Getting Under Your Skin: New Ways to Deliver Drugs--In-Depth Doctor's Interview
Michael Cima, PhD, Professor of Engineering at MIT, talks about a new way to deliver drugs without a needle.
What inspired you to try to deliver drugs wirelessly?
Dr. Cima: There are many drug therapies where compliance is a very important problem. We wanted to address that by making it extremely simple for a patient to get their therapy. This was at the beginning of the wireless revolution and it was natural to put the two together.
Mid 90s I guess, you were walking around with a big brick phones, you used this analogy and put it in a person. Is that kind of how you came up with it?
Dr. Cima: Sort of, I think the major idea was to use micro fabrication techniques to sequester drug into small containers. Then electronically open them one at a time and the step to take that to a wireless platform seemed like an obvious one.
How does a pharmacy chip work?
Dr. Cima: This technology puts drugs into a tiny container on a chip and what we have are many containers on a chip. It is possible that each one of those containers could have a different drug in it. We could decide wirelessly or have an onboard computer decide which drug to administer when.
That is exciting. I mean how could this affect medication errors, like people forgetting to take their medicines every day?
Dr. Cima: This is a huge problem. It is an under reported problem. In the case of osteoporosis, where you have to do daily injections of parathyroid hormone, 70% of the patients fall out of therapy within the first few months because they just can’t manage the self-injections.
So, it is a self-injection for the osteoporosis?
Dr. Cima: Right. Serious osteoporosis people get prescribed a drug called parathyroid hormone, but it requires a daily injection. There are a couple of problems with that; most of the people on this therapy are older people and they have difficulty giving themselves injections. This overcomes that completely. A small procedure is done and a device is implanted. It does the entire course of the therapy. Then at the end you remove the device.
Talk about the procedure a little bit.
Dr. Cima: Well it is actually much simpler than the implantation of a pacemaker. So here is the device used in our first clinical study. It is much smaller than a pacemaker and it does not have any of the leads; the wires that would go to your heart, for example, because it does not need that. This was implanted just below the beltline underneath the skin. It is a 2 or 3 cm incision with a local anesthetic. You don’t need to have general anesthetic. It is slipped underneath the skin. A couple of stitches close the wound and then this can be programed to release drugs daily or it can be wirelessly communicated with, so we can find out whether it is working or change the program. All the kinds of things you might do with your smart phone.
So, talk about the study a little bit. What were the patients again? Who were the patients and how long did it last? How successful were you?
Dr. Cima: This was a proof of concept study and it was actually a safety study. We wanted to show that this was safe for these patients. We also looked for markers of efficacy. We looked for markers of bone formation. As I mentioned, these were osteoporosis patients. They were elderly women and we did a small study for a month of therapy. We had the device in for a total of 6 weeks and we did, of course, follow-up to ensure that they had no problems. What we showed was that it was very safe. There were no infections. No serious adverse events of any type. Most importantly we showed that in their blood, the markers of proteins associated with the formation of bone. This was one of the measures of efficacy in this kind of therapy. So even over the course of a month, we were able to show that this type of therapy is efficacious. We also showed that it had the same sort of, we call it pharmacokinetics, as subcutaneous injection. What that means is when you do a subcutaneous injection, you see the drug in your blood spike and come back down and it turns out that that is important for the efficacy. We showed that it was very equivalent. The release of drug from our device and our individual reservoirs was very equivalent to the subcutaneous injection which was another objective for the study. So, we were pretty happy, after 15 years of studying this in preclinical models, to be finally in the clinic and showing that this works with patients. The last and most surprising thing to me was we asked these patients how they felt about it. Could they feel this device in them? Could they notice it? Were they spending their day thinking about this device in them? None of the patients mentioned any noticeable effect of having the device in them. They could not feel it; even though it looks quite large, we chose a location so that it would be unobtrusive. They seem to tolerate the therapy extremely well.
You said the drug we are talking about is for osteoporosis and it is injected. Could this be used for drugs that don’t need to be injected? I mean, could you get something that people take daily dose of and put it in liquid form so it can be kind of released when needed?
Dr. Cima: It is conceivable. The one requirement that we have is that the drug has to be very potent because the volume of the drug has to be inside the device. If it is 100 mg or 200 mg dose, and you have to take many doses that would be too large a volume. Fortunately, many drugs nowadays are extremely potent. Parathyroid hormone is an example of that. That dose is mcg. You can get many doses in a device of this size. We are thinking of more therapies like that. The potent drugs are drugs like hormones; those types of things; endocrine deficits of some type. The endocrine system is a lot like a control system your body has, like your nervous system. Most people think of the electrical stimulation that controls a muscle or your heart. The endocrine system is another regulatory system in your body, but it sends chemical signals. That is essentially what this device was doing in those patients. It was sending a daily chemical signal to the rest of the body to grow bone. What is interesting about that is this was the same function as a gland. It is sort of like an organ replacement, an artificial organ in this case.
What other possibilities are there? For example, diabetes is the one we think of when we think of injecting yourself every day. Would that be something that would be viable to this?
Dr. Cima: Well, certain types. For example, insulin would not be appropriate because it is not very potent. However, drugs to stimulate the production of insulin are very potent, like GLP drug that is used to stimulate insulin production. Notice it has the similarity to stimulating bone growth now or stimulating insulin production. There are many of these types of drugs in development and exist already, so I think these types of devices could be very important for those types of product.
How would it work in the long run? Would you have to have it refilled, kind of like your prescription bottle?
Dr. Cima: In this first study, all we needed was 20 doses because we wanted a very short period. In the next study, we will have a whole year’s supply in one of these, so 360 doses or 400 doses. That is what we will be doing. We have plans to make such devices for a 30-year therapy.
So that would mean your daily medication would not even be a thought.
Dr. Cima: Well at least for that particular therapy, yeah.
How exciting was it to see those study results?
Dr. Cima: We had done this a lot in preclinical or animal models, so we knew it was going to be safe and we knew it was going to work. However, we could not ask the animals how they felt about it. I think, the thing that surprised me most was how much the patients liked this kind of therapy. They would all sign up for it if they could avoid having to do a year’s worth of daily injections.
What is the risk of it opening up and every dose being released at the same time?
Dr. Cima: We designed these types of devices so that it is virtually impossible for that to happen. What I mean by that is, it takes some amount of power to open one of these reservoirs. The available power at any instant is not much greater than that. There is just not a physical way for this device to power up all the reservoirs at once. That was part of the design. It is a safety feature. Also, the communications to these devices are encrypted using the FDA approved encryption technologies for medical devices. So it is not like somebody could hack into this and change the program.
So, again, tell me how it is released. Is it set to a clock? Is it set to you calling in and telling it to release the medication or somewhat along those lines?
Dr. Cima: The way this device was controlled in our study was actually two ways. We had to have the patients come in on 4 separate occasions during the therapy and we wanted them present when the device released so we could sample blood and look to see what the release profile was. On the other days of the study, it was preprogramed. They were at home doing whatever they wanted to do when it released. So we had both. We preprogramed it and then on the days that they were told to come in, it was told to wait until it got a command and so we did both on demand as well as preprogramed in the study. We did that because we did not want them caught in the subway when it released on those days.
You wanted to look at the reaction?
Dr. Cima: We wanted to take a blood sample before we released and then tell it to release and then start taking blood samples every few minutes so that we could see the
When are we going to see this hit the market? What are your hopes?
Dr. Cima: This is not the final version of this device, for parathyroid hormone for example. It has to be able to have a year’s worth of supply on board. So, we had to do this first study, a small study to show that it was both safe and it had the likelihood of being very effective in a year study. Now we are in the process of designing 400 reservoir devices to do that kind of study.
Is it going to be osteoporosis medicine again or is it going to be something else?
Dr. Cima: It remains to be seen, but it turns out the 400 reservoir device will be a platform for many other types of therapies with these potent molecules. It is my belief that we have a winner with PTH. I am hoping that in the end, we will be in a yearlong trial for osteoporosis.
Is that recruiting now or is it still too early to be recruiting?
Dr. Cima: No, it is too early to be recruiting. We have to construct the clinical supplies of these 300 reservoir or 400 reservoir devices.
Any idea when that next stage is?
Dr. Cima: I hope in the next year and a half.
So, the first one, was that phase I? And this is phase 2?
Dr. Cima: That is right. That would be a phase 2 proof of concept study; that is what you actually do to go to a pivotal study. You need to have that kind of true proof of concept where you are actually doing a clinical study with the final device that will be used in the commercial product.
So, talk again about how it communicates and like you said, it is like a smart phone, right?
Dr. Cima: Yeah, there is a designated medical device frequency or band as we call it and the actual chip part, which is where the drug reservoirs are. There are many of them there, but if you turn this device over you see the dark area is actually an antenna. This device is placed underneath the skin and this is faced towards the muscle and this side is toward the skin. This is just got a thin layer of tissue on top of it and you can communicate directly to the antenna.
When it releases, it is just like a little door opening and it gushes into the muscle?
Dr. Cima: Actually what happens is the reservoir is covered by a thin metal membrane. It is only a few hundred microns in dimension; a micron is one millionth of a meter, so it is very, very small. If you are in English units, 100 microns is around 4000th of an inch to give you an idea of how small these are. Now it is a very thin metal membrane and what we do is we pass current through that membrane and it basically melts. It peels back and the drug is free to come out. It is just a few microseconds of current that goes through. That is all that is required. It is like an old fashion fuse if you will. Except that this is a micro scale fuse. That is all that is required to get it to open up. It is really a solid state device.
END OF INTERVIEW
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