In part 1 of this exclusive ADA interview, Anthony Cincotta discusses the mechanistic science behind the development of Cycloset, and why preclinical and clinical findings suggest the therapy may reset clock mechanisms governing postprandial glucose metabolism.
If you have a question for Anthony Cincotta, you can submit it here.
Steve Freed: We’re at the 76th Scientific Sessions in New Orleans for the American Diabetes Association. This is an exciting time with all the new research that’s going on out there. We’re learning all kinds of new things. I’d like to introduce to you Anthony Cincotta. He is the CEO of a company called VeroScience. I’d like to go back four years. This is one of my favorite stories. We we’re sitting at dinner with Aaron Vinik and Stanley Schwartz and I asked them what’s the most exciting thing that you’ve heard here at ADA. They both came up with the same answer which blew me away. They said Cycloset is the most important thing coming out of the ADA back three or four years ago. I said “Cycloset, I don’t understand. It’s a drug that reduces postprandial blood sugars but we have a lot of drugs that reduce postprandial blood sugars.” They said “It’s not about blood sugars it’s about cardiovascular disease and the way it works.” I said “Well I’ve got to talk to this guy.” And we got in touch. We’re working on a plan to get the information out there, exactly how this drug works and why it is so different. I don’t want to take up the whole conversation so let’s start out with: What led you and how did you come across basically manufacturing a dopamine agonist? How it works? Talk about migration. It boils down to helping people with diabetes living a longer and better life. So let’s get that out of the way.
Anthony Cincotta: Our interest in using a dopamine agonist to treat cardiometabolic disease and type 2 diabetes specifically actually originates from work done many decades ago, [studying] animals in the wild under natural conditions. As animals go through the year in the wild, they go through marked changes in their metabolic activity. At certain times of the year, the animals become very obese and when tested they’re always [observed] to be hyperinsulinemic and insulin resistant at those particular times of the year in the environment. As the ensuing season comes along, that obesity and insulin resistance seem to vanish. It actually improves. The animals become lean, they’re eu-insulinemic, and now their insulin sensitivity is markedly enhanced. This change from one season to the next is associated with changes in food availability in the environment, but it’s not what most people would anticipate or think is actually happening; the times of year when animals become obese and insulin resistant are the times of year when food availability is quite scarce and it’s actually the obesity and insulin resistance that helps them survive those times of year when food availability is scarce. They’re in essence running off of the fuel of the accrued body fat storage and the tissues of the body become insulin resistant and increased hepatic glucose production keeps the central nervous system operating well…… even when there’s very little to no glucose in the environment. Then the animals move into the next season when it’s springtime. From winter to springtime in temperate zones, food availability becomes quite prevalent. There’s no [metabolic] need for that obese and insulin resistant condition. It vanishes. So we became interested in using this naturally occurring phenomenon as a model to study human insulin resistance and type 2 diabetes because it was so pervasive among the vertebrate species. What I’m describing to you, this annual cycle of metabolism that is observed on planet Earth, is observable among all the vertebrate classes studied , from fish to mammals, and everything in between. Fish have been on Earth for an estimated 425 million years. These mechanisms that operate to regulate these annual cycles of metabolism are ancient. They’re extremely well preserved despite evolutionary divergence off of the main evolutionary tree….from birds to mammals,… it’s extremely well preserved. So we thought if we could understand how these animals were, in essence, curing themselves of the obese and insulin resistant condition, and copy it we would have a therapy potentially for the human obese and insulin resistant condition as well. So, our studies — I’ll summarize them quickly because this is a long period of time that we’ve done these investigations over — started really in Al Meier’s Lab at LSU in the 1960s. To summarize a long series of studies, it was found that the annual cycle of metabolism was the manifestation of changing phase relationships of circadian neural oscillations around the biological clock, the suprachiasmatic nuclei within the hypothalamus. The circadian neurotransmitter profile in winter animals is very, very different than the circadian neurotransmitter profile of those animals in the springtime. One major change that you see when animals move from the insulin resistant obese condition to the insulin sensitive lean state is that there’s a reinstatement of the circadian peak of dopaminergic activity at the biological clock that’s absent or greatly diminished in animals during the insulin resistant obese time of year. So we did a series of studies where we merely introduced dopamine agonists to the body, either systemically or into the brain via ICV (intracerebral ventricular) administration, or directly into the clock area of the brain, to see if in fact we could shift the animal out of their winter seasonal obese and insulin resistant condition into a lean insulin sensitive state, by the administration of these dopamine agonists, at the time of day that it peaked [at the clock] in the spring animal. We’re trying to make the prediabetic winter metabolism shift to the spring non prediabetic, or normal metabolism, merely by providing back that circadian peak of dopamine at the biological clock. There are many CNS neurotransmitters that change from one season to the next in these animals; however, one of the prominent alterations is the alteration in the dopamine activity at the clock. So we chose that as our first target to investigate. In fact, when we did [this, we found that ] those [dopaminergic] administrations, whether systemic, ICV, or directly to the clock area of the hypothalamus, were able to shift the animal out of the obese and insulin resistant state to the lean insulin sensitive state.
We then said to ourselves, is this a phenomenon that is just specific to seasonal animals in the wild. It’s been preserved over 100s of millions of years, but how does this translate to other model systems for diabetes? We then began looking at OB/OB mice that have no functional leptin, or DB/DB mice that have no functional leptin receptor, AY mice that have a dysfunction of the MSH signaling system in the hypothalamus, and high fat, fed animals. In all those cases, our laboratory and several other laboratories had identified low brain dopamine levels in all those model systems. When we administered dopamine agonists at the appropriate time of day to reset the central clock circadian peak of dopamine that was diminished in these model systems, we were able, (just like in seasonal animals) in these genetic models, to improve the metabolic condition, reduce hyperglycemia, insulin resistance, and body fat stores. Now, that was even in animals that lacked leptin…..in The OB/OB mouse without leptin, we were able to essentially ameliorate many of the metabolic disorders of those animals. We have several posters, I believe 5 or 6 at this ADA session, on this mechanistic work. So the composite of all of this information led us to the conclusion that in fact this is a very common phenomenon among a wide variety of animal models, of the obese insulin resistant condition……..there is a lack, or a reduction, of the circadian peak of dopamine. Now it’s not just dopamine period………. any old measure of dopamine at any time of day…. it’s the circadian peak of dopamine feeding into the biological clock that has a major impact on the output messages coming from the clock, which is really important because the clock (the SCN neurons) regulate to a large extent, the neuroendocrine axis. There are major output neurons from the SCN to the pre-autonomic hypothalamic centers that impinge on the sympathetic and parasympathetic nervous systems, to control their activities. So we began investigating the possibility that we could use a dopamine agonist to treat hyperglycemia in type 2 diabetes based on the composite of these studies that we had done in a wide variety of animal model systems. What we decided to do was look for a dopamine agonist that had been used in the general population that was already FDA approved. We chose bromocriptine, because we had demonstrated in a variety of animal model systems, that that particular dopamine agonist functioned well to improve the metabolic dysfunctions of obesity and insulin resistance. So when we ran those studies in the animal model systems, it proved so effective with this agent, we were giving timed injections that were very specific pulsed rapidly absorbed administrations. To mimic that time pulse delivery in humans, we took the bromocriptine molecule and we reformulated it to make it very rapidly dissolving, more water soluble and with increasing absorptive capacity of the formulation so we could attempt to get a sharp peak and short pulse of the bromocriptine in the circulation that would then make it to the CNS. We ran a series of clinical trials with this reformulated bromocriptine product, administering at what we believe is the appropriate time of day……. early in the morning, at the onset of waking. The dopamine rise early in the morning is part of the waking mechanism and there is indirect evidence from measuring hormones in the blood that even in humans with insulin resistance, diabetes, or prediabetes, that the dopamine peak was diminished just as we had seen in all of those animal model systems.
About the time that we were doing this in the mid-90s and early part of 2001, 2002, there came reports in the literature, using different methodologies that in fact dopamine activity in other parts of the brain, primarily the mesolimbic system that regulates feeding, were also observed by other laboratories to be diminished. Most interestingly, it’s been demonstrated by our laboratory and by a few other laboratories now that high fat diets diminish dopamine activity in the brain. We had shown in model systems, (and we had some of this data presented today at the ADA), that the effect of a high fat diet to induce that obese and insulin resistant condition can be blocked merely by giving dopamine to the biological clock for a minute at the appropriate time of day that mimics the peak of dopamine [activity] in normal animals on a normal diet. So, it’s across the board of model systems used (and including in response to a high fat diet) that we see low dopamine in the brain, particularly in the hypothalamus, particularly in the biological clock, particularly at the appropriate time of day…… the loss of that dopaminergic activity, associated with, coupled with and driving now, (we’ve got evidence that it’s actually driving the induction), participating in the induction of that metabolic syndrome. We formulated our product to run these studies in humans.Just as we had demonstrated in animal model systems, [and found that] replenishing the dopamine at the appropriate time of day, improves metabolism. And to summarize the studies that were conducted to garner the FDA approval for the treatment of type 2 diabetes, we had looked at patients, being treated with sulfonylureas, metformin plus sulfonylurea, one or two antidiabetic oral agents, patients that had been treated with insulin, and looked at the effect of our bromocriptine formulation, termed Cycloset, (we call it bromocriptine QR to distinguish from the traditional formulation of bromocriptine, that’s used in much higher doses to treat Parkinson’s disease….this is a completely different scenario, opposite intent…..we want a very short pulse of dopamine delivery to the brain and at a very distinct time of day. So on the glycemic side of things, we noticed that we improved glycemic control in these patients with type 2 diabetes and the effect was primarily by reducing postprandial hyperglycemia, however it’s interesting in that it’s not an insulin secretagogue, in fact it reduced postprandial hyperglycemia in these patients without altering the plasma insulin level, and improved the postprandial hyperglycemia across all the three meals of the day. Yet, the dopamine agonist bromocriptine is removed from the circulation very early after its administration because it’s quickly absorbed and quickly metabolized……… a couple of hours after, it’s below 50% of its C max. Yet we see the effect, not only after breakfast but also after lunch and after dinner….. the reduction in the postprandial glucose.
Again this relates to the impact of the therapy we believe to reset clock mechanisms governing postprandial glucose metabolism. There’s actually a presentation today by Dr. DeFronzo’s laboratory investigating the impact of bromocriptine QR on postprandial glucose metabolism where they’re showing in humans that are refractory to GLP-1 therapy (They’re in poor glycemic control on GLP-1 therapy) a fairly marked improvement in their postprandial hyperglycemia in response to bromocriptine-QR therapy.. We improve maximally insulin stimulated glucose disposal in type 2 diabetics which is also an important aspect of the therapy, improving postprandial glucose levels without raising insulin.Obviously those two fit together mechanistically and a third important aspect of the therapy, the bromocriptine QR therapy, is that it is sympatholytic. Dopamine agonist therapy in general is sympatholytic in various sites in the brain, however the timed dopamine agonist therapy to the biological clock area in an animal that has overactive sympathetic drive, (that is a known risk factor, not only for cardiovascular disease but also for insulin resistance and dysglycemia reduces it back down to normal upon administration of a dopamine agonist to replenish that low level of dopamine at the clock. The clock then sees that circadian peak in dopamine signal as a message to then reduce the overactive sympathetic tone in the bodythat we believe, it’s been shown, participates in inducing insulin resistance, dysglycemia and also cardiovascular dysfunction.