In part 2 of this exclusive ADA interview, Anthony Cincotta discusses the Cycloset Safety Trial study design and findings regarding the cardiovascular safety of Cycloset.
If you have a question for Anthony Cincotta, you can submit it here.
Steve Freed: What you’re saying is very interesting. It’s a whole new way to look at diabetes. A little bit complicated. It’s something that probably most physicians aren’t aware of because it’s new technology, a new way of looking at a drug. I think that it would be nice if more physicians could learn about it. Especially some of the other things that you’ve discovered probably by accident [Note from Anthony Cincotta – truly not by accident.] Cardiovascular benefits right now are huge. We’ve got drugs like the SGLT-2s. It’s changing the paradigm of the way we treat diabetes. Blood sugars obviously are important but most people with diabetes are not going to die from high blood sugars per se. They are going to die from cardiovascular disease. You have a drug and even though it was a small study, you showed some significant improvements. Maybe we can talk about that.
Anthony Cincotta: Let’s talk about that. So, as I was just mentioning: decreased dopaminergic input to the clock results in elevated sympathetic tone. Another interesting aspect is that it results in leptin resistance in the body and insulin resistance in the periphery. When we were going through our FDA approval process for bromocriptine QR (Cycloset) for type 2 diabetes, the Agency requested that we run a cardiovascular safety trial to investigate the impact of this therapy on cardiovascular outcomes. We obliged not only their recommendation, but requirement for us to run a cardiovascular safety trial with bromocriptine QR in patients with type 2 diabetes. They specified the parameters of the clinical trial to be conducted. We ran, at their basic guidance, a clinical study – a double blind, placebo controlled, randomized trial with a pre-specified endpoint of a composite cardiovascular endpoint of MI, stroke, and hospitalization for congestive heart failure, hospitalization for unstable angina, or hospitalization for revascularization surgery. We then conducted the study – 2,000 patients on bromocriptine QR Cycloset and 1,000 patients on placebo….. at the request of the agency, they had given us those numbers to run the trial. We ran the study; it was independently adjudicated,that is the events, all SAEs including the cardiovascular serious adverse events were independently adjudicated), to see if they met the criteria for the composite cardiovascular endpoint. At the end of the trial, what we found was that relative to placebo, the hazard ratio for the composite endpoint was 0.58 with an upper bound of hazard ratio at 0.96. So there was a 42% relative risk reduction in that study that was required by the Agency and that we worked on the design of which with the Agency. Those data demonstrating cardiovascular safety are in the package insert for Cycloset today. They’ve been in the package insert from the day it was improved. So it was obviously, for us, very exciting. Not only did we have an agent that improved glycemic control by a very unique mechanism, that is it reduced postprandial glucose levels without raising the insulin, ….it’s not another insulin secretagogue type mechanism, but it also improves maximally insulin stimulated glucose disposal. We had done those studies and demonstrated that. It’s the sympatholytic component of the mechanism that, in our current understanding based upon the data, is an important contributor to the improvement in dysglycemia and it improves cardiovascular biology. So we thought potentially, we would see this (CVD) effect. In fact we saw a reduction in cardiovascular events, the pre-specified cardiovascular endpoint that was employed in the study. Obviously it was quite exciting and it delineates this mechanism going through the central nervous system in essence to potentially treat the umbrella of cardiometabolic disorders from those agents that actually are working peripherally on the kidneys, such as the SGLT-2s, that have now demonstrated a cardiovascular benefit, or we’ll hear tomorrow the Leader trial results with the GLP-1s, this is yet another mechanism through the neuroendocrine axis for improving glycemic control.
Steve Freed: One of the things I have to ask you, when the Empagliflozin outcome was reached they showed that it reduced cardiovascular events by… do you remember the amount?
Anthony Cincotta: Fourteen. I think the MACE was 14% reduction. The reduction in cardiovascular mortality was in the 30% range.
Steve Freed: Your drug trials show that Cycloset had even a better reduction. It didn’t make front page news. I always ask myself, why is it that way? Obviously they’re a bigger company. They’ve got 500 sales reps. It makes it tough for a smaller company to get that information out. It must be very frustrating for you.
Anthony Cincotta: Well, in fairness our study was a one year trial, it wasn’t a longer study as the Empa-Reg trial or the Leader trial. We had a fewer number of patients but we still had a fair number of patients: 3,070 patients in that trial. The analyses that were conducted on that study were consistent in demonstrating a hazard ratio of the primary endpoint being less than one, irrespective of gender or demographics. I believe that the conduct of another trial would obviously bolster the results of the first study. But in and of itself the results of that trial when you take it in composite with the mechanistic data and the biological plausibility of such an agent improving cardiovascular outcomes strongly suggests that more attention should be paid to investigating this neuroendocrine axis in the regulation of cardiovascular biology.
Steve Freed: Do you see any other benefits coming out of a larger study or looking more into it?
Anthony Cincotta: Yeah, for instance, we have a poster presentation today where we’re showing the reduction in elevated heart rate with bromocriptine QR therapy. Elevated heart rate is a well-accepted risk factor for cardiovascular disease but also as a predictor for type 2 diabetes. What we’re showing in that poster that’s being presented by Dr. Chamarthi, our medical director at VeroScience, is that bromocriptine QR reduces elevated heart rate and the higher the elevated heart rate the more effective bromocriptine QR is at reducing the elevated heart rate. The heart rate reductions in her data sets are between 5.5 to 9 beats per minute, which is a fairly substantial reduction in heart rate for individuals with heart rates greater than 70 and 80 beats per minute, respectively. That’s important. That impact on elevated heart rate should translate into improvements in vascular biology and vascular health, throughout the entire cardiovascular system. So it’s possible that further research in this area will lead to discoveries of improvements in other cardiovascular endpoints, besides the ones that we’ve looked at in our original trial. One thing that we’re particularly excited about is [treating] congestive heart failure. Elevated sympathetic tone is an aggravating factor for congestive heart failure, it worsens the disease. It actually is a culprit in the development of congestive heart failure. Dopamine agonist therapy with bromocriptine has been known to reduce elevated sympathetic tone. We’ve shown a reduction in elevated heart rate so there’s a strong potential that timed therapy with bromocriptine QR could reduce congestive heart failure disease progression. We don’t know, we need to find out and that’s one area that we’d love to begin investigating on top of the traditional MACE composite of MI and stroke, and CVD death.
Steve Freed: Let me ask you a question that I should have asked you in the beginning. I got so excited talking to you about this, I forgot to ask. Tell us a little bit about yourself, what you do, how you got to where you are?
Anthony Cincotta: The way I got into the work that we’re doing today in diabetes is really the result of my interaction with my graduate school mentor Al Meier at Louisiana State University. When I first went to LSU, I was working in the biochemistry department in a few different research areas outside of diabetes completely and I had gone to visit Al Meier’s laboratory because I had a question relating to a hormone that we were working with at the time. While I was there he sat down and told me his story about observing animals in the wild under natural conditions and how their metabolism changes during the course of the year and that he had developed a mechanism for resetting the annual cycle in these animals. What really got me was he was able to make migrating birds that migrate north and south at particular times of year, by resetting the clock, migrate the opposite direction, that is, make them migrate north when they were supposed to be going south. It’s a huge change in physiology and behavior that puzzled humanity since antiquity and he was able to crack the code and basically reset the annual clock. At that moment I switched laboratories. I said “I want to become your graduate student. Do you have room for me to join your team? This is fascinating.” And I did join his team and started to study biological clocks and the annual cycle. His laboratory was the first laboratory that demonstrated in vertebrates a circadian rhythm response to any molecule. It was the first (such) study. If you look in the literature today, how many papers have been published on circadian rhythms today, this is now 50 years after his first publication in 1964. It’s (about) in the 10,000s. It’s (one of) the largest areas of research in neuroendocrine science. It has the greatest potential for improving the human condition I think in medicine and medical investigation. Really it was those early conversations with Al Meier which really happened by chance many years ago at Louisiana State University that garnered my interest and fascination and got me started working in his laboratory. When we were looking at body fat changes during the course of the year, I knew that that was linked to hyperinsulinemia and I knew hyperinsulinemia in a lot of ways is linked to insulin resistance so I took a short tangential road off of the obesity path and said let’s look at glucose metabolism and insulin resistance and see if these mechanisms are also operating to regulate those parameters that are so closely linked to obesity. In fact they were, and then we were off and running and I’ve been doing it ever since.
Steve Freed: I want to thank you for your time. I think it’s very educational and interesting. I think there will be a lot of interest going forward.