Five years ago, when Dana Elias, PhD, first clutched a publication reporting that a synthetic peptide had halted beta-cell destruction in mice that already were showing high blood-glucose levels, she felt a shiver of excitement. She had helped develop the synthetic peptide, called DiaPep277.
“For the first time,” she told Diabetes Health, “I saw in my own hands that we could stop progression [of beta-cell destruction] in the very late stages.”
Since those days as a postdoctoral fellow at the Weizmann Institute of Science in Rehovot, Israel, Dr. Elias has experienced “a series of excitements.”
Now vice president of research and development at Peptor Ltd., the biopharmaceutical company in Israel that developed DiaPep277, she and her colleagues are feeling the latest excitement: the news that DiaPep277 appears to work in humans, too.
If all goes well, the drug could be available for people with newly diagnosed type 1 diabetes as early as 2005, Peptor’s president and chief executive officer, Yoram Karmon, PhD, was quoted as saying in the October 12, 2001, issue of The Wall Street Transcript (TWST).
It’s in the Numbers
Research results reported in the November 24, 2001, issue of The Lancet say beta-cell destruction was halted in 15 men who had type 1 diabetes for less than six months and who received just three injections of DiaPep277 over a six-month period. However, insulin production plummeted in 16 type 1 men who received injections of a placebo.
The numbers tell the story.
In a person who does not have diabetes, an infusion of glucagon, which raises blood-glucose levels, stimulates the beta cells to release insulin. People with type 1 diabetes have increasingly insufficient numbers of beta cells that can release insulin in response to glucagon.
C-peptide, or connecting peptide, joins the alpha and beta chains of each molecule of insulin made by a person’s body. Because manufactured insulin does not contain C-peptide, measuring the amount of connecting peptide in a person’s body determines the amount of naturally occurring insulin (the insulin released by beta cells in the pancreas).
When the double-blinded study began, the men who would later receive injections of DiaPep277 had an average C-peptide concentration of 0.66 nmolL after glucagon was given, while those in the group who would receive injections of a placebo had an average post-glucagon C-peptide concentration of 1.12 nmolL.
Ten months later, those who had taken DiaPep277 had an average C-peptide concentration of 0.93 nmolL after glucagon was given. However, those who had received the placebo produced an average C-peptide concentration of only 0.26 nmolL.
In addition, those in the placebo group nearly doubled the amount of insulin they needed to inject to maintain blood-glucose control—from about 24 units per day to nearly 44 units per day, according to figures provided by Itamar Raz, MD, of Hadassah-Hebrew University Medical School in Jerusalem. Insulin needs of those receiving DiaPep277 rose from 22 units per day to about 28 units per day to maintain control. Both groups had an average A1C of 7%.
Pulling the Trigger
According to data from Peptor, DiaPep277 works by triggering cells that stop the autoimmune attack on healthy insulin-producing beta cells.
The number of injections needed or even the amount of the peptide to be given per injection is still unknown. Dr. Raz, who was principal investigator in the published study, explains that the dosages and intervals used in the research were based on animal studies and phase 1 clinical trials on people with long-standing diabetes. One person in the phase 1 trials showed an increase in insulin production and a positive change in the immune mechanism, according to Dr. Raz.
“We have to show that it works, find the right amount of peptide and the right interval between injections,” he says.
As for those who participated in the published study, “people who were treated on placebo were asked if they wanted to go on the peptide,” Dr. Raz reported. “Everybody wanted on the peptide.”
Encouraging News for People With LADA
DiaPep277 holds promise not only for people with type 1 diabetes but also for those with LADA (latent autoimmune diabetes in adults).
Frequently misdiagnosed as having type 2 diabetes because of their age, people with LADA do have the GAD antibodies that are present in type 1 diabetes. However, beta-cell destruction occurs much more slowly in an individual with LADA than in someone with type 1, which would give doctors the time necessary to preserve beta-cell function if DiaPep277 proves effective.
About 2 million people in North America, Europe and Japan have type 1 diabetes and between 4 million and 6.5 million have LADA, Dr. Karmon told TWST.
Results Less Positive in Children
While results of a study performed with 32 children were not published, Dr. Raz says the outcome was less positive than in adults, possibly because of the more rapid progression of type 1 diabetes in children.
“When we took children under the same conditions [as the adult study], we did not show this beautiful difference in C-peptide [levels].”
“There is… agreement,” says Dr. Elias, “that type 1 diabetes in children is more aggressive and progresses faster. It might require more frequent injections, and, in order to get a real effect in children, we quite likely will need to start treatment at an earlier age. We’ll need to catch it immediately after diagnosis” rather than up to six months following diagnosis, as has been the case in current clinical trials.
Going to Trial
Phase 2 trials for people with LADA began in January 2002 in the United States, according to a release issued by Peptor on January 14. These trials will take place at five centers. Altogether, 100 people with LADA will be accepted into the U.S. trials.
Only one center, the Veterans Administration Puget Sound Health Care System in Seattle, Washington, had been announced as of mid-January; the other four were still awaiting institutional review board approval.
The principal investigator for the LADA trials in the United States is Jerry Palmer, MD, professor of medicine and director of the Diabetes Endocrinology Research Center at the University of Washington in Seattle and section head of the Veterans Administration Puget Sound Health Care System.
Phase 2 trials for people with type 1 diabetes are being conducted in four centers in Europe and Israel, with phase 3 trials beginning later this year in the United States.
Dr. Elias says people who wish to be considered for participation in the trials may log on to www.peptor.co.il and click on the “Contact Us” button.
During phase 2 trials, control groups are used and the safety and effectiveness of potential drugs are determined, according to the U.S. Food and Drug Administration. Those trials are followed by phase 3 trials, which can involve thousands of subjects. If clinical benefit can be demonstrated during phase 3, those results generally are used to submit a new-drug application.
“I would say somewhere around the middle of , we should have in hand enough clinical evidence to initiate phase 3 trials,” Dr. Elias says.
Not Yet a Preventive Method
Although DiaPep277 could, in the future, be used for diabetes prevention, “we at Peptor decided to start [investigating] treatment for those with newly diagnosed diabetes,” Dr. Elias explains. “All of our ongoing clinical trials are with people who already have diabetes, to see if we can preserve beta-cell function from any further deterioration and to see if metabolic control is improved. That’s where we want to go first.”
Also, Elias adds, it’s a matter of risk assessment, noting that screening procedures to determine the possibility of a person developing type 1 diabetes are not perfect.
“From an ethical perspective, even people at high risk are still healthy,” she says. “So far, our safety profile has been very, very good. I would like to see some more data before we actually embark on prevention studies.”
At diagnosis today, she says, only an estimated 10 to 15 percent of beta-cell function remains.
“It’s not a lot, but if you have to lose 85 to 90 percent of your beta cells to develop the symptoms of diabetes, it might mean that if you can preserve 20 to 25 percent, it might be enough” to keep from becoming insulin-dependent.
Dr. Raz sees DiaPep277 being used as a preventive method in the future, noting that results of the Diabetes Prevention Trial 1 in the United States showed that type 1 diabetes can sometimes be predicted several years in advance.
“The best time to treat would be when you still have a large reserve of beta cells—several years before the clinical diagnosis of diabetes,” he explains.
For now, however, Dr. Elias is quick to point out that DiaPep277 is not a cure for type 1 diabetes and will not prevent the disease.
“The main thing is to be realistic,” she says. “If you are already insulin-dependent, the likelihood of you becoming insulin-independent is very low.”
Because C-peptide is believed, by some, to help protect against complications and because natural insulin production aids in blood-glucose control, Dr. Elias feels that “the main advantage would be to have better control and avoid complications. If we can achieve just that—personally, I would be very, very happy.”