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Research into a cure for type 1 diabetes proceeds on several fronts. One interesting approach is seeking ways to manipulate the autoimmune system to prevent the body's mistaken destruction of pancreatic beta cells. Another tack is the transplantation of pancreatic tissue, either from human cadavers or carefully isolated "clean" pigs that have been specially raised for the purpose.
It turns out pigs will be crucial to both approaches. Burlington, Mass.-based Coronado Biosciences is looking into using pig worm ova as shields against autoimmune attacks on the pancreatic cells.
In a recent interview with me, Karin Hehenberger, MD, PhD, chief medical officer at Coronado Biosciences, explained the fascinating thinking behind this line of research, called "Trichuris Suis Ova Suspension" (TSO).
Nadia: In your research with Coronado, you're using pig worms to modulate the immune system?
Dr. Hehenberger: Yes, our company is in clinical trials using pig worm ova. We place the eggs in a 15 mL saline solution that we give orally to patients every two weeks. In humans, the ova develop into microscopic larvae, but don't-and cannot-become worms. That's because pigs are their natural host and humans are not, so they can't really colonize a human.
But what they do is modulate the autoimmune system. For the two or three weeks that they live in the human intestine, their presence makes the autoimmune system focus on and attack them rather than other targets, such as pancreatic beta cells. In a way, they act as a drug patch that diverts the autoimmune system.
In people with autoimmune disease, instead of fighting outside dangers, which we normally do when there's an infection, for example a virus or a bacteria, they fight their own bodies. There's a switch where something goes wrong in the development of the immune system in very young people. It may even start in utero. So the autoimmune system needs to be retrained. In TSO, we're introducing an outside agent for the autoimmune system to deal with, with the result that we get a decrease of the pro-inflammatory markers usually associated with autoimmune disease and an increase in certain good markers that indicate the autoimmune system is doing its intended job.
Nadia: Why dose every two weeks? Wouldn't it be better to find a way to keep the ova in the body permanently?
Dr. Hehenberger: It wouldn't be good to permanently colonize a patient with the ova because then it would be difficult to get rid of them if you wanted to.
Nadia: Do patients have any aesthetic problems with drinking the solution?
Dr. Hehenberger: You can't see the eggs. They're microscopic and the solution is tasteless and odorless.
Nadia: Assuming this approach works, I'd anticipate a very large demand for your product. How does Coronado plan on meeting market demand?
Dr. Hehenberger: That's a good question. We announced a few weeks ago in a press release that we are building a second manufacturing source in the US. Right now, the pigs are raised and the manufacturing is done in Europe. Even at that distance, the process is extremely efficient. From just one pig you can produce essentially millions of doses of this product, so you can supply any number of patients with the product. If this approach is successful, we won't need a large number of pigs to address the entire market. We also hope to use this approach in many different indications. Its whole mechanism of action is applicable across the spectrum of autoimmune diseases.
Nadia: Conceivably you could give someone a solution for the pancreas, another for the nervous system, or multiple sclerosis, or rheumatoid arthritis?
Dr. Hehenberger: Exactly. That's why we are initiating a number of different trials, because we do have to prove that it works in these different indications. Our current primary indication is in gastrointestinal disease, specifically Crohn's disease. That's where our Phase II trial is. We also have a number of other trials that are ongoing in MS and RA, and we are about to start studies on psoriasis and type 1 diabetes. We also just started a study on autism.
Because we're going through a regulatory process, we're working closely with the FDA in the US and with the EMA in Europe. We need to show, of course, that it's efficient and safe.
Nadia: How do the different trial phases work?
Dr. Hehenberger: As soon as you start clinical trials, you have to do them with human beings. Phase I is normally with healthy volunteers, so it's a study really just to check safety. We did Phase I trial with a group of patients with Crohn's disease, but we only gave them one dose. That was enough for the FDA to give us permission to go forward into a Phase II trial.
Phase II is normally a dose-ranging study where Coronado is tracking 220 U.S. patients and our European partner, Dr. Falk Pharma GmbH, is tracking 250 European patients. By the end of 2013, we will have data from almost 500 Crohn's disease patients.
If Phase II is successful, the company will decide to go to Phase III, which will involve thousands of patients. Essentially Phase I is usually 20 to 50 patients, or even fewer. In Phase II, where you're looking at what dose to use in Phase III, you have a few hundred patients-up to maybe 300 or 400. In Phase III, it will be probably be 2,000 patients. So it really ramps up as you go to larger studies and further along the regulatory pathway.
Nadia: How do you assure consistency in the pig worm ova so that each batch is exactly the same?
Dr. Hehenberger: These are clean pigs. They're kept in a very regulated, virus-free, pathogen-free environment in Denmark. They, and the people who tend them, are tested regularly. You cannot walk in there without wearing a mask and gown, and there are specific standard operating procedures people have to observe. The manufacturing facility is inspected regularly by the European authorities. The manufacturing facility we're building in the US will operate under the same kind of tight regulations.
So you're absolutely right, the ova have to be produced consistently, and the cleanliness and health of the pigs are crucial. There are many tests we do on the product to make sure that, first of all, it doesn't have any contaminants. Secondly, if we've set the dose at 7,500 ova, every time we give that dose, it must have 7,500 ova, and those ova must be viable.
Nadia: If this formula were to be approved for people with type 1 diabetes, would they go to the pharmacy to pick it up?
Dr. Hehenberger: It's a 15 mL solution, so it would come in a small bottle. It would have to be refrigerated and dispensed from a specialty pharmacy, so it probably would be a prescription by a physician. You'd keep it in the fridge, similar to how you store insulin.
The Personal Side of
Dr. Hehenberger's Work
Nadia: You have a personal interest in type 1 diabetes?
Dr. Hehenberger: I do. I developed type 1 diabetes when I was 16. The first 10 years with diabetes, everything went really well. I was in high school and then went on to medical school. But the 10 years after that, when I worked in different places, it was more difficult to control.
Nadia: Was that because of an erratic work schedule?
Dr. Hehenberger: Yes. When you're working and being stressed, you don't have as much control even if you're perfectly healthy otherwise. So I developed complications after about 20 years with the disease. Over a very short period of time, my kidney function deteriorated from almost normal to less than 10 percent functioning. It was absolutely devastating. I had to change my diet, couldn't have protein, and I lost a lot of weight. I became obviously very tired. Kidneys essentially clean the system, so I had lots of toxins in my body because my kidneys didn't work well enough.
When you have kidney failure, you only have two options: One is to go on dialysis and the other one is to try to find a kidney match. Once they told me I needed a transplant or to go on dialysis, they said that with my blood type, I probably would have to wait between five to 10 years to get a transplant from a deceased donor.
Nadia: Were you able to find a kidney donor?
Dr. Hehenberger: I was incredibly fortunate: My father gave me one of his kidneys for the transplant. I was very lucky to have a father who was both a good match and very healthy. He actually volunteered to give me a kidney, which was fantastic! So I got the kidney from him and, essentially, that helped me so that I could go on living. Otherwise I would have been on dialysis, and the average time a person with diabetes survives on dialysis is five years. It would have been a terrible time for me and I probably couldn't have worked because I would have had to go every two days to get dialysis and it really would have drained me.
The transplant cured my kidney problems. But I still had type 1 diabetes, which complicated my hopes for getting a pancreas transplant, which I had been offered nine months after receiving my kidney. I was having a difficult time with my diabetes. I was very brittle and becoming very much hypoglycemic unaware. In the past, every time my sugar came down I felt bad and would eat something or change my behavior in some way. But now I was becoming hypo unaware, so I didn't really feel a sugar low until it was too late. One time I passed out in the kitchen, fell on my forehead, and broke teeth and my nose. It was awful.
That was in December 2009. Luckily, on New Year's Eve, I got a call from Minnesota, where they were going to do my pancreas transplant. I flew there and they did the surgery, which was very long but incredibly successful. Since then, I have not required any insulin injections or any exogenous insulin because the pancreas has worked very well. So for three years now I've been cured of diabetes and cured of kidney failure.
Nadia: Do you take the immuno-suppressants?
Dr. Hehenberger: I do. And that's another reason why I'm so motivated to really work on TSO. I believe that if you have something that is immune modulating versus immune suppressing, you can avoid some of the complications that often come with the use of immuno-suppressants, such as multiple infections. For example, people with Crohn's disease, MS and RA who need to take immuno-suppressants have a higher risk of developing lymphoma. They also have higher risk of tuberculosis and even just simple infections.
So I definitely am running some risks. of those. I've been lucky enough to not develop anything since I had the kidney transplant, but it's definitely something I have to be aware of all the time. Still, I would take that anytime over kidney failure and the very brittle type 1 diabetes that I had.