Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial

Abstract

Summary Background Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve β-cell function and decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the safety and efficacy of one such antibody, teplizumab. Methods In this 2-year trial, patients aged 8–35 years who had been diagnosed with type 1 diabetes for 12 weeks or fewer were enrolled and treated at 83 clinical centres in North America, Europe, Israel, and India. Participants were allocated (2:1:1:1 ratio) by an interactive telephone system, according to computer-generated block randomisation, to receive one of three regimens of teplizumab infusions (14-day full dose, 14-day low dose, or 6-day full dose) or placebo at baseline and at 26 weeks. The Protégé study is still underway, and patients and study staff remain masked through to study closure. The primary composite outcome was the percentage of patients with insulin use of less than 0.5 U/kg per day and glycated haemoglobin A1c (HbA1C) of less than 6.5% at 1 year. Analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00385697. Findings 763 patients were screened, of whom 516 were randomised to receive 14-day full-dose teplizumab (n=209), 14-day low-dose teplizumab (n=102), 6-day full-dose teplizumab (n=106), or placebo (n=99). Two patients in the 14-day full-dose group and one patient in the placebo group did not start treatment, so 513 patients were eligible for efficacy analyses. The primary outcome did not differ between groups at 1 year: 19·8% (41/207) in the 14-day full-dose group; 13·7% (14/102) in the 14-day low-dose group; 20·8% (22/106) in the 6-day full-dose group; and 20·4% (20/98) in the placebo group. 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p=0·03). Across the four study groups, similar proportions of patients had adverse events (414/417 [99%] in the teplizumab groups vs 98/99 [99%] in the placebo group) and serious adverse events (42/417 [10%] vs 9/99 [9%]). The most common clinical adverse event in the teplizumab groups was rash (220/417 [53%] vs 20/99 [20%] in the placebo group). Interpretation Findings of exploratory analyses suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in β-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children.

TNF-α Antibody Therapy in Combination With the T-Cell–Specific Antibody Anti-TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-iddmRat

“…Therefore, monotherapies have proven not to be particularly successful (23,(38)(39)(40) even with the most promising antibodies, anti-CD3 in humans and mice and in analogy anti-TCR in rats (25,27,28,(41)(42)(43)(44). We report here a successful combination therapy for T1D in the IDDM rat, an animal model of human T1D (25), using two antibodies with different target profiles.…”

What is the role of autoimmunity in type 1 diabetes? A clinical perspective

“…Indeed, this observation has given rise to the hypothesis that the generation of autoantibodies in type 1 diabetes may be a secondary event triggered by a primary islet-destructive process. Follow-up studies using other immune modulatory treatments, including cytotoxic T-lymphocyte antigen 4 (CTLA4)-immunoglobulin fusion protein [12], anti-CD20 antibody [13], anti-CD3 antibody [14][15][16], DiaPep277 [17], TNF-α receptor fusion protein [18] and anti-IL-1β antibody or IL-1 receptor antagonist [19], showed mild initial benefit, or no benefit at all. Of note, in cases where clinical benefits were observed, the typical pattern was an initial improvement in insulin production, followed by a decline which paralleled that observed in untreated patients.…”

Agent-Based Modeling in Systems Pharmacology

“…The lack of established analytical techniques used in the analyses of equation‐based systems is often perceived as a shortcoming of ABM. However, it is possible to measure and analyze the visual output of ABM in the same manner as wet‐lab systems,15 as demonstrated in Butler et al .,63 with the development of a tool‐chain for enabling existing ABMs to produce emulations of flow cytometry, immunohistochemistry, and gene expression microarrays. An existing simulation of lymphoid organogenesis was modified to produce flow cytometry data, permitting analysis with standard software tools, such that in silico and experimental data can be treated and presented in an identical manner.…”