Dr Kevan Herold Explains Teplizumab's Potential in Newly Diagnosed T1D

Kevan Herold, MD, professor of immunobiology and medicine at Yale School of Medicine, discussed recently published results from the PROTECT trial of teplizumab in patients newly diagnosed with type 1 diabetes.

Transcript

What were the main end points in the trial, and how did teplizumab perform compared with placebo?

The primary end point was whether the drug treatment—2 drug treatments—would improve C-peptide at 18 months in patients with new-onset type 1 diabetes, and the answer is it did. That's the primary end point, then the secondary end points included insulin use, hemoglobin A_1C, and hypoglycemia, for the most part. The insulin use did not meet statistical significance in the calculation at month 18—the P value is like .085—but if you look at all the time points, it's significantly different with repeated measures, analysis of variance. That’s why the figure looks the way it does in the paper, but I don't think it's fair to say that it didn't improve insulin use. It reduced it, there's no doubt about that, at least in my mind.

The hemoglobin A_1C was essentially identical in the drug and placebo groups. That is actually a good thing, because one of the major concerns about particularly the first trial that I did, back in 2002, was that the hemoglobin A_1C was better in the drug group compared to placebo. And that was also true in the next trial, the AbATE trial. Then people would say, “Oh, the reason the C-peptide is better is because the glucose is better.” You know, it's hard to know what's the chicken and egg here, but this sort of takes that argument off the table. The hemoglobin A_1C was controlled by the investigators with an attention to a target treatment level, and they did that. The effect of glucose on the outcome, I think, is no longer an issue. But what it does tell you is in order to achieve the same hemoglobin A_1C, it requires less insulin if you're treated with the drug. So that's the way I would interpret those findings.

The hypoglycemia is a bit of a more difficult issue, because it really depends on how you gather the data. So, in the secondary analysis that was just looking at severe events, it used the continuous glucose monitor data, and it was not capturing adverse events that were reported by the investigators. So, if you take a look at the table in the paper, it doesn't really show a difference. We then did a sensitivity analysis, so they incorporated all the information about hypoglycemia, including events that were recorded in the case report forms. And there, it turned out that there was certainly a trend for grade 2 and grade 3 hypoglycemia being reduced in the drug-treated group. And in fact, it was statistically different for grade 3 events.

Grade 3 events are quite severe, and they're not very frequent, but they were statistically better with teplizumab. To me, that's a very important finding, and the reason it's important is because the most common complication of diabetes—it's reduced with pumps and so on, but doesn't go away—is insulin-induced hypoglycemia, because the kinetics of the insulin that you inject is not the same as the insulin that’s made by a beta cell. And what this showed, and it actually mirrors what had been shown in another trial with a drug called alefacept, is that when you improve C-peptide, you reduce the rates of hypoglycemia. And there's a lot of data now that is supporting that notion, even in people who have had diabetes for years, that retaining some C-peptide seems to reduce the rates of hypoglycemia.In summary, I think there was a lot of very strong metabolic data indicating the drug has metabolic benefit.