Drugs Show Promise for Preserving Body’s Ability to Produce Insulin
The progression of type 1 diabetes may be slowed in those newly diagnosed through the use of promising new medications currently under development, according to data presented by researchers at the American Diabetes Association’s 71st Scientific Sessions®. Researchers believe these findings could eventually lead to the development of drugs to prevent or treat type 1 diabetes, since current work focuses on preserving beta cell function and prolonging the body’s ability to produce its own insulin.
A total of eight studies of therapies in various stages of clinical development were presented at the ADA symposia on the last two days. They represent a mix of trials funded by government agencies and those sponsored by biotechnology and pharmaceutical developers. All of the studies look at the potential for preventing the slow loss of insulin production that occurs within the first several months following the diagnosis of type 1 diabetes.
According to Kevan Herold, MD, co-chair of the Tuesday symposium and Professor of Immunobiology at Yale University, “Presenting the findings together gives researchers an opportunity to discuss what worked in this approach to treating type 1 diabetes, what didn’t, and why.” “We can see that some drugs are successful in slowing the progression of this disease, but thus far we have not been able to prolong that effect permanently. Others are not as effective and some have not been effective at all outside the laboratory setting. These presentations will help us to determine the best way to move forward as we continue to explore this promising direction of preserving beta cell function, which is critical to ultimately finding a cure.”
The drug, DiaPep277, a potential vaccine for type 1 diabetes, was developed with the goal of preventing beta cell destruction. During the development of type 1 diabetes, it is believed that an increase in a protein in the beta cell called “heat shock” protein causes beta cell destruction through activation of destructive T-cells. However, part of this protein has the ability to change the destructive T-cells into protective T-cells.
Researchers therefore removed 24 of 500 amino acids from the “heat shock” protein, to see if doing so would protect beta cells from attack by the T-cells, a hypothesis that had previously held true in studies conducted in laboratory mice with a form of diabetes similar to human type 1 diabetes.
In this phase two study, the altered “heat shock” protein (known as DiaPep277) — administered subcutaneously to 100 patients newly diagnosed with type 1 diabetes — succeeded in protecting the beta cells, replicating in humans the findings in laboratory mice. “The drug works by increasing protective T-cells that secrete cytokine, which prevents the destruction of beta cells from immune attack,” said lead researcher Itamar Raz, MD, Professor of Medicine and Head of the Hadassah Diabetic Center in Jerusalem, Hadassah Hebrew University Hospital.
Administering this vaccine also allowed beta cells to continue to secrete insulin for up to two years following a type 1 diagnosis, he said, a promising result that points toward the potential for prevention. “This shows that the vaccine protects the beta cell function over time,” Raz said.
The drug is currently undergoing phase three trials in which beta cell function, insulin use and glucose control are being monitored as key outcomes.
Previous trials of teplizumab found that giving a 14-day course of this drug to people ages 8-30 years who were newly diagnosed with type 1 diabetes preserved beta cell function for 12 months or longer, but that the effects of the drug began to wane about a year after receiving it. This phase two study looked at whether giving a second course of the drug intravenously a year after it was first administered could prolong its effects.
While it was unclear as to whether the second course of the drug provided any additional benefit, the study did confirm that those who were given teplizumab, an anti-CD3 medication (which modulates T-cells), did continue to show improved beta cell function even two years after diagnosis, over those not given any medication, said lead researcher Kevan Herold, MD. Researchers are continuing to analyze data that will help them compare the benefit of receiving one course of the drug with that of two courses.
The data showed that those who received teplizumab experienced a 45 percent decrease in beta cell function over two years, compared to a 77 percent decrease for those in the untreated group, he said. In addition, at 24 months, the untreated group used 57 percent greater amounts of insulin, on average, than the group that received medication.
“The effect seemed to be most pronounced from the first course of the drug,” Herold said. “It also seemed to be effective in younger subjects, age 8-12.”
In summary, Herold said, the study answered the question: “Can your body make more insulin as a result of having had this treatment? Yes, it can.”
In this phase three trial of an anti-CD3 drug, researchers administered substantially lower doses of the medication (one-sixteenth the dose administered in previous trials, where significant side effects were seen) to see if reducing the dose would reduce side effects while maintaining a benefit in insulin production. Previous investigations have shown that maintaining a certain level of C-peptide can reduce future complications, prevent hypoglycemia and improve A1C levels.
Though previous trials did find that otelixizumab was effective in preserving C-peptide, it was not effective in doing so at the lower dose, said Peter Gottlieb, MD, co-investigator of the study, which examined the effect of otelixizumab on those newly diagnosed with type 1 diabetes between the ages of 12 and 44 years.
“The dose that was chosen was clearly too low,” Gottlieb said. “Future trials using a dose between the two previous ones may be useful in reaching the desired therapeutic goal.”
This phase three, double-blind, placebo-controlled, multinational study of the anti-CD3 drug teplizumab had a combined goal of reducing A1C to less than 6.5 percent for those newly diagnosed with type 1 diabetes and reducing the amount of insulin needed to less than 0.5 units per kg of body weight per day. Though the study did not achieve this combined goal, it did have some positive results, according to lead researcher Nicole Sherry, MD, Director of the Diabetes Center at the Massachusetts General Hospital for Children in Boston.
Five percent of participants who received treatment no longer needed insulin at the end of one year, compared to none of those who received a placebo, she said. In post-hoc analysis, 40 percent of those who received a 14-day regimen of the drug experienced a preservation of or increase in C-peptide levels, compared to 28 percent of those in the placebo group.
“We found an especially potent effect in certain subgroups,” Sherry said, “namely children, participants in the United States and those who were treated within six weeks of their diagnosis.”
This phase two, randomized clinical study compared the effects of the drug abatacept to placebo in people newly diagnosed with type 1 diabetes, ages 6 to 45 years. It found that those who received the drug experienced a 59 percent higher level of C-peptide at the end of two years, compared to those who received placebo. The drug was first given to people within three months of diagnosis. The study showed that on average it preserved beta cell function for an additional 9.6 months.
Jay Skyler, MD, chairman of the National Institutes of Health (NIH)-funded Type 1 Diabetes TrialNet study group, which conducted the study, said while the results were positive, it is only a step in the right direction.
“The problem is, in spite of giving the drug for two years we only had a 9.6-month delay,” he said. “That means that the effect over time may have been lost. It may have had an effect early on that created the delay and then may have lost further effect as time went on.”
The medication, he added, was noted to be less convenient to administer as it needs to be given in 27 separate intravenous infusions over a two-year period of time. The company is currently working on a subcutaneous (under the skin) form of the medication that would be easier to administer, he added.
In this TrialNet study of 145 people newly diagnosed with type 1 diabetes as young as age 3 (and as old as age 45), participants were randomized into one of three groups: those given an injection of the GAD65 vaccine plus two boosters; those given an injection, one booster and one placebo; and those given all placebos.
However, all three groups experienced identical effects, said Skyler. That is, there was no benefit at all from taking the medication. The positive news was that there did not appear to be any side effects either, he said.
“What we don’t know is whether in a different dosage or on a different dosage schedule, we would have seen an effect,” he said. “When you don’t see something, you’re not sure if it’s because of giving the wrong amounts or if it just doesn’t work.”
The medication has worked well in previous animal studies, he noted.
Interleukin-2 in Combination with Rapamycin (Sirolimus)
In this phase one safety trial of nine people previously diagnosed with type 1 diabetes (who had lived with the disease for up to four years), researchers tested the safety of combining two Food and Drug Administration (FDA)-approved drugs that are currently being used to treat other diseases.
Previous studies in laboratory animals had suggested that these drugs (Interleukin-2, used to treat cancer, and Rapamycin, which is used in organ transplantation), when used together, could turn off the immune attack on the beta cells. However, when tested in humans, the same effect did not occur. But, there were positive changes to the immune system that suggested that this approach could still be useful, said Carla Greenbaum, MD, lead investigator on the study. Researchers are continuing to analyze data to better understand these findings.
Oral Presentations presented Monday June 27, 2011 and the Symposium presented Tuesday June 28, 2011 7:30 PDT, at the 71st ADA Scientific Sessions.