Teplizumab: The first drug to delay T1D diagnosis
A 2-week course of the immunotherapy drug teplizumab delayed the onset of type 1 diabetes (T1D) in individuals at high risk for the condition, according to a phase II trial conducted by the TrialNet Study Group and presented at ADA 2019.
“[A] single course of teplizumab significantly slowed progression to clinical T1D in high-risk, nondiabetic relatives of patients with diabetes [who] had at least two autoantibodies and abnormal results of an oral glucose tolerance test [OGTT] at trial entry,” said study chair Professor Kevan Herold from Yale University, New Haven, Connecticut, US, and co-authors.
“This is the first study to show any drug can delay T1D diagnosis a median of 2 years in people at high risk,” said Herold.
Participants were 76 individuals (n=55 aged <18 years) without T1D but were at high risk for the condition and were relatives of individuals with T1D. They were randomized to receive intravenous teplizumab (51 μg/m2 on day 0, 103 μg/m2 on day 1, 207 μg/m2 on day 2, 413 μg/m2 on day 3, and 826 μg/m2 on days 4–13; n=44) or placebo (n=32) for 14 days. Median age of participants in the teplizumab and placebo groups was 14 and 13 years, respectively, and 64 and 50 percent, respectively, had a sibling with T1D.
All participants were positive for ≥2 diabetes-related autoantibodies. They underwent OGTTs at 3 and 6 months after study onset and every 6 months thereafter, plus random glucose screening tests at 3-month intervals. They were followed up for a median 745 days, during which time 42 participants developed T1D.
The diagnosis of T1D was delayed by almost 2 years among those assigned to teplizumab compared with placebo (median time to diagnosis, 48.4 vs 24.4 months, hazard ratio [HR], 0.41, 95 percent confidence interval [CI], 0.22–0.78; p=0.006). [ADA 2019; N Engl J Med 2019;doi:10.1056/NEJMoa1902226]
Fewer patients who received teplizumab were diagnosed with T1D compared with those who received placebo over a 7-year period (43 percent vs 72 percent), with an annualized rate of diagnosis of 14.9 and 35.9 percent per year in the teplizumab and placebo groups, respectively.
The highest rate of T1D diagnosis, regardless of treatment group, occurred in the first year following the trial, with 40 percent progressing to T1D compared with 24, 14, and 12 percent in years 2, 3, and 4, respectively. Teplizumab appeared to have the greatest impact in delaying T1D diagnosis in the first year (7 percent vs 44 percent [placebo], unadjusted HR, 0.13, 95 percent CI, 0.05–0.34). Subgroup analysis identified absence of HLA-DR3 or anti-ZnT8 antibodies and presence of HLA-DR4, and baseline C-peptide below median levels (1.75 nmol/L) as factors predicting positive teplizumab response.
Blood or bone marrow adverse events (AEs) occurred in significantly more participants in the teplizumab compared with placebo group (75 percent vs 6 percent), as did dermatologic or skin AEs (36 percent vs 3 percent; p<0.001 for both). Sixteen teplizumab recipients experienced rash which resolved spontaneously, while lymphocyte counts reduced by a total of 72.3 percent, reaching a nadir on day 5 of treatment. Fifteen of the 20 grade 3 AEs affecting teplizumab recipients were lymphopenia, occurring within the first 30 days of treatment, and mostly resolving by day 45. Infection rates were comparable between groups.
Clinical implications of staving off T1D
“Non-diabetic relatives with multiple antibodies and abnormal glucose tolerance are at very high risk for progression to clinical T1D,” said Herold.
“The 2-year delay in diagnosis is clinically important,” he continued. “In light of the daily burden of disease management, any time without clinical diabetes has significance, particularly for children. Our results offer great hope to family members and possibly in the future to the general public who may be at risk for developing T1D,” he added.
Nonetheless, the small study population was a limitation, and the impact of the findings on individuals at high risk for diabetes but without first-degree relatives with T1D is yet unknown, said the authors.
“The difference in outcomes was striking … [however], more research needs to be done to address the trial’s limitations, as well as to fully understand the mechanisms of action, [and] long-term efficacy and safety of the treatment,” said Dr Lisa Spain from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the sponsor of TrialNet.
The role of immune agents in delaying T1D
“The key point for the millions of people at risk to develop this disease is we now have the first immunotherapy that significantly delays the onset of T1D,” said Professor William Russell, TrialNet principal investigator and director of the Division of Pediatric Endocrinology and Diabetes at Vanderbilt University Medical Center, Nashville, Tennessee, US.
“We hope to bring wider recognition to the fact that T1D is an auto-immune disease that can be treated with immune therapy, similar to other autoimmune diseases,” said Dr Carla Greenbaum, director of the Diabetes Clinical Research Program at Benaroya Research Institute in Seattle, Washington, US, and chair of Diabetes TrialNet.
“We now understand that essentially all close relatives of people with T1D and who also have multiple antibodies can be considered as having the early, asymptomatic form of the disease. Just as we treat the asymptomatic presence of hypertension to prevent a heart attack or a stroke, these findings provide strong evidence we are approaching a future in which we can identify and treat T1D long before symptoms occur,” she said.
According to Herold, TrialNet studies assessing the ability of other immunotherapy drugs to delay T1D are underway.
“We are now exploring a full-blown prevention trial in people even earlier in the disease process,” added Russell.