Immunotherapy May Shield Beta Cells in Young Diabetics

Jim Kling

June 15, 2012

June 15, 2012 — Among young people with newly diagnosed type 1 diabetes, immunotherapy attenuates the decline in beta cell function as far out as 12 months after diagnosis, according to a study presented here at the American Diabetes Association 72nd Scientific Sessions.

In addition, study subjects 8 to 14 years of age were more likely to respond well to anti-CD3 antibody immunotherapy than subjects 15 years and older.

Researchers recruiting patients with type 1 diabetes for immunotherapy trials typically recruit them within 3 months of diagnosis, but previous studies have shown that insulin production continues in most patients a year or more after diagnosis.

"A number of studies have shown [anti-CD3 immunotherapy] to be effective, but these were done during the 3-month new-onset period." We wanted to find out if it would work after that, Kevan Herold, MD, professor of immunobiology and internal medicine at Yale University in New Haven, Connecticut, who presented the research, told Medscape Medical News.

The researchers conducted a randomized placebo-controlled trial of the anti-CD3 monoclonal antibody teplizumab. The 58 subjects (mean age, 12.3 years) had been diagnosed with type 1 diabetes in the previous 4 to 12 months (mean, 7.11 months) and had a stimulated C-peptide level of at least 0.2 pmol/mL. Baseline insulin doses were 0.40 U/kg per day.

All subjects received a 14-day course of teplizumab. They were stratified into 2 groups: those diagnosed in the previous 4 to 8 months (early stratum) and those diagnosed in the previous 9 to 12 months (late stratum).

Subjects in the teplizumab group used less insulin than those in the placebo group (0.438 vs 0.522 U/kg per day; P = .019). In addition, at 2 weeks, there was a drug-dependent decrease in the ratio of CD4/CD8 T cells in the teplizumab group (P = .049).

The researchers used C-peptide level to assess beta cell function. At 12 months, they found that C-peptide production was better preserved in the teplizumab group than in the placebo group (P = .03). In fact, 5 subjects in the placebo group had no detectable C-peptide (P = .02).

In the placebo group, the decline in the baseline C-peptide level in the early stratum was greater than the decline in the late stratum (46.7% vs 26.9%). In the teplizumab group, the decline was similar in the 2 strata (18.0% vs 19.5%). This suggests that teplizumab prevents a steeper drop in those closer to diagnosis, according to Dr. Herold.

The researchers also found a trend for age. In the subjects 8 to 14 years of age, there was a 37.6% increase in C-peptide response with teplizumab, compared with placebo (P = .005); in those 15 years and older, there was no improvement.

Six serious adverse events occurred in 5 patients.

"[Teplizumab] was effective. It probably doesn't have quite the same potency as [if it is administered] during the new-onset period," said Dr. Herold. "But this is now the fourth randomized trial showing efficacy for this drug. It's becoming a recurring theme — the drug preserves beta cell function," he added.

It remains to be seen whether the effect will wane over time. "We'll get some answers to that in August, because we'll have patients who got the drug 1 year after enrolment, so some of them will have had diabetes for close to 2 years.... That will help determine if it's something that we can use year after year or only in the new-onset period," said Dr. Herold.

The research is intriguing because of its potential to lengthen the so-called "honeymoon period," during which patients continue to have functional beta cells and produce some endogenous insulin.

"There are lines of research to see how we can regenerate islet cells through in vivo methods or exogenous therapy. If you can prolong the honeymoon period, you might be able find drugs that would allow the beta cells to come back," Jonathan D. Katz, PhD, director of the Diabetes Research Center at the Cincinnati Children's Research Foundation in Ohio, who attended the session, told Medscape Medical News.

Dr. Herold reports receiving research support from Macrogenics. Dr. Katz has disclosed no relevant financial relationships.

American Diabetes Association (ADA) 72nd Scientific Sessions: Abstract 85-OR. Presented June 9, 2012.

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