Drug being developed to help people with both diabetes and cystic fibrosis

[00:00:00] Host Amber Smith: From Upstate Medical University in Syracuse, New York, I'm Amber Smith. This is "HealthLink on Air." Many of the people who have type 2 diabetes take medication that causes nausea, vomiting and other side effects. A chemist at Syracuse University is developing a drug that would control blood sugar without the side effects.

[00:00:20] Host Amber Smith: Robert Doyle is a chemistry professor at SU and also an adjunct assistant professor at Upstate. Thank you for making time, professor Doyle.

[00:00:28] Robert Doyle, PhD: It's nice to be here. Thank you.

[00:00:30] Host Amber Smith: Before I ask you about your work, how did a chemist get involved in diabetes research?

[00:00:36] Robert Doyle, PhD: Oh, that's a great question. So my interest has always been in making things, not surprisingly, as a chemist, and the, I guess you could say epidemic, of type 2 diabetes and comorbid obesity. So these sort of diseases go hand in hand, was really evident as a chemist who was coming up, the pharmaceutical industry that I'm involved with, or would aspire to be involved with, were very driven by looking at ways, new ways to control blood glucose because of this huge problem that we were seeing worldwide.

[00:01:11] Host Amber Smith: So let me ask you, because diabetes is a little complex to try to understand if you're not involved in the work that you're involved with. Can you give us a good layman's definition of glycemic control?

[00:01:23] Robert Doyle, PhD: Sure. In essence it means not having glucose levels in your blood that's too high and not having glucose levels in your blood that's too low. It really has to be a blood glucose that's in that "Goldilocks" zone, not too cold, not too high, not too low, right in that space between about 60 and 125 (mg/dL, or milligrams per deciliter). They're the sort of magic numbers.

[00:01:47] Host Amber Smith: So there's a lot of existing medications already on the market for controlling blood sugar and trying to get into that sweet spot.

[00:01:55] Host Amber Smith: But how do those work and why are they not doing everything that you would like them to do?

[00:02:01] Robert Doyle, PhD: First of all, I will start by saying they are wonderful drugs. And for the majority of patients who will take them, absolutely life affirming, life altering in all the right ways. And so they can work by increasing insulin secretion from your pancreas. So your pancreas is the organ that is responsible for controlling your blood glucose levels, keeping them at just the right level, and they will work to increase that insulin level, these drugs to increase these insulin levels, so as to facilitate glucose uptake into your cells and where it needs to be.

[00:02:37] Robert Doyle, PhD: So the big challenge with glucose dysregulation per glycemic control is the fact that you could be awash in glucose, in your blood. And in fact, the classic type 2 diabetes patient will have very high levels of glucose, but their cells are starving for glucose. So the problem is, they're like a teenager trying to get into a club; there's a bouncer in the way he says no, and if you're not on the list, you don't get in, and you need the insulin pass to get you through the door.

[00:03:06] Robert Doyle, PhD: And so these drugs can work to elevate that amount of insulin, in patients who require that additional boost to help get that insulin into the tissues, into their cells, across the body. Other ways to do it are simply to upregulate control mechanisms, whose job it is to protect these pathways that will either utilize the glucose, or again, drive this instant secretion and glucose uptake in cells.

[00:03:31] Robert Doyle, PhD: So they're all playing around, we're all playing around really the pancreas and insulin, or essentially helping the kidneys to flush glucose out of blood system. So there's a myriad of different ways to do it. I mean, I don't want to get too technical about it, but, there's a myriad of ways to do it and they're all wonderful.

[00:03:49] Robert Doyle, PhD: They all work really, really well for the majority of patients. You can even actually just inject straight insulin, but that's only done in type 1 patients who cannot produce insulin directly themselves. The majority of patients with diabetes are type 2.

[00:04:05] Host Amber Smith: So what about these medications might cause the side effects, the nausea, the vomiting, weight loss?

[00:04:13] Robert Doyle, PhD: Yeah. And these are not my words, (they're) the words of the physician community, the darlings of current treatment for patients with type 2 diabetes are what are called GLP-1 agonists, and you inject them into your body, so they have to be subcutaneously administered. You have to use a needle or syringe to administer them. And what happens is they go to your pancreas. And in concert with glucose level, they drive insulin secretion from your pancreas. And the really, really clever thing about this is that it models how we do it naturally.

[00:04:46] Robert Doyle, PhD: And so, because it only works when glucose level is high to release insulin, you never have an overproduction of insulin or over-release of insulin, which means it never drops too low, either, and so it achieves that wonderful Goldilocks state of bringing down the high, but not bringing it down to achieve the incorrect low.

[00:05:07] Robert Doyle, PhD: And so it really can bring about an excellent, what we call, metabolic norm. So something that's more akin to what, let's call it a typical patient would have, or a typical person would have in, in day-to-day blood glucose levels. The side effects are because of our quirky human physiology; the same receptor or target in the pancreas is actually also found in your lizard brain, in your hindbrain, which is the little space between your ears and in the middle.

[00:05:39] Robert Doyle, PhD: But in that case, it doesn't work to release insulin because your brain doesn't release insulin. What it does in that case is it triggers appetite depression and nausea and in a lot of cases, vomiting, so it goes to a part of your brain which is designed to test essentially your body for poisons or drugs or unknown substances with a view to getting them out of your system, if you need to. So it's an evolutionary protective mechanism. These drugs go to your pancreas that are wonderful, but they also end up in the hindbrain and trigger these side effects by hitting the same receptors that are located in these two very distinct places.

[00:06:22] Robert Doyle, PhD: Pancreas, glucose control, brain, weight loss, nausea, vomiting.

[00:06:27] Host Amber Smith: So what was your idea for avoiding the side effects? Was it to avoid going to the brain at all?

[00:06:34] Robert Doyle, PhD: Exactly. So if we could keep it out of the brain, particularly the hindbrain, you would get all of the peripheral effects, the pancreas effects, but you wouldn't get any of the brain effects.

[00:06:46] Robert Doyle, PhD: That was the theory. That was the hypothesis that we put forward, yeah.

[00:06:51] Host Amber Smith: Well, do I understand correctly, your new drug is a combination of two molecules?

[00:06:58] Robert Doyle, PhD: It is. It's what we call a conjugate. Yep.

[00:07:01] Host Amber Smith: So what can you tell me about each of these, molecules?

[00:07:05] Robert Doyle, PhD: The idea, I guess, it was born of the fact that I was studying vitamin B12.

[00:07:09] Robert Doyle, PhD: This comes back full circle. And I was looking to see as a medicinal chemist where the vitamin B12 pathway actively transports vitamin B12. And what I noticed using radioactive, radio-labeled vitamin B12 was that it really did not go to the brain at all. But it would still happily go to the kidneys, the pancreas, the liver, etc.

[00:07:32] Robert Doyle, PhD: And so I thought, if we put these GLP-1 drugs on the back, if you will, of vitamin B12 or vitamin B12 type compound, it might be like putting it on a specific bus or a specific airplane and saying you only fly this route. So I'll only take you to those locations. So if you're on the No. 16 bus to downtown Syracuse, you get to go there.

[00:07:56] Robert Doyle, PhD: But if you're on the 16 bus and you want to go to Binghamton, you're on the wrong bus. And so we said no bus to the brain, only on the vitamin B12 route. And as a consequence, some of it still goes to the pancreas and obviously it's dose dependent. And so we worked to figure out how much we need to maintain a relevant level to a trigger a glucose control, but no brain entry. And as soon as we did that, we saw no nausea, no vomiting, no weight loss, but nice, maintained glycemic control.

[00:08:27] Host Amber Smith: So does your drug have a name yet?

[00:08:30] Robert Doyle, PhD: Uh, no we call it "corrinated." We call the technology "corrination" because vitamin B12 has a beautiful red color. It has this, what we call a corrin ring. So corrination is the obvious, sort of, term from this. So the drugs in this family are called glutides. So I guess we could call it "corriglutide," if we take it that far. But certainly, we have just a generic internal, you know, moniker for it right now.

[00:08:59] Host Amber Smith: Why was it tested in the musk shrew?

[00:09:03] Robert Doyle, PhD: So yeah, it's very unusual. So the musk shrew, first and foremost, looks like a rodent. It looks like a rat or a mouse, but it's actually a mammal, and in fact it used to be, before the advent of more complex sequencing and DNA analysis, it used to be ranked as a pseudo primate. So it was originally considered to be a really small creature related to a monkey.

[00:09:25] Robert Doyle, PhD: So in other words, we're primates -- very, very high-order evolutionary species. But it can do something as well that a rat and a mouse cannot do. They cannot vomit, so you can't actually do emetic studies, or vomiting studies -- my little boy calls it barf studies, and he likes to say, "Did you do more barfing studies today, Dad?" -- to do it, you need a species that can truly vomit.

[00:09:51] Robert Doyle, PhD: And that's usually done in dogs, but here we have a small, rodentlike, higher-order mammalian model that can vomit that has the exact same pathway, the vitamin B12 pathway, that a human does. So in addition to rats and mice and guinea pigs, etc., not having the ability to vomit, they also don't have the same human vitamin B12 pathway.

[00:10:14] Robert Doyle, PhD: So they end up being completely incorrect as a model species for us to be able to do the work.

[00:10:19] Host Amber Smith: So this musk shrew was perfect for what you needed.

[00:10:23] Robert Doyle, PhD: Well, you had to prove it. We actually had to study the vitamin B pathway in the shrew because it wasn't known, and confirm it actually had the human setup, and which we did.

[00:10:33] Robert Doyle, PhD: And then, my collaborators at Penn, University of Pennsylvania in Philadelphia: They are experts. In fact, they're one of only two colonies in the entire world -- the other is in Hong Kong -- that actually utilize musk shrews in this way.

[00:10:45] Host Amber Smith: So the drug proved itself in the musk shrew.

[00:10:50] Robert Doyle, PhD: Yes.

[00:10:50] Robert Doyle, PhD: And actually it did better then an actual FDA (Food and Drug Administration) approved drug that's currently on the market, better in terms of its life span and its glycemic control. And unlike that drug, it did not cause vomiting or weight loss.

[00:11:06] Host Amber Smith: So, what is the next step after you finish looking at how this performs in this species, what do you do after that?

[00:11:14] Robert Doyle, PhD: Well, because the data was so good, we actually did two major things. We wrote an RO1, which is the primary mode of acquiring health funding in the United States through the NIH, the National Institutes of health, and the first submission, thankfully, they liked it enough to give us $3.4 million to pursue it over the next four years, which actually just began this past July, 2021. And we also, at the same time, and by we, I mean myself and my two collaborators at Penn, professors Matt Hayes and Bart De Jonghe, we spun out a company. So we started a company called Cantius Therapeutics, and one of our lead pipeline drugs now will be this corriglutide, as you've now inspired me to name it (laughs).

[00:12:00] Robert Doyle, PhD: And so we will now over the next 18 months, begin the process of acquiring the data we need to get what's called an IND, or an investigative new drug, application to the FDA. So it is something that we're actually very excited about, and we have really, really good, interesting lawyers and businesspeople who've come on board now at Cantius, whose job it will be to guide the scientists who don't know the business and legal aspects of drug development through the next 18 months into this process. And if the science holds up, that's where we should be in about 18 months.

[00:12:35] Host Amber Smith: So this 18 month period -- at the end of that period, is that when this may be tested in humans?

[00:12:41] Robert Doyle, PhD: Yes. At that point you can go into a phase one safety study just to make sure that it's tolerated and tolerated at doses that you will clinically use. And then our idea and the main focus for our work, to go back to my area, to come into, these are wonderful medications, the darling of research. They do have a limitation in that while a lot of type 2 (diabetes) patients do benefit from losing weight, that is absolutely true, some patients who have a comorbid disease like cystic fibrosis or HIV or cancer who are also type 2 diabetic, they cannot see their nutritional status suffer any further. And so what you would like is to be able to offer them another tool in the toolbox to give them glycemic control, but without affecting their nutritional status.

[00:13:32] Robert Doyle, PhD: They want the glucose control. They do not want the weight loss aspects. And of course that would also apply to lean type 2 diabetic patients. So this is more of a, a forgotten small percentage, if you will, that aren't able to benefit from these really wonderful drugs that would now be able to benefit from them.

[00:13:52] Robert Doyle, PhD: And we're focusing right now, particularly on patients with cystic fibrosis who also have type two diabetes. And that is usually the case with patients with cystic fibrosis. They will eventually develop diabetes, unfortunately.

[00:14:04] Host Amber Smith: This is very interesting. I appreciate you sharing this information with us.

[00:14:08] Robert Doyle, PhD: Sure.

[00:14:09] Host Amber Smith: My guest has been professor Robert Doyle. He's a professor of chemistry at Syracuse University and an adjunct assistant professor at Upstate. I'm Amber Smith for Upstate's "HealthLink on Air."