Type 1 diabetes mellitus (T1D) is an autoimmune disease that leads to the destruction of insulin-producing pancreatic beta cells by CD4+ and CD8+ T cells and macrophages infiltrating the islets1.
On November 17 2022, the US FDA approved teplizumab to delay the onset of Stage 3 type 1 diabetes (T1D) in adult and paediatric patients aged 8 years and older with Stage 2 T1D2, based on results of a clinical trial in high-risk relatives of individuals with T1D, making it the first ever medication indicated to delay the onset of T2D. The key milestones2 in the development of teplizumab in the treatment of T1D is indicated below:
So far2, the eligibility for treatment with teplizumab requires a confirmed diagnosis of Stage 2 T1D, comprising ≥ 2 positive pancreatic islet cell autoantibodies, dysglycaemia without overt hyperglycaemia based on an oral glucose tolerance test (OGTT) or an alternative method if an OGTT is not available (fasting plasma glucose or HbA1C).
Teplizumab is a CD3-directed monoclonal antibody (mAb) that is a genetically modified derivative of the CD3-directed murine OKT3 mAb. To reduce its immunogenicity, it was made by grafting a mouse anti-CD3 complementarity-determining region into a human IgG backbone3. As a result, it binds to the CD3 cell surface antigen on T cells but does not bind to the Fc receptor. Teplizumab has been investigated in the treatment of acute renal allograft rejection3, and autoimmune disorders such as T1D, psoriasis and psoriatic arthritis.
Two therapeutic trials conducted have been cited by FDA during the approval process:
- Stage 2 T1D4
Treatment with teplizumab significantly delayed the onset of Stage 3 of the disease. Progression to Stage 3 T1D was observed in 45% of teplizumab recipients, compared with 72% of placebo recipients.
- Early Stage 3 T1D5
Unfortunately, treatment with teplizumab in patients with recent-onset Stage 3 T1D requiring treatment with insulin did not achieve the endpoints of demonstrating greater efficacy than placebo. The proportion of patients achieving insulin use < 0.5 U/kg/ day and HbA1C < 6.5% at 1 year in the 14-day full dose (n = 207), 14-day low-dose (n = 102) and 6-day full-dose (n = 106) groups were 19.8%, 13.7% and 20.8%, respectively, compared with 20.4% in the placebo group. Changes in HbA1C from baseline at 1 year were − 0.41%, − 0.33% and − 0.36% in the teplizumab groups compared with − 0.40% in the placebo group.
Overall6, teplizumab has been well tolerated in both paediatric and adult patients with Stage 2 T1D. The most common side effect during the Stage 2 T1D trial was: rash (36%), leukopenia (21%), headache (11%), neutropenia (5%), increased ALT (5%), nausea (5%), diarrhoea (5%), and nasopharyngitis (5%). Cytokine release syndrome (CRS) was reported in 2% of teplizumab recipients and did not result in serious adverse consequences.
The table2 below summarises the features and properties of teplizumab.
| Alternative Names | Teplizumab-mzww; TZIELDTM; MGA031; PRV031 |
| Class | Antihyperglycemics; Monoclonal antibodies |
| Mechanism of action | CD3 antigen inhibitors; may involve partial agonistic signalling and deactivation of pancreatic β cell autoreactive T lymphocytes. |
| Route of administration | IV infusion |
| Adverse events | Lymphopenia, rash, leukopenia, headache, neutropenia |
| ATC codes | A10X (Other Drugs Used in Diabetes) |
As of today, there is a phase 3 trial7 of teplizumab (two 12-day cycles of teplizumab or placebo 6 months apart; treatment administration starting within 6 weeks of diagnosis) in 8-17 years old recently diagnosed Stage 3 T1D patients ongoing. More clinical data is expected to be published in coming years once more countries approve the use of Teplizumab.
Reference
1.Gillespie KM. Type 1 diabetes: pathogenesis and prevention. Canadian Medical Association Journal. 2006 Jun 27;175(2):165–70.
2.Keam SJ. Teplizumab: First Approval. Drugs. 2023 Mar 6;
3.Woodle ES, Xu D, Zivin RA, Auger J, Charette J, O’Laughlin R, et al. Phase I trial of a humanized, Fc receptor nonbinding OKT3 antibody, huOKT3gamma1(Ala-Ala) in the treatment of acute renal allograft rejection. Transplantation [Internet]. 1999 Sep 15 [cited 2023 Mar 24];68(5):608–16. Available from: https://pubmed.ncbi.nlm.nih.gov/10507477/
4.Herold KC, Bundy BN, Long SA, Bluestone JA, DiMeglio LA, Dufort MJ, et al. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. New England Journal of Medicine. 2019 Aug 15;381(7):603–13.
5.Sherry N, Hagopian W, Ludvigsson J, Jain SM, Wahlen J, Ferry RJ, et al. Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial. The Lancet [Internet]. 2011 Aug 6 [cited 2020 Nov 26];378(9790):487–97. Available from: https://www.sciencedirect.com/science/article/abs/pii/S0140673611609318
6.TZIELDTM (teplizumab-mzwv) is now approved [Internet]. www.tzield.com. [cited 2023 Mar 24]. Available from: https://tzield.com
7.ProventionBio [Internet]. ProventionBio. [cited 2023 Mar 24]. Available from: https://proventionbio.com
