Transcript – Discussion of the Preclinical and Clinical Evaluation of the COBRA PzF NanoCoated Stent – Aloke Finn MD

Dr. Don Cutlip:

Don Cutlip from Boston, Massachusetts. I’m here with Dr. Aloke Finn from CV Path Institute and University of Maryland. And we’re here at EuroPCR to talk about the development and some clinical trial data on the COBRA Polyzene-F Nanocoated stent. Hello, welcome.

Dr. Aloke Finn:

Thank you very much. Thanks for having me.

Dr. Don Cutlip:

So CV Path has been involved in testing Polyzene-F since 2012, or maybe longer, tell us a little bit about the characteristics and what you’ve learned in the testing.

Dr. Aloke Finn:

Well, the PzF is really a polyphosphazene coating, which is a polymer, which coats the COBRA PzF stent. It’s essentially a fluorinated polymer, which we’re somewhat experienced with in interventional cardiology. Fluorinated polymers are really unique in that they have thromboresistant and anti-inflammatory properties. And that really comes from the fact that they really highly bind to albumin in the body.

Essentially albumin comes, coats the surface and prevents other unwanted blood elements from binding to the surface, such as platelets, leukocytes, fibrinogen, etcetera. So there’s a protective sort of coating for the surface then that produces this anti-inflammatory thromboresistant property, which I think is ideal for the vascular space. And I think it has a good application for stents, because I think obviously we want some thromboresistant properties for all of our stents to prevent stent thrombosis. And I think the clinical data has really yielded a fact that this has a very low rate of stent thrombosis, this particular stent.

Dr. Don Cutlip:

Okay, can you elaborate on some of the specific tests that have been done and what some of the results were in terms of some evidence or proof against the thrombosis and inflammation?

Dr. Aloke Finn:

We have done several different experiments with different end points in pre-clinical models. One of the first experiments is to evaluate intrinsic thrombogenicity of different stent types. In this kind of experiment what we do is we do a AV shunt model in the porcine, in the pig model. Basically set up an AV shunt and we put three stents in line. We basically let the pig blood run through that stent under low ACT. And we, over the course of 60 minutes, we see how much clot or thrombus is formed within the stents. And that really gives us an idea of how much thromboresistance each type of stent has. In this case, we’ve tried Cobra PzF versus bare metal stents where it’s bested bare metal stents in the sense that the coated PzF surface is thromboresistant, it develops less platelet accumulation than a bare metal stent has.

We’ve also tried it against stents, such as XIENCE, which also has a fluorinated polymer, essentially XIENCE, and the Cobra PzF performed equivalently in terms of thromboresistance. But we also tested against Synergy, which as you know, does not have a fluorinated polymer coating, but a biodegradable polymer coating. There, PzF performs superior to the Synergy stent in terms of thromboresistance.

The second type of study we’ve done in animal models is looking at healing in the intimal formation. We’ve shown that the COBRA PzF stent versus a bare metal vision and the rabbit model at 28 days has significantly less new intimal formation. So there’s some component of less intimal formation just from the PzF coating itself. And that also goes with less inflammatory reaction around the stent. As I was talking about the anti-inflammatory aspects of the coating. The third type of study we’ve done is to look at the return of functional endothelial healing in the PzF stent versus competitive DES to see which type of stent really produces functional healing.

I think we would talk about healing as multiple stages of healing. When stents heal, we talk about endothelial coverage, but in addition to endothelial coverage, we also want endothelial function back. We want normal endothelial function. And so we did the same kind of study in the rabbit model at 28 days where we compared the Cobra PzF stent to the Synergy stent, to XIENCE durable polymer stent, and to the BioFreedom no polymer stent. And basically Cobra PzF performed superior versus all three stents in terms of return of functional endothelium as well as coverage. So it was covered more quickly and the return of functional endothelium was much better in the COBRA PzF stent.

Dr. Don Cutlip:

Yep. Can you tell us a little more about the functional recovery? I mean, I think we tend to think of that as a return of vasomotor response, which obviously in a fixed that’s not going to happen, but maybe other parts of the function are important.

Dr. Aloke Finn:

Yeah. I mean, I think some of the research we’ve done in CV Path really shows that drug-eluting stents, as you know, have a problem of neoatherosclerosis, accelerated atherosclerosis forming in the stented segment. Now, what is the cause of that, we’ve shown in recent studies that essentially endothelial cells after stenting become dysfunctional, the barrier function of endothelial cells never really turns back to normal for long periods of time after drug-eluting stent placement, especially if they’re durable polymers. That really allows inflammatory cells and lipids to enter the arterial wall and that accelerates the process of atherosclerosis. So that’s really the genesis of neoatherosclerosis.

So I think there is an advantage to having a stent that simply heals in a functional way, more quickly than other types of stents. And that’s really the importance of this type of study, but it also points the fact that, of course we want cessation of DAPT in some patients. They’re high bleeding risk patients, some patients can’t tolerate dual antiplatelet therapy for long periods of time. This type of stent I think, is especially targeted towards those type of patients because simply because it heals very quickly.

Dr. Don Cutlip:

Thank you. So here this week at Euro PCR, the e-COBRA trial results have been presented. Tell us a little bit about your opinion of the design of that trial, the results, and whether it correlates or confirms some of the preclinical testing that you’ve done.

Dr. Aloke Finn:

I liked the e-COBRA registry. I think that it wasn’t all-comers registry, as you know, it took ACS patients. Those with stable angina, I think over 50% were ACS patients STEMI or non-STEMI and it allowed basically the interventionists to implant the COBRA PzF stent and follow these patients for one year.

The data was quite remarkable. The overall TLR rate was 4.3% with a stent thrombosis rate, probable and definite of 1.2%. That really compares favorably with patients who have high bleeding risks, which is what this trial was for in terms of stent thrombosis. As you know, the leader’s free trial had a stent thrombosis rate of around two, two and a half percent. These were the same type of patients enrolled in this particular registry. But the stent thrombosis rate was 1.2%. I think that really testifies to the thromboresistant properties of this particular product. And I think overall, the TLR rates are extremely acceptable for something that really doesn’t have a drug.

Dr. Don Cutlip:

Right. So the high bleeding risk population is likely going to be an important group for this stent if it’s going to be used. So the COBRA reduced trial is enrolling patients on oral anticoagulation and wants to compare the COBRA with two weeks of DAPT compared to either three or six months with the drug-eluting stent. No other studies are, as far as I know, are shortening the DAPT regiment to two weeks. Tell us your thoughts on that and whether the COBRA stent is ideally suited for that, or whether that’s a bit risky.

Dr. Aloke Finn:

I don’t feel that’s a risky proposition. I feel that this is really a stent designed for those high bleeding risk patients that are excluded from a lot of clinical studies. And that have been understudied in the past, but still represent a sizeable proportion of patients coming to the cath lab for intervention, as you and I both know, who see patients in the cath lab, we have a lot of patients that would qualify as high bleeding risk.

So my feeling is that this stent really has properties that are designed for short term DAPT. Remember, there’s no drug, there’s a phosphazene polymer, which is really thromboresistant. That kind of system, I think requires very minimal DAPT. I think that’s consistent with a PzF trial you yourself conducted in terms of the rate of stent thrombosis, which was in that trial, I think it was 0% in that trial. So I feel like this is a really good product for those type of patients.

Dr. Don Cutlip:

So as you know, where you have been accustomed to thinking of stents and sort of a dichotomy of bare metal versus drug-eluting, so the COBRA is a little different than being a modified or a nano coated stent, should that be a separate category or is it just a glorified bare metal stent?

Dr. Aloke Finn:

I think I would tell you that the era of the bare metal stent has probably ended. The reality is when you coat a stent with a polymer, especially a fluorinated polymer, I’ve just believed the outcomes are superior to a bare metal stent. We’ve shown in several assays, how metal itself is not only perhaps thrombotic in the sense that it accumulates platelets and thrombus more readily than fluorinated polymer coated surfaces, but it also I think he doesn’t necessarily have a great long-term results in the sense that there may be some metal ion leaching from metallic stents. So we don’t really appreciate causing low grade inflammation, we published a paper on that recently.

When you coat the surface with polymers, especially fluorinated polymers, it really seems to protect the artery in terms of inflammatory response long-term. So I think it’s a really, those two things are a real good advantage of this particular type of stent.

Dr. Don Cutlip:

Okay. Thank you.

Dr. Aloke Finn:

Now, can I ask you a question?

Dr. Don Cutlip:

Certainly.

Dr. Aloke Finn:

I know you are on the steering committee of COBRA-reduce, which is a very interesting trial. What do you think of the COBRA-reduced design, first of all, and why is it looking only for patients on oral anticoagulation and not all high bleeding risk patients? Number two. And number three, do we currently have a good definition of high bleeding risk patients? I hope you can remember all three questions.

Dr. Don Cutlip:

I’ll do my best. I think the COBRA-reduced trial is a very important part of the development of the COBRA stent. As you mentioned earlier, we’ve seen in the trial so far, you’re pretty consistent in good clinical re-stenosis rates with TLRs four to 5%, but I think we really need to compare it head-to-head to a drug-eluting, and not that we expect to be equal or should expect to be equal or better than drug-eluting, but we need to know how much of a margin there is.

So the COBRA-reduce are randomizing a thousand patients at, I think about 60 international sites and is going to look at that question around two end points. First, with only two weeks of DAPT in the COBRA device versus three to six months with the drug-eluting, the first end point should be fairly easy, is, does it cause less bleeding? And is designed for superiority around that end-point.

The second is an ischemic end-point, which will include death MI, stent thrombosis, and target lesion revascularization. And I think if the stent has a good showing there of non-inferiority, that will really be a game changer for this device, at least for high bleeding risk patients.

And I think the reason for doing oral anticoagulants rather than a mixture of risk factors for bleeding is because we really need to know how it performs in patients who we know are at high bleeding risk. And that really is the oral anticoagulation group. A lot of other risk factors are important, renal function, age, and so forth. And I think eventually those may come into play, but I think having a homogenous group where you can really test the effect is important.

Dr. Aloke Finn:

Yeah. I think those are good comments. And I think that the trial should give us some very interesting results in perhaps the first time to my knowledge Don, that we’ve been able to test a stent with just two weeks of antiplatelet therapy on board, which I think is probably a very unique aspect of that trial.

Dr. Don Cutlip:

Yeah. I think that’s an important part of it. And based on your data that should be safe to do we have healing and so forth taking place very early. We have a thromboresistant device, but as you know, the clinical evidence will carry the day.

All right. Well, thanks to everyone. It was a pleasure talking to you about this device and we’ll see how the results come out. Thank you.