Key:
NZ Nahida Zaman
IR Professor Itamar Raz
NZ You are listening to Nahida Zaman with Diabetes Radio. My guest today, Professor Itamar Raz. Professor, hello and a very warm welcome to Diabetes Radio.
IR Hello, good to hear you.
NZ You are a Professor of Medicine and Head of the Hadassah Diabetes Center in Jerusalem, Israel. Do tell our listeners, what is your current research focus?
IR I am focused on basic research mainly on the beta cell, the cell that secretes insulin, how you can save this cell from dying, how you can keep it continuing to function and my clinical research is actually based on three things, one is on type I diabetes, trying to look for drugs to prevent autoimmune attacks on the beta cells. I also do clinical research on the kidneys which I published several times, looking at drugs to prevent diabetic kidney nephropathy, diabetic disease and I am also running now a very large study on 16,500 people looking at a drug called saxagliptin to see whether this drug can improve the cardiovascular outcome of our patients worldwide.
NZ Your recent research culminated in a presentation at the 2011 World Diabetes Congress in Dubai. Your lecture was titled New Avenues for Prevention of Beta Cell Loss in Type I Diabetes. Can you tell our listeners about your presentation?
IR We are looking for drugs to prevent type I diabetes and one of the drugs that was developed in Israel was a vaccine that we believe stops the autoimmune attack on the beta cell that is causing the destruction of the beta cell in humans and we actually tested it in animals and later on in humans and now we are actually going to publish the data of a very large study that we did, a phase 3 study on 450 type I diabetic patients.
NZ Professor Raz, you recently led a large trial of type I diabetes vaccines known as DiaPep277, the results of which have gained international attention and were presented at the 2011 American Diabetes Conference. Can you tell us what were the objectives of this trial?
IR The objective of the trial was to see whether we can stop the immune attack on the beta cell and the way to see it was first to see whether the beta cell will continue to secrete insulin after two years of diabetes because we know that in most of the type I diabetic patients, if you look at the ability of the beta cell to secrete insulin two years after the diagnosis, in most of the patients they are losing this ability because the beta cells are dying and there are no beta cells to secrete insulin so the purpose was to see whether we can protect the beta cell and whether the beta cell can continue to secret insulin two years after.
NZ How was the trial designed?
IR We took patients who have newly diagnosed type I diabetes with diabetes known for less than three months and we checked whether they still have beta cells that secrete insulin, we are checking it by what we call C-peptide. C-peptide is part of the insulin and is part of what we call proinsulin when the insulin is being produced, part of it is being degraded and it cause peptide C and we are following how much insulin can be secreted and whether we can prevent it so we take the patient and we actually had 457 newly diagnosed type I diabetic patients and we randomised them blindly to receive either the DiaPep277 or placebo. What I should mention is that those on placebo received what we call adjuvant. Adjuvant is something that when you inject it at least to animals with type I diabetes you might prevent the progression of the disease so half of the patients received adjuvant and half of the patients received adjuvant together with a DiaPep277. We followed the patient for three years, we followed their ability to secrete insulin after one year and after two years in response either to a meal or to glucogan tests. Glucogan is a hormone that when you inject it to people, it increases the development of glucose and it has an anti-insulin effect and it causes the beta cells to secrete insulin so we actually checked how much insulin the beta cell will secrete after one year and two years under the adjuvant only or under adjuvant plus the DiaPep277.
NZ And what type of patients were included in this trial?
IR The patients were newly diagnosed type I diabetic patients aged 16 to 45 who still have functioning beta cells as we measured by measuring the insulin and the C-peptide and we also have antibodies to the beta cell to demonstrate that they really have type I diabetes and also in one attack on the beta cells and not type II diabetes.
NZ The results?
IR What we found was actually for the first time active now because all the other similar studies up until now failed to show a successful result in phase three studies. What we found was that after two years their ability to secrete the insulin was higher in the patient who received DiaPep277 than in those who only receive the placebo. The difference was between 25 and 30% of ability to keep the beta cell to secrete insulin. We also looked at how many patients got to their goal and you know what when you treat type I diabetes, the goal is that their blood glucose control will be very good as measured but what we call haemoglobin A1c. Haemoglobin A1c gives you an idea about how good blood glucose control is on the last three months and what we found that 45% of the patients who got the DiaPep still was in the goal of haemogloblin A1c less than 7 versus only 35% of those who got the placebo and the difference was significant so we actually show that it is not only that we improve the function of the beta cell, we also improve the control of blood glucose level in our patients.
NZ Tell us, what is DiaPep277 and what is its mechanism of action?
IR DiaPep277 is part of the heat shock protein. Heat shock protein is a protein that is produced in different cells in our body in response to stress. When the cells are on stress you see an increase in the production of a protein that is called heat shock protein. What we found originally and this was done by Professor Irun Cohen from the Weizmann Institute, he found that the heat shock protein has both pro-inflammatory and anti-inflammatory effect. We know that the destruction of the beta cells is go to inflammation and what he found was that there are some receptors, there are some places on the white blood cell that when they are exposed to the heat shock protein, they are causing inflammation so they are increasing their damage to the beta cell. On the other hand there are other places on the same white blood cell that when they are activated by the heat shock protein, they protect the beta cell so what we assume was, it is known that during the development of diabetes, the beta cell is under stress. It is known that during the development of type I diabetes, the stressed beta cells also produce an increase of heat shock protein which is exposed to the surrounding causing an attack of the white blood cells that are now being activated by the heat shock protein causing an attack of the white blood cell on the beta cell. What is the DiaPep277? The DiaPep277 is part of the heat shock protein but it has one very good difference from the heat shock protein. While the heat shock protein activates both inflammatory damaging attack and also anti-inflammatory, the DiaPep277 only activate the receptors of the anti-inflammatory attack so when you give the DiaPep277 to patients with newly diagnosed type I diabetes or with autoimmune attack on the beta cell, what happens is the DiaPep277 now activities anti-inflammatory attack on the beta cells which anti-inflammatory attack is mediated to what we call cytokine and there are cytokines that protect the beta cell and you can see that when you give DiaPep277 it protects the beta cell because it increases those cytokines that protect the beta cells.
NZ Professor, you talked about heat shock protein produced in type I diabetes, what is the rationale for targeting this protein as a way of managing type I diabetes?
IR The rationale was, and actually even is, that we know that during the development of type I diabetes there is an increase in the production of heat shock protein in the beta cells. We assume that when the beta cell increases its heat shock protein production and this heat shock protein is presented to the surrounding, it is causing an attack of the Th1 of the attacking T cell on the beta cell that destroy the beta cell but during the research, the lab research, the cell research, we found that the heat shock proteins do not only activate the attack cells or the inflammatory cells, it also has an effect on cells that protect the beta cell on anti-inflammatory effect so Professor Irun Cohen looked what part in the heat shock protein has the protective effect, he found the part that has only protective effect and he now took only this part, only the DiaPep277 which is 24 amino acids out of 480 amino acids of the whole protein, now when you inject this thing to animals, for example with type I diabetes or animals who are going to develop type I diabetes, you can show that this 277 protein now protects the beta cell from the attack of the T cell, of the white cell, and it is doing it by changing the attacking cells from Th1 to Th2 to protecting cells so this is the rationale behind the development of it and the rationale was found to be true in animal model and because it was so successive in animal model, we did several phase 2 studies in humans. First we did the phase 1 study to make sure that there is no damage or nothing wrong with giving it to humans and then we did several phase 2 studies which demonstrated to us that when you inject people with type 1 diabetes, with DiaPep277, you can see that you change the immune profile of these people against the beta cells, they are now producing more hormone, more cytokines that protect the beta cell and much less cytokine that attack the beta cells. This is what we can show in animals and we could also show in animals and also in humans that together with the reduced cytokine that attack the beta cells, there was an improvement in beta cell function over time and in our phase 2 studies we demonstrated that the amount of insulin and C-peptide that will be produced by the beta cell after one year, after two years was higher in those who were injected DiaPep277 than it was in those who were injected with placebo only and that is why we went to the phase 3 study which was a much larger study and we were able to show a similar result that after two years of treatment the people who were injected with DiaPep277 have a better beta cell function and the reduction in beta cell function over two years were 25 to 30% less with those who were injected with the DiaPep277 than it was with those who were injected with placebo. Moreover, because beta cell were functioning better, we were also able to show that the percentage of patients who were ideally controlled, who were controlled very well with their blood glucose levels was 45% in those treated with the DiaPep and only 35% in those treated with the placebo and you have to remember that this is very hard to show in the first one or two years of diabetes because in the first one or two years of diabetes, you still have beta cells so it is very easy to control the patient and most of the patients will be well controlled whether you treat them or not treat them so we were able to show at the very short stage already the treatment with DiaPep give better result of blood glucose level in the blood and I have to tell you that we are now following patients for nearly eight to ten years, we have about 30 people who are injected with DiaPep277 now more than six years and we have more than 100 who are injected with DiaPep277 between four to six years and what we see is that those patients which we continue to inject the DiaPep are continuing to have beta cell function and continue to secrete insulin and C-peptide and this is something which is very, very rare. We know the patients with type I diabetes, most of the patients after two, three, four years will not have beta cell function at all and we see that those patients who were on our study for two years and then all of them transfer to the DiaPep277 in an open trial, all those that were transferred to the DiaPep actually are continuing to have, not all but most of them, are continuing to have good beta cell function and good blood glucose control. We even have women patients who gave birth one, two, one of them even three times, taking the DiaPep277, we always stop it when the woman becomes pregnant until she gave birth but we have, for example, one beautiful Arabic woman from Nazareth in Israel who are now nearly ten years on the DiaPep277 and they are still producing insulin in spite of giving birth to three babies and in spite of the fact that she stop it each time when she was pregnant.
NZ Did you notice any adverse events in the human trials?
IR In general I can say that this is a very safe treatment, you hardly see adverse event. We have one case where there was a slight hypersensitivity with a rash over the body and in that case we stop the treatment. We have three cases of severe events that were found to be unrelated to the drugs. Actually in two of them when we opened the study at the end, we found that they were on the placebo. Most of the patients get it very, very easily. Sometimes you see a local reaction around the place of injection, a little bit of redness, a little bit swollen or something but it disappears within several hours and we do not really see any problem. I can tell you that I personally in my clinic followed about 200 people that were treated either with a DiaPep or with a placebo and as I mentioned, another nearly 50 people who are now treated with DiaPep for several years and safety is hardly an issue.
NZ Professor, how long after administration in participants did the vaccine continue to protect attack on beta cells?
IR What we believe the vaccine is doing is it protects the attack on the beta cells so most probably when we give the vaccine, the amount of beta cells this is going down. We know that when we diagnose type I diabetes, about 80 to 90% of the beta cells are destroyed in most of the people so we have very small amount of beta cells. We know that these beta cells will most probably die completely within one or two years in most of the patients. We know today that even if we will be able to keep this beta cell for another two, three, four years, it has a great advantage to the patient with type I diabetes because it make control of blood glucose much easier and it presents late complication years after. We learn this from the large DCCP study, the American study so it is very important to immunise patients with newly diagnosed type I diabetes although we cannot cure them completely because we are already starting too late. Whenever we give the injection, we can see that the immune effect of the injection, the change in the attacking profile continues for about two months, that is why we give it every three months and we can see that the effect on insulin secretion continues for about three months, that is why we give it every three months. The hope is we know today how to diagnose who will be the people who will develop diabetes within three years. We can even diagnose today who will be the people who will most probably will develop diabetes within six years so the hope is that if this vaccine can stop the immune attack then we will be able to give it not when we diagnose the disease but three, four years before the patient has diabetes at the time when he still has 50, 60, 70% of the beta cell, not 10 or 20, we can actually cure the patient or prevent him from developing type I diabetes.
NZ Professor Itamar Raz, thank you so much for joining Diabetes Radio today.