medwireNews: Phase II findings show that the immunotherapy teplizumab significantly prolongs the time until people at very high risk for developing type 1 diabetes are diagnosed with the condition.
The median time to diagnosis was 48.4 months in study participants given the Fc receptor-nonbinding anti-CD3 monoclonal antibody, compared with 24.4 months in those given placebo.
The researchers presented their findings at the 79th ADA Scientific Sessions in San Francisco, California, USA, with simultaneous publication in The New England Journal of Medicine.
The study participants were all relatives of a person with type 1 diabetes and were all at stage 2 of type 1 diabetes development; that is, they had two or more autoantibodies (71% had at least three) and an abnormal oral glucose tolerance test, but had not yet developed overt diabetes. They ranged in age from 8.5 to 49.5 years, with the median being 13 to 14 years.
Following randomization, 44 participants received intravenous teplizumab, given daily across 14 days starting at a dose of 51 µg and escalating to 826 µg per m2 body surface area, and 32 patients received saline.
During up to 7 years of follow-up, 43% of people in the teplizumab group and 72% of those in the placebo group developed diabetes, giving annual rates of 14.9% and 35.9%, respectively.
The rate of diabetes diagnosis was highest overall in the first year, at 40%, falling to 24%, 14%, and 12% in years 2, 3, and 4, respectively. The effect of teplizumab was greatest in the first year after treatment, during which 7% of the teplizumab group versus 44% of the placebo group were diagnosed with diabetes.
Subgroup analyses revealed that the patients who most benefited from teplizumab were those who had HLA-DR4, did not have HLA-DR3, did not have anti-zinc transporter 8 antibodies, and had a below-median C-peptide response (<1.75 nmol/L) to the oral glucose tolerance test.
The safety profile of teplizumab was as expected, with the most common events being transient lymphopenia, in 75% of participants, and spontaneously resolving rash in 36%.
In a linked editorial, Clifford Rosen (Maine Medical Center Research Institute, Scarborough, USA) and Julie Ingelfinger (Massachusetts General Hospital, Boston, USA) describe the findings as “striking.”
But they caution that “the result should not be taken to imply that immune modulation constitutes a potential curative approach,” adding: “Rather, these data provide strong albeit indirect evidence about the pathogenesis of beta-cell destruction and the potential to modify the course of type 1 diabetes with newer biologic agents.”
However, addressing reporters at the conference, lead study author Kevan Herold (Yale University, New Haven, Connecticut, USA) stressed the clinical importance of being able to delay progression to diabetes.
He said: “I think if you were to ask the families of any of the participants of this trial, or even the families of people with diabetes, they would reiterate this point […] But it’s particularly an issue for children, who represent about three-quarters of participants in our study.”
In the paper, the researchers also note that they have not yet tested the effects of repeated teplizumab dosing, which could potentially increase its benefits.
They suggest that the efficacy of the treatment during the immediate prediagnosis period “supports the development of an active screening program to identify persons who are at extremely high risk for disease progression.”
medwireNews is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group
N Engl J Med 2019; doi:10.1056/NEJMoa1902226
N Engl J Med 2019; doi:10.1056/NEJMe1907458
79th ADA Scientific Sessions; San Francisco, California, USA: 7–11 June 2019