A single course of teplizumab delayed the time to a type 1 diabetes (T1DM) diagnosis in 50% of high-risk individuals in an extended follow-up study of a small randomized controlled trial. "The study cohort was at high risk - evident from the finding that the median time to diabetes was 27 months in the placebo group," Dr. Kevan Herold of Yale University School of Medicine in New Haven told Reuters Health by email. "At the end of the study, half of the drug-treated participants still did not have diabetes, and we are following them since we don't know when or whether they will develop diabetes," he said. "This suggests that there may be some at-risk individuals who have very robust responses from the single course of therapy. In addition, the treatment improved metabolic function." "The drug action appears to involve induction of exhaustion among CD8+ T cells rather than the cell depletion that is common for other monoclonal antibodies," he added. "The T-cell counts returned to normal within two months of treatment. Our data would not suggest risks of long-term immune suppression." Dr. Herold and colleagues had previously analyzed the long-term effects of a single 14-day course of teplizumab on metabolic function and immune cells of nondiabetic relatives at high risk for T1DM (median age, 13). In a more recent study, to test the hypothesis that the immune therapy would improve participants' beta cell function, the team analyzed metabolic study results obtained before, during, and after conclusion of the original trial, as well as participant immune responses. As reported in Science Translational Medicine, median times to diagnosis were 59.6 and 27.1 months for teplizumab- and placebo-treated participants, respectively (HR, 0.457). Fifty percent of teplizumab-treated patients - but only 22% of those who received placebo - remained diabetes-free. Teplizumab improved beta cell function, as reflected by the average on-study C-peptide area under the curve (1.94 versus 1.72 pmol/ml). Drug treatment also reversed a decline in insulin secretion that started before enrollment, which was followed by stabilization; by contrast, the declining C-peptide AUC continued with placebo. Proinsulin:C-peptide ratios after drug treatment were similar between the groups. Further, as Dr. Herold said, the changes in C-peptide with teplizumab were associated with increases in partially exhausted memory KLRG1+TIGIT+CD8+ T cells, which showed reduced secretion of IFN gamma and TNF alpha. The authors note, "Our findings have implications for other autoimmune diseases by showing how immune intervention can change the pathobiology even before disease diagnosis and lead to a clinically meaningful outcome." Dr. Herold said the team is looking forward to approval from the U.S. Food and Drug Administration and noted that the drug was given "prime" designation by the European Medicines Agency. Dr. Navinder Jassil, Director of Endocrinology and Diabetes Services at Deborah Specialty Physicians in Southern New Jersey, noted in an email to Reuters Health, "The sample size was small (and) the participants were screened to be at high risk for developing T1DM. Thus, it's unclear how this medication will affect those at low or moderate risk." Further, she said, "the average age of the participants was 13. It is known that younger/immature immune systems may react differently to medications such as teplizumab than a more mature immune system. Due to these specific factors, it is too premature to generalize to the population at large." "We can still take away a great deal from this groundbreaking study, as it shows a novel way to delay progression of T1DM in high-risk individuals." Dr. Minisha Sood, an endocrinologist at Lenox Hill Hospital in New York City also commented by email. "This treatment provides hope for people who are at increased risk for type 1 diabetes, but potential recipients of this medication should be aware that...almost 50% did ultimately develop the disease." "Patient selection will be very important," she said, "and, based on subgroup analyses in prior studies of more robust responders, it may be beneficial to base selection on other criteria, such as MHC subtype and the breakdown of islet cell antibodies." —Marilynn Larkin Source
