Immunotherapy improves beta-cell function, delays type 1 diabetes diagnosis
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A single 14-day course of the monoclonal antibody teplizumab had lasting effects on delay of type 1 diabetes diagnosis and improved beta-cell function for high-risk individuals, according to new data.
In an extended follow-up of a randomized controlled trial, researchers also found that a cohort of children and adults who were autoantibody positive and had a relative with type 1 diabetes also experienced an improvement in glucose response when assigned teplizumab (Provention Bio), even if they did not develop type 1 diabetes.
“In the last study, we showed there was a delay in progression of type 1 diabetes in individuals who were at risk for the disease treated with teplizumab,” Kevan Herold, MD, the C.N.H. Long Professor of Immunobiology and Medicine at Yale School of Medicine, told Healio. “At the end of that study, there were still a substantial number of individuals who had not developed diabetes after drug treatment. The question was, would they develop diabetes with more extended follow-up, or would things regress to the mean and everyone would develop diabetes? It turns out that was not the case. There seemed to be persistent delay in the development of diabetes in the drug-treated group. When the study was over, half the people who were drug-treated did not develop diabetes.”
Study data
As Healio previously reported, Herold and colleagues recruited 76 TrialNet participants aged at least 8 years at high risk for but without a clinical diagnosis of type 1 diabetes (median age, 13 years). All participants tested positive for a least two diabetes autoantibodies within 6 months of study enrollment and had dysglycemia as measured via an oral glucose tolerance test.
Researchers randomly assigned participants a single, 14-day course of teplizumab — a humanized anti-CD3 monoclonal antibody — or placebo for 2 weeks. During a median follow-up of 742 days, participants assigned teplizumab vs. placebo were significantly less likely to develop type 1 diabetes (43% vs. 72%). The annualized rate of type 1 diabetes diagnosis was 14.9% for the teplizumab group and 35.9% for placebo. Time from baseline to diabetes diagnosis was nearly twice as long for the teplizumab cohort compared with the placebo group, at 48.4 months vs. 24.4 months (P < .006). The findings were presented at the American Diabetes Association 79th Scientific Sessions.
In a new analysis, Herold and colleagues evaluated the effects of teplizumab therapy on metabolic function and immune cells among the study participants during an extended follow-up (median, 923 days). Researchers assessed glucose tolerance, C-peptide area under the curve and insulin secretory rates, as well as relationships to T-cell subsets and function.
During follow-up, 50% of teplizumab-treated participants and 78% of placebo group developed type 1 diabetes, for an HR of 0.457 (P = .01). Median times to type 1 diabetes diagnosis were 59.6 months and 27.1 months, respectively.
“There is nothing that you do that is not impacted by type 1 diabetes if you have it,” Herold said in an interview. “Even if this is only as good as it appears, if you are in early elementary school, and now you are not going to get diabetes for 5 years, that is a big deal; or delaying diagnosis from high school until college, that is a huge deal. There is a medical and personal benefit with this.”
Researchers also found that teplizumab therapy improved beta-cell function, as reflected by average on-study C-peptide AUC (mean, 1.96 vs. 1.68 pmol/mL; P = .006). Drug treatment reversed a decline in insulin secretion observed before enrollment, followed by stabilization of the declining C-peptide AUC seen with placebo.
The teplizumab group also saw improved glucose response vs. those assigned placebo. Average on-study glucose AUC was higher for those who received placebo vs. teplizumab (unadjusted mean, 175 mg/dL vs. 165 mg/dL; P = 0.02). Changes in CD8+ T-cell subsets indicated that partially exhausted effector cells were associated with clinical response, Herold said.
“The way we think this works is it probably induces something my colleagues and I have termed ‘partial exhaustion,’” Herold said. “Particularly for CD8+ T cells. It seems to reduce their function. [The drug] does not really ‘deplete’ T cells. It seems to turn off that subset of T cells, and our speculation is the cells causing the disease reside in that subset of T cells.”
More screening recommended
Herold and the TrialNet investigators will continue to follow those who do and do not develop type 1 diabetes. For those who develop the disease, retreatment with teplizumab is an option, he said.
Researchers are also considering treatment for even younger children, he said.
“The big increase in diabetes has been happening in the very young,” Herold said. “The question is how much younger can we go with administering the drug? For this study, we went down to age 8 years. If we could offer something to younger children, there is great emotional benefit. I do not think anyone is saying that this is the end of the disease, but this [drug] may be a first step in making a difference. Maybe what we need to do is treat with this as a starter to stop it from progressing, and then come in with a second agent to maintain it.”
Herold said the findings also support the case for universal screenings for autoantibodies in children.
“The vast majority of people who develop diabetes do not have a relative with the disease,” Herold said. “In the past, there was not much of a reason to think about screening people because we didn’t have anything to offer. Well, now we do. ... Can we start to think about population-based screenings to identify those at risk for diabetes?”
In January, Provention Bio announced that it filed a biologics license application with the FDA for the delay or prevention of type 1 diabetes in at-risk individuals. The FDA also granted Provention’s request for priority review and assigned a user fee goal date of July 2, under the Prescription Drug User Fee Act.
For more information:
Kevan Herold, MD, can be reached at kevan.herold@yale.edu.
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