Teplizumab (1) – Teizeild®

• Clinical trials
  • To assess the additional benefit of teplizumab compared with the appropriate comparator therapy, ‘watchful waiting’ in adults and children aged 8 years and over with stage 2 type 1 diabetes mellitus, with the aim of delaying progression to stage 3, the TN-10 study was submitted.
  • The randomised, double-blind, controlled TN-10 trial compares teplizumab with placebo.

Adults and children aged 8 years and over with stage 2 type 1 diabetes mellitus who do not (yet) have clinically manifest type 1 diabetes mellitus, to delay the progression of type 1 diabetes mellitus to stage 3

• Hint for a non-quantifiable additional benefit.
• Overall, based on the demonstrated advantage of teplizumab in terms of the endpoint ‘manifestation of type 1 diabetes mellitus’, there is an additional benefit, the extent of which, however, cannot be quantified.
• Consequently, a non-quantifiable additional benefit is identified for teplizumab in delaying the progression of type 1 diabetes mellitus to stage 3 compared with a ‘wait-and-see’ approach.
• Due to the uncertainties described above, the certainty of the evidence is classified as ‘hint’.
• mortality
  • No deaths occurred in the TN-10 study.
• Morbidity – manifestation of type 1 diabetes mellitus
  • This endpoint was defined as the primary endpoint and operationalised as the time to diagnosis of clinically manifest type 1 diabetes mellitus.
  • Manifest type 1 diabetes mellitus was defined as meeting one of the following criteria: marked hyperglycaemia with acute metabolic decompensation, clinical symptoms of diabetes, and random PG ≥ 200 mg/dl (11.1 mmol/l), fasting blood glucose (FBG) ≥ 126 mg/dl (7.0 mmol/l), or 2-hour postprandial blood glucose (2h-PG) ≥ 200 mg/dl (11.1 mmol/l).
  • For the primary endpoint, ‘time to onset of type 1 diabetes mellitus’, there was a statistically significant advantage of teplizumab compared with placebo.
  • Median data showed a two-year delay in the onset of clinically manifest type 1 diabetes mellitus with teplizumab compared with placebo.
  • However, the data from the event time analyses show that a marked clustering of events relating to the first-time onset of type 1 diabetes mellitus occurred as early as 3 to 9 months after the start of the study only in participants in the placebo arm – but not in those receiving teplizumab.
  • Due to methodological shortcomings in the assessment of this endpoint and the uneven distribution of patient characteristics across the two treatment arms, which could influence the results regarding the onset of type 1 diabetes mellitus, the extent of the demonstrated advantage of teplizumab in delaying the onset of clinically manifest type 1 diabetes mellitus cannot be conclusively assessed.
  • Furthermore, no further data are available on other patient-relevant endpoints such as metabolic decompensation, diabetic ketoacidosis or clinical symptoms.
• health-related quality of life
  • No health-related quality of life endpoints were assessed in the TN-10 study.
• Side effects – Serious adverse events (SAEs)
  • There was no statistically significant difference in the overall rate of SAE between the treatment arms.
• Side effects – Therapy discontinuation due to adverse events (AE)
  • The study showed no statistically significant difference between the treatment arms for the endpoint of therapy discontinuations due to AEs.
• Side effects – Severe AEs (CTCAE grade ≥ 3)
  • For the endpoint of severe AEs, there was a statistically significant disadvantage for teplizumab compared with placebo.
• Side effects – infections (AE), serious infections (SAE)
  • In detail, there was no statistically significant difference between the treatment arms for either the endpoints of infections (AEs) or serious infections (SAEs).
• Side effects – severe lymphopenia (AE), disorders of the skin and subcutaneous tissue (AE)
  • In detail, for the endpoints severe lymphopenia (AE) (CTCAE grade ≥ 3) and skin and subcutaneous tissue disorders (AE), a statistically significant disadvantage of teplizumab compared with placebo was observed in each case.
• Overall assessment
  • The TN-10 study was submitted to assess the additional benefit of teplizumab in adults and children aged 8 years and over with stage 2 type 1 diabetes mellitus in delaying progression to stage 3.
  • No deaths occurred in the TN-10 study.
  • The endpoint ‘time to manifestation of type 1 diabetes mellitus’ was the sole endpoint assessed within the morbidity endpoint category. Progression of the disease from stage 2 to stage 3 is accompanied by the typical clinical symptoms of type 1 diabetes mellitus and results in permanent and irreversible insulin dependence. The first-time manifestation of type 1 diabetes mellitus therefore represents a patient-relevant endpoint. For this endpoint, a statistically significant advantage of teplizumab over placebo was observed; on a median basis, teplizumab delayed the onset by two years. Due to methodological shortcomings in the assessment of this endpoint and the uneven distribution of patient characteristics across the two treatment arms—which could influence the results regarding the onset of type 1 diabetes mellitus— the extent of the demonstrated advantage of teplizumab in terms of delaying the onset of clinically manifest type 1 diabetes mellitus cannot be conclusively assessed.
  • Endpoints in the health-related quality of life category were not assessed in the study.
  • In the ‘side effects’ endpoint category, there is a statistically significant disadvantage of teplizumab compared with placebo for the endpoint ‘severe AEs’ (CTCAE grade ≥ 3). More specifically, for the specific AEs of severe lymphopenia and disorders of the skin and subcutaneous tissue, there is a disadvantage associated with teplizumab compared with a ‘wait-and-see’ approach.
  • Overall, an additional benefit is observed due to the demonstrated advantage of teplizumab at the endpoint ‘manifestation of type 1 diabetes mellitus’. However, due to methodological limitations of the study—namely the limited number of participants and an uneven distribution of patient characteristics across the treatment groups—and taking into account the fact that a high number of early events of overt type 1 diabetes mellitus occurred only in the comparator arm – and that this does not correspond to the expected natural course of the disease – the extent of the advantage cannot be quantified. Furthermore, a disadvantage regarding the endpoint of severe AEs must be taken into account.

Courtesy translation only, please refer to the German original.