clinicians see T1DM mostly in stage 3, so beyond use of Teplizumab.
Dr. N K Singh:
- How to catch them in stage 1?
- Think about testing multiple auto antibodies.
- We are very conservative due to economy.
- How this can be improved?
Dr. Basab Ghosh, Agartala:
- Diagnosis of stage 1 of T1DM has to be incidentally or for academic interest!
- But I am scared if this molecule would be used for T1DM in regular treatment!!!
Dr. N K Singh:
- We are not talking about treatment.
- Question is how to delay?
- If you delay onset of T1DM for 3 years, will it be productive.
Dr. Basab Ghosh, Agartala:
- Of course, but selecting cases would be incidental only, as I believe.
Dr. Meena Chhabra, Diabetologist, Delhi:
- Routine screening for antibodies of first-degree relatives is not done as this just makes the family depressed.
- And we have nothing to offer. This is the situation.
Dr. Ashish Gautam, Assoc. Prof Med, Agra:
- Kids exposed to raw milk during weaning are at high risk.
- Mycobacterium paratuberculosis exposure is associated with type 1 diabetes.
- These kids can be screened.
Dr. Arun Kedia, Diabetologist, Raipur:
- How many of us see patients in stage 1 and 2?
Dr. Om Lakhani, DNB Endo, Ahmedabad:
- None of us do. But if a prevention option is available, I am sure more screening would take place.
Dr. Amrita Ghosh, Consultant diabetologist, Fortis, Delhi:
- Is delay of type 1 diabetes by 2 years will have a lot of impact on eventual complications?
- Many a times I do screen the siblings of T1Dm but very rarely I see T1Dm in siblings (out of my 350 plus I have 1 set of siblings).
- So will it be beneficial. Long term benefits of the usage of teplizumab should be seen. Short term effect like decrease in lymphocyte or having a cytokines storm has been seen in the trial.
Dr. Meena Chhabra, Diabetologist, Delhi:
- All 4 antibodies are not checked in most labs in Delhi.
- Only GAD is done easily. Zinc transporter 8 not done anywhere.
- Islet cell antibodies ICC and insulinoma associated antibody 2 IA2 not available easily in labs.
Dr. Shalini Jaggi, Diabetologist, Delhi:
- At Dr. Mohan’s Chennai their lab does ZnT8 though it takes about 4-6weeks to get the results.
- No doubt, it is a landmark step in T1DM prevention.
- However, I agree with Dr Amrita Ghosh, a delay of 2 yrs. can surely have an impact on, maybe delaying the mental trauma of a TIDM diagnosis and its eventual effect on the quality of life, but I don’t see how it benefits in the long term.
- Eventually onset of T1DM is not being permanently prevented! Just getting delayed by 2 yrs., the sword is always hanging on the head even after teplizumab therapy, is not that again a mental strain? And as correctly pointed out short effects need more exploration.
Dr. Debmalya Sanyal, Sec RSSDI, WB:
- IA 2 is there for some time.
- Now Zn transporter is also available.
Dr. Awadhesh Kumar Singh, DM Endo., Kolkata:
- Good news but not for resource constraint countries like us.
- There are not only limited but hand counted lab that test type 1D antibodies in India.
- Forget screening in family members of type 1.
- Let’s think practically not emotionally!!!
Quick Take-Aways
(by Dr. Awadhesh K. Singh)
| 1. Teplizumab – evaluated in a DBRCT in 76 patients – with stage 2 -type 1D against placebo |
| 2. Teplizumab – once daily iv infusion for 14 days. |
| 3. The primary measure of efficacy was the time from randomization to development of stage 3 of type 1 diabetes diagnosis. |
| 4. The trial results showed that over a median follow-up of 51 months-45% of the n=44 who received Teplizumab were later diagnosed with stage 3 type 1 diabetes vs. compared to 72% of n=32 who received a placebo. |
| 5. The mid-range time from randomization to stage 3 type 1 diabetes diagnosis was 50 months for the patients who received Teplizumab and 25 months for those who received a placebo. |
| 6. This represents a statistically significant delay in the development of stage 3 type 1 diabetes. |
CME INDIA Tail-Piece
Dr. Meena Chhabra on Role of antibodies in diagnosing:
Dr. Awadhesh K. Singh, DM Endo., Kolkata:
- Please remember that previous trial of Teplizumab in 516 patients (PROTEGE trial) in stage 3 T1D failed to show any benefit against placebo!
- An average 14-day course of Teplizumab over 14 days to delay the development of T1D will cost, list price, $193,900 USD in USA.
Dr. Shashank Joshi, DM Endo, Mumbai:
References:
- https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-can-delay-onset-type-1-diabetes
- https://www.jdrf.org/t1d-resources/t1detect/
- Staging Presymptomatic Type 1 Diabetes: A Scientific Statement of JDRF, the Endocrine Society, and the American Diabetes Association Diabetes Care 2015;38:1964–1974 | DOI: 10.2337/dc15-1419
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Teplizumab can act only for Type 1 Diabetes and the trial is in such a small number that’s its Efficacy can not be proved , it’s just like launching a drug with pomp and show which will fail in days to come.
Very simplistic analysis.
If today we are planning to delay… maybe tomorrow cure of T1DM comes.
Without evidence, nothing is approved.
Future is bright, we are heading towards curing Type 1 DM, may be in next 10 years.