MGH & BU: Steven Russell & Edward R. Damiano on Artificial Endocrine Pancreas




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Video title: MGH & BU: Steven Russell & Edward R. Damiano on Artificial Endocrine Pancreas
Released on: November 10, 2010. © PharmaTelevision Ltd
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In this episode of PharmaTelevision News Review, Fintan Walks with Steven Russell from Massachusetts General Hospital and Edward R. Damiano from Boston University about an artificial endocrine pancreas as a way to improve the therapy for people with type I diabetes by measuring blood glucose every 5 minutes and automatically infusing insulin. They discuss:

• Edward R. Damiano's research background in artificial pancreas

• Steven J. Russell's interest and involvement in Type 1 diabetes research

• Development of technology to adjust mathematical algorithm from animal to human

• Funding for clinical trials

• Results and key findings from first stage clinical trials

• Complications of Hypoglycemia

• What is needed from the pharmaceutical industry for the device?

• Next stages of device development

• Partnership and collaboration strategy
Edward R. Damiano's research background in artificial pancreas
Fintan Walton:
Hello and welcome to PharmaTelevision News Review here at BioPharm America in Boston. On this show I have Steven J. Russell and Edward R. Damiano, welcome to the show.
Steven J. Russell:
Thank you.
Edward R. Damiano:
Thank you.
Fintan Walton:
Edward R. Damiano, I am gonna start with you, you're a Professor of Biomedical Engineering at Boston University, we are gonna talk about an artificial pancreas in fact an artificial endocrine pancreas and it was your early work that lead into this research we were gonna talk about, could you give us the background to that?
Steven J. Russell:
Sure, when my son was 11 months old he was diagnosed with Type I diabetes, and it was at that point that I realized that I potentially had a role to play in improving the lives of people with Type I diabetes, I was motivated to find a way to improve the therapy in which people are managed with diabetes. So I started working with a graduate student of mine Firas El-Khatib to develop a technology which automatically infuses insulin, which lowers blood glucose to automatically regulate my son's blood sugar anybody with Type I diabetes, so one of that is general algorithm mathematical formulation that makes therapeutic decisions every five minutes or so to automatically infuse insulin there by removing the clinician or the caregiver from the loop, so essentially you have to sense blood sugar and get blood glucose values in order to inform yourself as to how to regulate blood sugar and need to infuse insulin response to that information and there are some decisions that are being mailed all the time throughout the day to manage this information and you know we decided this could be potentially be automated now that there have been a lot of people thinking about these problems, so we have we thinked several unique approaches to the problem so we began developing this technology, and soon there after we started testing it in animal model and when I presented those results at the Joslin Diabetes centre in the spring of 2006 I met Steven J. Russell who was in the audience at that time and he approached me and suggested that we are ready to move to a clinical trials.
Steven J. Russell's interest and involvement in Type 1 diabetes research
Fintan Walton:
Okay, so Steven J. Russell you've got involved in this tell us little bit about your own background and why this science that was going on was of interest to you?
Steven J. Russell:
One endocrinologist that treats primarily people with diabetes, and so I have an appreciation of how difficult it is to do this balancing act the people with diabetes have to do everyday probably not as much an appreciation as Edward and his son, but an appreciation none the less, it's tremendously difficult task, they have to check the blood glucose many times a day, they have to inject insulin usually multiple times a day it's despite the best efforts and the most careful attention to diet and calculating the dose it's often not just right because the body is not the same everyday and so they get hyperglycemia they have to take carbohydrates, so it's like having a second job really for these people with diabetes. So it's tremendous amount of work, but it's worth it because we know that if the blood glucose is kept below about a 150 milligrams per deciliter on average you can nearly eliminate the complications of diabetes, unfortunately it's almost impossible to maintain it at that level without relatively frequent belts of hyperglycemia and so that is associated with far amount of anxiety especially if they occur at night when somebody is sleeping. So it's a hard job, it needs to be done to protect their health, but it's tremendously difficult and so the idea of having a device that never sleeps, never gets tired can check the blood glucose instead of 6, or 8, or 10 times a day they can check it every five minutes make decisions all night long whether person is sleeping that was incredibly appealing to me, and there were a couple of points about Edward R. Damiano's work that really struck me, but I think the one that was really the most innovative was the use of glucagon as a kind of regulatory hormone and that really had not been used before in this context and if you think about it, it makes a lot of sense this is what the pancreas does, uses insulin to lower blood glucose, it uses glucagon to raise it and well lot of people know that in Type I diabetes you are missing insulin so you can't lower blood glucose what's not really appreciated is that there often after the first couple of years of the disease they are no longer able to produce glucagon in response to hyperglycemia so their first line of defense is missing, and this was the first system to replace both of those critical functions of the pancreas.
Development of technology to adjust mathematical algorithm from animal to human
Fintan Walton:
Right, so Edward R. Damiano, you now had basically a clinical partner somebody who could conduct some of the clinical trials take it from out of an animal into humans so that comes back to the further development did you have to now develop the technology a little bit further in order to put into patients for an example going back to your mathematical algorithm do you need to adjust that mathematical algorithm from animal to human?
Edward R. Damiano:
Yes, it's a good question. So we were not really sure how well the experiments that experiment were ultimately obtained in the pigs we were gonna translate to human, we were pleasantly surprised that they translated quite well there was one important difference that we found and that was that the pigs that we used who didn't actually have the Type I diabetes they had a diabetes of like pathology that we induced. And one thing they didn't really have was an autoimmune disorders they didn't have this immune system that's you know that people in Type I diabetes are suffering from this stack on the (indiscernable) on the (indiscernable) cells and so essentially our pigs didn't have these antibodies to insulin and so we suspected what we found really was at the subjects with Type I diabetes had much more delayed absorptions of insulin than the pigs did and we attributed to potentially this anti-insulin antibodies that people with Type I diabetes or could have at higher levels than the pigs. So that was the main difference however we were able to accommodate that quite easily, because the general formulation of our mathematical model accounted for insulin absorption in the design of it so these controller knows that when it doses insulin it takes a finite amount of time to appear in the blood and then to clear it was very simple matter to just slow down that assumption basically tell the controller that things take little bit longer in people with Type I diabetes so we did a first round of experiment in subjects where we assume very fast insulin absorptions like we saw in the pig and then we came back and repeated those experiments and we had some hypoglycemia in those insulin's for the people that were most you know most delayed we saw hypoglycemia, so then we brought all those subjects back and repeated experiments telling the controller that these absorption is slower so we made a global change to the parameters and in that process we've found that we could regulate virtually in all these subjects with no hypoglycemia, so that was the major learning point for us from the translational from animals to humans.
Funding for clinical trials
Fintan Walton:
Right, now Steven J. Russell you were conducting these clinical trials on behalf of that, and first of all just in terms of this is not a simple task obviously you need funding and so forth just at this stage what support were you getting and where were your how did you cost the these particular trials that you needed to do?
Steven J. Russell:
Well initially we had a small amount of funding from an organization called The Coulter Foundation which has as its goal the translation of basic biomedical engineering science into the clinical round, so that was the small amount of money that allowed to do the preclinical experiments and allowed us to have the space to design a clinical trial, but it certainly wasn't the kind of money you need to actually conduct a clinical trial. So we went to a number of organizations, but the one that stepped to the point to provide funding was the Juvenile Diabetes Research Foundation and they provided funding for this the first Phase of this study which we've now completed and subsequently using those results we were able to go to other funding institutions including the National Institutes of Health and relatively new organization called the Helmsley Trust to get the funding required to expand our efforts and do the current clinical trials we are conducting now.
Results and key findings from first stage clinical trials
Fintan Walton:
Okay, so the clinical trials you said of first stage has come to an end is that correct? And what are the results from that and then what key findings came out of that?
Steven J. Russell:
The key findings were that with a what we call a bio hormonal artificial endocrine pancreas that is one that uses both insulin and glucagon that we could achieve really quite good blood glucose control that was safe meaning that we didn't have any hypoglycemia in those experiments without any need to give extra carbohydrates, what do I mean by good glycemic control well we had a average blood glucose just above the 150 mg per deciliter goal that is set by the American Diabetes Association, and I should point out that's actually better than most people with Type I diabetes are able to achieve on their own. If you look at the whole population the average blood glucose is substantially higher than that, it's still not quite to our goal, but the key point was that in our study we didn't provide the controller any information about when a meal was coming, we didn't do any pre-bolusing for the meal with insulin this was a truly closed-loop the algorithm was just reacting to what it's on terms of blood glucose, but even in those really very very challenging circumstances when we provided big meals we picked subjects that had absolutely no residual insulin secretion, we designed the trial specifically to really be a torture test for closed-loop algorithm it's still performed remarkably well and the results of the pigs translated remarkably well into humans except for this difference in the pharmacokinetics and then that was easily dealt with by a tweak to the parameters. So it was tremendously encouraging and it gave us the impetus to move on to a trial where we would get closer to the kind of device that would actually be could be approved and released into the general into general use.
Edward R. Damiano:
So in the current study we've actually made number of changes, the most important would be perhaps the fact that the sense that we were using is going to a portable sense so that's more like the system you would have viewed actually in vision a subject varying. In the first trial we actually used the glucose sense of that sample blood from the vein and that's not a practical implementation device, but there were a number of scientific reasons why it was good to made this choice and to design the trial a little bit initially, but now with the success that we had in the first trial we move to the second trial and we start replacing components with more realistic practical portable devices and in that process we had to make certain changes to the algorithms, but you know we were also testing those technologies in the pigs while we were conducting our first clinical trials, so in parallel we were prep you know making the transition already in preclinical experiments while we were doing our first clinical trial. So that was one of the main things that came from that, so we in the current study we will be you know we will be actually testing more realistic system, I should mention now there is also a practical way this device would likely could be used is that subjects will give a little bit of insulin before their meal, and when we did the first study we really wanted to as Steven J. Russell mentioned challenge the controllers as much as possible and then get entirely reactive system, but we think in reality people will use this system in a way that would give it would favor the system a little bit more and when they sit down for a meal they would primate with a little bit of insulin.
Fintan Walton:
So it's a proactive reactor device?
Steven J. Russell:
Little proactive.
Edward R. Damiano:
And so now that's what we are testing in our current trials, so we do expect to see this average blood sugar that Steven J. Russell referred to go down and hopefully with no additional hypoglycemia, we are also challenging the system by testing things like exercise which also is a challenge to glycemic control.
Complications of Hypoglycemia
Fintan Walton:
If I can ask you Steven J. Russell , I mean you've worked with patients as you said and clearly we're talking here about modulating glucose levels, but the implication of this is not just simply convenience or inconvenience it's a long-term outcome for the patients themselves, because the ultimate side effects of having insulin are detrimental obviously?
Steven J. Russell:
Well the side effects of hypoglycemia are relatively minimum on the short run, but in the long run they can be very detrimental the common complications the so called microvascular complications of diabetes of course are retinopathy which can lead to blindness, nephropathy which can lead to kidney failure and the need for dialysis and neuropathy which can leave people vulnerable to severe injuries to their feet that they won't even feel an amputations so these are all terrible complications that are very expensive to our healthcare system and very damaging to people's lives, but what we know from important trials, landmark trials like the diabetes controlling complication study was that if you can maintain the average blood glucose below about a 150 milligrams per deciliter you can almost completely eliminate these microvascular complications, so that's our goal and that's always been the goal of diabetes care, the difference is with the system like this I think it's realistic to maintain that level of control without hypoglycemia and that's something that's never really been practical or possible in so called open-loop control, there just isn't enough monitoring no matter how dedicated somebody is to managing the diabetes no matter how much time they are willing to devote to it it's almost impossible to avoid hypoglycemia there is a famous graph in one of the DCCT papers that shows the average blood glucose on this axis and the complications on this axis and they go up very slowly and then they take a sudden rise after this average blood glucose of about 150, and then companion graph is the rate of hypoglycemia, severe hypoglycemia that the kind that requires somebody else to assist you or you could die potentially and that graph is flat and then takes a sudden rise upward and it is about the same place, so you are walking this tremendously dangerous line between long-term complications and short-term disaster and what I think this system could do for my patients and for Edward R. Damiano son is to allow them to walk that line with very little input from themselves and to walk that line at night when they are not paying any attention.
Edward R. Damiano:
To sleep at night.
Steven J. Russell:
Exactly, for them to sleep and their parents to sleep.
Fintan Walton:
Right.
Edward R. Damiano:
People have to sleep the controller doesn't need to.
What is needed from the pharmaceutical industry for the device?
Fintan Walton:
I am gonna come back to you Edward R. Damiano about the device itself and how it needs to go forward, but just one another question to you Steven J. Russell , this research has revealed a couple of things I understand and one is that the current insulins could be improved upon and also glucagon itself is not a an FDA approved "drug"?
Edward R. Damiano:
For this application?
Steven J. Russell:
For this particular application, that's right.
Fintan Walton:
For this particular application, so what do we need from the pharmaceutical industry in order to get this device up and running really?
Steven J. Russell:
Absolutely, so we found a couple of things one was that the pharmacokinetics of insulin are absolutely critical, the faster the insulin is the better control we are gonna get and current insulin's are certainly faster then they use to be and they've really provided a revolution in diabetes care the three rapid acting insulin analogs that are available today have really improved blood glucose control and reduced hypoglycemia in people with diabetes, because they better match the absorptions of food, however their limitations became clear when you have a system when you are measuring blood glucose every five minutes the controllers are responding and there is this loop you are trying to close a loop and the longer the more time the lapse is between the time the controller does something and the effect is felt the more conservative the controller has to be in controlling the blood glucose, so if we could shorten that time by improving the rate of insulin absorptions that would be a tremendous benefit to improving closed-loop control. The second thing is that we have found that glucagon in the very small doses that we use in this trial and I should point out they are very small doses as opposed to the 1 milligram dose that's the FDA approved treatment for severe hypoglycemia we are using 10, 20 micrograms at a time of glucagon just to slow a descent of a blood glucose as it falls toward the hypoglycemic range of flat it out this is not an approved indication of glucagon, and glucagon has never been approved for using a pump like this it's meant to be reconstituted and injected immediately and in that current formulation that's approved it's not very stable it degrades over time and so we need to stabilize formulations of glucagon that can go into a pump reservoir and stay there for two or three days just like insulin currently does to make this a practical system. And so not only is somebody going to have to stabilize the glucagon which I know a number of people are working on now, but they are actually going to have to pursue this as an indication for this glucagon. And the potential benefit is that well glucagon is not a very commonly, I mean it's commonly prescribed as a rescue kit, but most of those kits aren't used and so it's not a very big market, if this closed-loop system using both where to come into general usage glucagon will be as bigger market as insulin.
Next stages of device development
Fintan Walton:
So Edward R. Damiano, from a medical device point of view you are still it's very much still an assembly on the lab bench in someways, so what the next stages to turn this into a proper portable device?
Edward R. Damiano:
Well so what we've been working on is essentially moving from a system that was manually controlled and had components that work practical, more practical in a (indiscernable) closed-loop system or artificial endocrine pancreas to something that ultimately can be miniaturized and made portable, so that involves things like changing the glucose sensors I mentioned before from one that sampling blood to the one that sampling glucose just under the skin and also coming up with technologies by which we can infuse both insulin and glucagon those also have to be developed, so potentially pumps with two reservoirs one that contains insulin, one that contains glucagon in a single unit that also receives a signal from a continuous glucose monitor all needs to be sort of built and miniaturized, our algorithm which currently runs on a laptop computer that because it needs the computational overhead of such device, but because it's convenient to work on a system like that ultimately once we converge and we come up with something that we are satisfied with that would be embedded into the logic of a pump essentially and that would receive input from this continuous glucose monitoring. So there is the process of anticipating the kinds of devices that are gonna be changed which we've already started to do by switching the glucose sensing technology from a blood glucose to a endo fluid glucose device, but also we are making changes to the logic as well to some extent, because we are now giving small boluses before meals to prime the system which is where we expect the system would ultimately be used, we have to think about things like what happens when the system goes offline and then you have a sensor that you are wearing under the skin and I can get pulled out the system needs to be able to switch into a system that is similar to what people use today an open-loop system temporarily and so you can bring the sensor back on run system can't run without glucose sensing continuous glucose sensing and that can fail, so failure modes have to be thought about at and we've been working on those kinds of things, challenging the system in new environment right now all of our studies are in the clinical research centre, but even within the context of the clinical research centre in hospital setting we need to introduce exercises subjects with little more (indiscernable) that's the study we are working on right now. The next study we want to a graduate where subjects have free range of motions throughout the hospital they can eat at will they don't have to eat structured meals, but they can eat snacks they can eat when they want they can exercise to great extent or to less extent so we want that kind of variables we have to test it in several more in-patient studies, but then ultimately we need to move in transition to an out patient study and we have to design together would design an experiment that will allow subjects to test this to the first time at home in that system this there can't be a laptop computer it's got to portable, it's got to something that hangs on your on a belt clips so to speak. So those are the kinds of things we are working on was looking at a horizon hopefully of getting those experiments done over the next two to three-years and then a pivotal trial would ultimately be need to be done multi-centre study in which subjects are wearing these things for a period of three to six months and you can really get matrix of success over a longer period of time, for that to happen of course the system really has to look just like the device that you know that we envision the subjects people would be using so that would involve you know our partnerships with the industry collaboratives that we currently have sort of coming on board and taking more initiatives of this and building the device and putting our logical into sort of permanent way. So we are headed towards that we'll hope that in about five-years we could potentially have you know a commercially available closed-loop system, but that would require you know several companies in the medical device industry and even in the pharma industries to step up and play a big role.
Fintan Walton:
Right, so this is a none of the technology that's gonna be required to go into the future is really that program breaking, I mean it's within the grasp of our current capabilities?
Edward R. Damiano:
It's right. Yes, but the point was to test what we what is the best we can do with current state of the art FDA approved glucose sensing technologies and insulin infusion technologies that's really we're constrained ourselves as well want to be using you know technologies that are three or four steps down the road really want to be the current technologies and then the closed-loop system envision would involve with those technologies as they evolve.
Steven J. Russell:
Right, I mean the sensor we are using right now is an FDA approved sensor, it's not approved for using a closed-loop system, but it's approved for people with Type I diabetes.
Edward R. Damiano:
My son wears one of these.
Steven J. Russell:
And the pumps are also FDA approved. So you know it's really new as the way we are putting them together and the algorithm that's driving them in the use of glucagon right now it takes two pumps to do that, but there is no reason why you could never single one that would do both.
Partnership and collaboration strategy
Fintan Walton:
But to take this forward to become a commercial product that will serve the interests of patients ultimately requires a new partnership?
Edward R. Damiano:
Or to enrich the ones we have and potentially new ones, so I think that you know it's both, I mean we certainly have collaborations that we think will go forward, but we will indeed need some additional ones as well.
Fintan Walton:
But there is the medical device to take the medical device forward, but then there is equally requirements for fast track the insulin?
Edward R. Damiano:
Right.
Steven J. Russell:
Right.
Fintan Walton:
And glucagon that's appropriately approved and has the stability that's required for the device to work effectively, so just pulling those two together and getting it, because I you know what I've heard is a fantastic story it's essential now that the next stage allows you to realize the great ideas that you've brought together?
Edward R. Damiano:
We are also hoping that some of the excitement that we're generating in our preliminary results will attract the attention of the pharma industry, because that's the one group that we really haven't interfaced with too much, but I think we are laying some ground work to show them that they have a big role they can play here and there is a great advantage to getting involved.
Steven J. Russell:
And to some extent that has happened, I mean there is interest in generating stable glucagon's that I don't think would necessarily have been the case.
Edward R. Damiano:
I agree, you know that's the news in the last few months.
Steven J. Russell:
So there is at least two companies that are developing stable glucagon formulations that we know perhaps we also got to put a plug in for a special issue of the Journal of Diabetes Science and Technology that we are co-editing along with Kenward and Jessica Casale and this is an issue specifically on stabilized glucagon.
Edward R. Damiano:
Yes, so I mean I think that the idea of course is to do these things as much in parallel as possible so while we are working on the device side we like the pharma industries to get involved in stabilizing glucagon and pushing that through a regulatory pathway, because that's gonna add it's own you know regulatory you know issues that's gonna have to sort out over the course in the next several years.
Fintan Walton:
Edward R. Damiano and Steven J. Russell , thank you very much indeed for coming on the show.
Edward R. Damiano:
Thanks Fintan Walton.
Steven J. Russell:
Thank you, it's a pleasure.
Fintan Walton
Dr Walton is the Founder and CEO of PharmaTelevision. After completing his doctoral research on the genetics of cell proliferation at the University of Michigan (US) and Trinity College (Dublin, Ireland), Dr Walton gained broad commercial experience in biotechnology in management positions at Bass and Celltech plc (1982-1992).
Edward R. Damiano
Associate Professor of Biomedical Engineering
Edward R. Damiano Biomedical Engineering at Boston University. His educational training is in the areas of biomedical and mechanical engineering, applied mechanics, and applied mathematics. His research group is engaged in basic scientific research that combines fluid dynamics with intravital microscopy to study blood flow in the microcirculation and to elucidate mechanisms by which the lining of blood vessels determines vascular health and disease. In particular, his lab has been focusing on the endothelial glycocalyx, which forms a complex hydrated mesh of cell surface macromolecules that is situated at the interface between the luminal vascular wall and flowing blood. His group has developed new analytical and experimental tools to interrogate the glycocalyx in vivo and in vitro. They have demonstrated that this layer of macromolecules extends ~500 nm from the wall of healthy blood vessels, but is significantly degraded in the presence of vascular inflammation Chronic hyperglycemia. His group is also testing therapeutic interventions aimed at preventing and counteracting the damage to the glycocalyx, which may underlie vascular pathologies such as atherosclerosis and microvascular complications associated with diabetes. In addition to this research, he is also personally committed to creating and integrating closed-loop control technologies for automatically regulating blood glucose in diabetes. After testing and qualifying his group's blood-glucose control algorithms in diabetic swine, their system became the first academically sponsored investigational device to receive FDA approval for testing in subjects with type 1 diabetes. The first-phase clinical trial testing their device was recently completed at the Massachusetts General Hospital. The second-phase clinical trial is underway in children and adults with type 1 diabetes.
Steven J. Russell
MD
Steven J. Russell MD, PhD is an Instructor of Medicine at Harvard Medical School, an Assistant in Medicine at the Massachusetts General Hospital, and a staff physician in the Massachusetts General Hospital Diabetes Center in Boston Massachusetts. He received his, doctoral degrees from the University of Texas Southwestern Medical Center in Dallas, Texas and completed his residency and fellowship training at the Massachusetts General Hospital. He is a Diplomate of the American Board of Internal Medicine, with certifications in Internal Medicine and Endocrinology, Diabetes, and Metabolism. His research focuses on the use of technology to improve the care of patients with diabetes or hyperglycemia of critical illness. Dr. Russell directs human studies in an interdisciplinary effort to develop an artificial endocrine pancreas for automated blood glucose regulation. He also has a basic research program at the Joslin Diabetes exploring the role of insulin signaling in the regulation of mammalian aging.
PharmaVentures
PharmaVentures is a corporate finance and transactions advisory firm that has served hundreds of clients worldwide in relation to their strategic deal making in the pharmaceutical, life science and healthcare sectors. Our key offerings include: Transactions / deal negotiations; Product / technology valuations; Deal term advice; Due diligence & expert reports; Strategy formulation; Alliance management; and Expert opinion for litigation/arbitration cases. PharmaVentures provides the global expertise to ensure our clients generate the highest possible return on investment from all their deal making activities. We have experience of all therapeutic areas and can offer advice on both product and technology commercialization.
Boston University
Founded in 1839, Boston University is an internationally recognized private research university with more than 30,000 students participating in undergraduate, graduate, and professional programs. As Boston University's largest academic division, the College and Graduate School of Arts & Sciences is the heart of the Boston University experience, creating an extensive global reach that enhances the University's reputation for teaching and research.
Massachusetts General Hospital
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The Massachusetts General Hospital conducts the largest hospital-based research program in the United States, with an annual research budget of more than $600 million. The hospital is home to major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, photomedicine, regenerative medicine, systems biology, transplantation biology as well as a number of others.