InspireMD, Inc. (NSPR) Earnings Call Transcript & Summary

Good afternoon, and welcome to the InspireMD KOL event on the CGuard stent platform and MicroNet portfolio. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the InspireMD website following the conclusion of the event. Before we proceed, I'd like to mention that we will be making forward-looking statements during today's webinar. Please refer to the slide on the screen for further reference. I'd now like to turn the call over to your host, Marvin Slosman, Chief Executive Officer of InspireMD. Please go ahead, Marvin.

Thank you all for joining the call today. I'm Marvin Slosman, CEO of InspireMD, and it's truly a pleasure to have been able to assemble this world-class group of physicians, all leaders in their respective specialty in vascular medicine, here to share an important update on the trends in carotid disease management and stroke prevention. With us today are Dr. Chris Metzger at Ballad Health System in Kingsport, Tennessee; Dr. Adnan Siddiqui from Gates Vascular and Jacobs Institute in Buffalo, New York; and Dr. Sean Lyden from the Cleveland Clinic. Next slide, please. Carotid disease management is the final segment of vascular medicine that remains a surgically dominated procedure. Transition to an endovascular standard of care has been slow due, in large part, to the lack of technology innovation to replace surgery as a first-line option. At InspireMD, our entire focus as a company is based on the foundation of building and marketing a stent system in CGuard EPS that disrupts this change from open surgery to endovascular standard of care for improvement of patient outcomes. CGuard's advanced MicroNet mesh has proven to be the catalyst to maintain post-procedural cerebral protection, with over 27,000 devices sold to date, tested in real-world and ongoing studies with unmatched evidence across the broadest base of physician specialists treating carotid disease to enable this transformational change. I think today's panel is a great example of how this remains our priority. Next slide, please. Carotid endarterectomy is a surgical procedure, which you will hear much about today, which remains the standard of care but with all the associated surgical risk. The transition to an endovascular approach was ambitious and promising to enable this change. However, the results have proven that first-generation open and closed cell stents have inherent weaknesses in their design, which limits significant improvement of outcomes against surgery. Next slide, please. As you can see from these images, on the left is a tight stenosis and associated MRI image of the brain infarc. And on the right, following stenting, you can see an improved angiographic result. But due to the plaque prolapse to the open cells, particles are released into the brain causing post-procedural strokes, as demonstrated by the white spots. Next slide. To demonstrate the value of MicroNet mesh, the images on the left show the exposed to open-cell struts of this first-generation device associated with an IVUS image of the lumen of the artery, where you can visualize this protrusion of plaque. While on the right-hand side, you see how the mesh of CGuard embeds itself against the artery wall to protect this plaque prolapse and maintains protection to the brain with a clean lumen of the artery. Next slide. After many years of design and development, we believe we'd optimize the best of stent scaffold design in combination with mesh pore size to allow flexibility and strength while building a pore diameter of our mesh that prevents damaging embolic particles from escaping to the brain. As you can see, graphically, there is a significant size difference in pore opening, exposing plaque to the artery with other devices. Next slide. Under electron microscope, you can appreciate the stent structure in combination with the mesh. Remember, 20 microns is roughly the diameter of a human hair for reference. Next slide. Another unique feature of CGuard is built into the geometry of the stent frame that provides for tapering of the vessel to gain optimal opposition to the wall. As you can see in the model, the stent tapers nicely to conform with vessel sizing. This is what we call SmartFit, and it provides not only a clinical advantage but also allows for fewer sizes to be stocked in labs as a result of the ability to upsize the stent. I think Dr. Metzger will share his experience and preference of these sizes. Next slide. Finally, for reference to our mesh innovation, we use a proprietary method of knitting the mesh fiber into a sleeve, which is then applied to the exterior of the self-expanding stent structure. This technology is manufactured and applied in our facility in Tel Aviv. Next slide. Turning our attention now to data and clinical results. We have data from over 1,600 patients in multiple studies, with some being followed up to 5 years, demonstrating the superiority of CGuard through this unmatched body of evidence. Our panel will certainly comment on the value of this evidence as a lever to driving adoption, both in current practice and additional indications. Next slide. When you aggregate the data across these numerous clinical studies, which includes 1,650 patients, the result for CGuard delivers the lowest 30-day DSM against both C and first-generation CAS by significant percentages. Additionally, we have long-term data to support consistent late outcomes, out over 5 years, reinforcing the biological response of our mesh as compared to double-layer competitors. Next slide. Finally, our pipeline of innovation remains full, including new -- a new transfemoral delivery device, CGuard Prime, our TCAR accessory device, [ Switch Guard ], as well as advancing indications where we believe that the MicroNet mesh has unique capabilities. We look forward to advancing our plans to deliver new and innovative devices built around our CGuard stent system. And it's now my pleasure to introduce Dr. Chris Metzger to present his perspectives and experience. Dr. Metzger, go ahead.

Okay. Great. Thank you very much, Marvin. A quick check. Can everybody see my slides okay? Okay. Well, first of all, it's an honor to be with this panel, with you, Marvin, and with the team and with the potential investors to share a passionate carotid stenter's perspective on this technology and also from the IDE trial going on in the United States. Here are my disclosures. Again, importantly, I am the national PI for a trial in a compensated role, and I've been the PI for other carotid stent trials as well. And I promise, this is from the heart, not from the wallet, my discussions here. So as an important background, as Marvin mentioned, but now for the first time, we see a definite trend towards carotid stenting away from endarterectomy, even from vascular surgeons, with TCAR and carotid stenting. There is a lot of carotid disease out there. And as everyone knows, patients are terrified of themselves having a stroke. Carotid stenting, as mentioned, has had some issues with minor peri-procedural strokes. An ideal carotid stent is needed to reduce these types of strokes, conform to the anatomies of the vessels that we treat and to be usable whichever way we choose to get to the carotid, whether it's TCAR, transfemoral or transradial, et cetera. So our goal, of course, is carotid stenting performed safely without any peri-procedural stroke. It's very important to realize that the majority of strokes after carotid stenting don't occur during the procedure, but rather in that short time interval after it, okay? And what that means in various studies is that the more the cell is open, in other words, the biggest size in the stent pores, the more likely that, that plaque is able to get through the stent later and then go upstream, even though you had a nice result. Marvin showed this is a standard stent over here, and you see that coverage is not so great. And even though the stent looks good, for most of it, there's that little plaque protrusion at the arrow. So even though the angiogram looks good, the brain does not look good if some of that material extrudes, gets through the stent after a procedure and gets to the rain. Now what would be an ideal carotid stent? It would conform to the majority of the vessels that we treat and yet maximize plaque coverage to reduce particles that get up to the brain on a later basis. While the available conventional stents that we've had for years are either open cells, the great thing is they're conformable. They'll go around bends, but they have the least plaque coverage. Then there are closed-cell stents that coverage is better, but these are more rigid tubes and less conformable. And as you'll see, it's still not ideal plaque coverage. The CGuard micromesh carotid stent may be that ideal stent covering this micromesh layer that we'll look at on a conformable stent. It may combine the best of 2 worlds. It's extremely conformable as well as anything that's been out there through that proprietary SmartFit technology, and yet has by far the best plaque coverage through the micromesh layer with the smallest cell size that has been seen to this date. So here you see this conventional stent in the metal stretch, covered with this much smaller micromesh layer, fits on the outside stent, which is important, on this conformable design with increased coverage. You've seen this. This is just a conventional stent, and sewn on the outside is this micromesh layer. You've seen the SmartFit technology. But what I will say is that now, you don't have to have a taper with a 7-millimeter on one side, 10-millimeter at the other and then a twist of things in between. You can have 1 stent that itself will conform to both ends, as you said, reducing the inventory that we need as physicians, and Sean Lyden and others need as supply chain directors. This is a good thing. Despite this conformability, it has unbelievable plaque coverage. If you look here at the open cell, this huge circle. Closed cell is the best we've had, look at that size. The other 2 micromesh-covered stents are here, and then in green is the CGuard. And if you look at -- on a graph over here, you can see how much smaller the pore size is, the opening here, to let plaque not get through is what we're trying to do. So going back to our initial picture, you start with this plaque protrusion, who is the metal layer, and replace it with the same picture without plaque protrusion because of this extra insulating layer or protective layer. Now there are 2 other micromesh stents. In Chris' opinion, I've been in all 3 of the trials, I think this stent has advantages. It has increased conformability with kind of an auto-tapering, okay? It's an exact stent, a 40-millimeter stent. It's a 40-millimeter stent as opposed to others that greatly elongate, where you don't need it. The mesh sizes are smaller. The pore sizes are smaller, and it's on the outside of the stent, so it's not infolding inside the tent, and there's no coating on this. In the data, long-term data, it has a lot less restenosis or occlusion compared to the others and durable data. It's easier to size and deliver, and there's a large matrix so stent size is available and no supply chain issues. We've looked at this, but it is important, again, this is a slide Marvin's shown. But as a doc, when you're -- you really -- hey, I can show you great animations, but I -- we want to see data. And the bottom line is, in 27,000 implants and 1,600 in rigorous clinical trials, you can see durable results up to 5 years. And again, this is where we see the advantages against the other stents. Again, you've seen this slide as well. This is not a direct comparison, but this is the conventional stents in surgery in the CREST randomized trial in the New England Journal. So this is very carefully adjudicated data. And you can see the CGuard performed very favorably, and no major strokes seen with this protection against plaque protrusion. A brief word about the C-Guardians U.S. IDE pivotal trial. This is for U.S. approval, for CMS and others. We've done this very carefully, Christina Brennan and others and Marvin have done a great job with this. We require either the NAV6 distal protection, the best-in-class for distal filter protection, or the MoMa proximal protection. These are the only 2 you're allowed. We know it's -- these are the best protections. The sites and operators are very carefully selected. Cases must be approved by an experienced screening committee to get into the trial. So we're not letting bad cases in the trial. The protocol has been carefully prepared and undergoes revisions on a regular basis, from anything that we learned that wasn't perfect. We review the cases after they're done. And so what you have is what I think is an excellent stent combined with an excellent study with experienced sites, operators, mandated procedural techniques and the right technology and carefully selected and reviewed cases. Here's one of our cases in the trial. You can see the aortic arch here, you can see very slow flow in the red dotted arrow in the left carotid system. This is a severely symptomatic patient. You can see how tight at the red arrow of the carotid is. You really want protection for this kind of person, who's already thrown a lot of pieces to her brain. Look how slow the flow is getting to the brain in the dotted arrows. That's at baseline. So here's the proximal protection system. This is a balloon in the external carotid. We're going to shut the blood supply. And in the red circle, you'll see me steering a 0.014-inch wire in a protected fashion, okay? With the protection, we do a balloon. And then in the dotted area, this is a CGuard being released, and it comes out into the carotid artery. This is that stent, and then we inflate a balloon within the stent. And here's the final nice result with the protection of the micromesh to present -- prevent any of this from getting up to the brain now or later. And here's -- look at how brisk the flow is compared to what I showed you before. This patient, right after this, was asking me immediately for a calculus book, which we had to deliver to the bedside. I may be exaggerating slightly, but the flow is a lot better. So if I was an investor, I'm not, I'm a plumber, so this is up to you guys. But if I was an investor, why would I consider investing here? I think it's an awesome stent. I believe, and it's got a lot of data and experience already, with more accumulating. The company is a nice company. When you have savvy leadership, and yet they're user-friendly, you all know, and we know as docs, it's nice to have that combination of user-friendliness. I believe it's there. There is a potential that CMS is currently reviewing the National Coverage Decision so that we may even expand coverage for carotid stenting. That comes -- although we have a "predictable" IDE trial that's ongoing, now predictable is in quotes. But we've designed it to be a win for the stent because it's a good stent and done correctly in a good trial. Again, there's already an increasing trend toward carotid stenting, even amongst the vascular surgeons, couple that with increasing reimbursement options, it may be a very good time. And again, this stent is going to be designed in such a way, and again, these are the forward-thinking statements, so that could be compatible with TCAR, which the vascular surgeons are embracing, or from transfemoral. And there are other new indications and devices being tested in their technology pipeline. So in conclusion, InspireMD has a very unique stent and a lot of suggestions that it will be the best-in-class carotid stent. There's already excellent experience in data, long term, for this. In the U.S., pivotal IDE trial is enrolling well, with very favorable results to date and expected to continue with favorable results. Increasing trend towards carotid stenting and potential increases or increases in reimbursement, in my opinion, make this a unique time and opportunity for mutually beneficial partnerships amongst all of us. And I thank you very much, to any Steeler fans out there, and look forward to any questions in the session later. So thank you very much. And with that, it's going to be a pleasure to throw the slide deck over to my good friend and colleague, Dr. Adnan Siddiqui, a neurosurgeon and one of the better interventionalists in the world for this, for both stroke prevention and carotid, vast experience. So Adnan, I'm going to pass the baton to you, my friend.

Thank you very much, Chris. What a great start. Marvin and team, appreciate the opportunity to talk to you and people you might be trying to educate this afternoon. I think Chris really started off with a great presentation about the actual device and the value that it presents to carotid disease. I'm going to take a slightly different path. For those who might not know, I'm a neurosurgeon and I'm an interventional neuro specialist who does both open, endovascular procedures. And I live in Buffalo, at the Gates Vascular Institute and the Jacobs Institute. And what I want to educate you about is this opportunity, which is currently completely unrealized, and I'm going to serve -- here are my disclosures. And I did recently sign on with Marvin's team to advise them on their neuro strategy. So I'll start off by talking about a case example. It's a 65-year old who presents with an acute cervical internal carotid artery occlusion. Here's a CTA. You sort of see the vessels on the left side, but you see this entire right side of the head with missing vessels. NIH stroke score is 17. For those who may not know NI stroke score, 5 or less is mild, 5 to 10 is moderate, over 15 is likely fatal. So what we know with this person, based on all the natural history data, is that the chances of good recovery are 0, the chances of a dramatic recovery are 0. And so this is -- patient is taken to the cath lab. And here, you can recognize from the picture, as just shown by Chris, there's a carotid occlusion. And there's the flow from the other side. And you can see, there's really no flow going to that hemisphere. And so we crossed this acute occlusion, revascularized the carotid, and we realize there's an additional lesion in the neck, and then there's another one in the middle cerebral artery. And we go ahead and we revascularized that with a stent retriever now, in the end, resulting in complete revascularization. The patient improves from an NIH of 17 to 8; discharge, 6; 3 months, 0. And so we looked at our own data to look at patients, how patients did with carotid occlusions with thrombectomy versus with just best medical therapy, particularly IV tPA. So this is now patients who didn't get IV tPA. And the significant improvement was quite spectacular, almost double the group in the endovascular achieved excellent outcome compared to those that were not treated. And to tell you this is not a rare group. This is a study, which really started the entire revolution from mechanical thrombectomy for stroke. It was a Dutch study called MR CLEAN. And MR CLEAN included all comers who came in with a stroke and had a large vessel occlusion. And guess what, 26% of them in the higher NIH and 32% lower NIH had a tandem occlusion. So it's a very, very, very common finding in these patients. And what you can realize is that this is a population that was treated both in the interventional group. And I would like you to appreciate the likelihood of good outcome, this is another trial called ESCAPE, was highest in the tandem occlusion group. So the benefit of mechanical thrombectomy, every other category, whether it's age or good-looking CT scan or tPA or no tPA or severity of stroke, all those measures live out here except for one right here, cervical carotid occlusion. So this is the population that you can help the most out of all the populations, and it's not a minority. I just shared with you, it's a quarter to 1/3 of patients. And so this is really an important category. Now this is the Spanish study that was done. And by the way, I'm showing you all these international studies because the FDA, unfortunately, has excluded all these patients from stroke trials in the United States because there is nothing on label for this disease. So when you look at these patients, this is the REVASCAT study, again, 26%, almost 20% had ipsilateral carotid occlusion. And again, when you look at all these tandem lesions, you can see that there is value. Now the Spanish study, not a lot, not a big population underwent CAS. In MR CLEAN, a larger population did. And subsequent to that, again, you can see cervical occlusions are the ones that are best helped. So the question really becomes, what's the best way to deal with this? Here's a tandem lesion review done by my friend, Francis Turjman from France, and it really showed that looking at 11 studies that were published, 237 patients, the recan rates were very good, and the favorable outcomes were just as good in tandem lesions than those who did not have tandem lesions. And you can see in this particular series, the vast majority underwent acute stenting. And the symptomatic intracranial hemorrhage rate, that dreaded hemorrhage in the brain, was no higher than any other thrombectomy trial of only 4%, and that's well within the norm. So we know the efficacy of tPA in these occlusions is essentially 0%. We know tPA doesn't work in this population. So it is really hard to ascribe these patients to just medical therapy. So here is a 55-year old, you can again see there's the CTA. The entire right circulation is missing. There's the basilar, there's the carotid, the right circulation is missing. Again, chances of good outcome are 0. There you can see there is barely -- you don't even see the carotid. There's no slow flow here. There is no flow here. But you sort of see where the carotid probably exists. We go ahead, we stent this as step one, and then we go up north and we use Solitaire, improves NIH of 21 to 0, goes home. So should we stent? Do we do stenting first? Do we do stenting second? What kind of stent? I think those are all things that we still need to quite figure out. I believe I treat this as a case of a symptomatic carotid because that's what has happened. The clot's broken off and gone up north. So I think in the acute situation, what we will do is we load the patient with aspirin and BRILINTA in the emergency room. And then I like to do it anterograde, although we have looked at our data in this kind. The benefit is so good either way that it's kind of hard to prove what may be better. I'd like to address the primary causative lesion, especially if we had a stent on the shelf that we could use for this, such as CGuard. I know that I could go ahead and plasty and not worry about this plaque [ shelving ] off stuff as I go up north and improve collateral circulation. Other people believe that maybe open the head first, and on the way out to open this. Again, that's an open discussion. And again, we looked at our own series, it was kind of hard to really establish what was better. But what I like to do is use a balloon guide catheter and be sure that there's actual flow reversal with just a balloon guide. We don't need to use a MoMa. We cross the lesion, and then we go ahead and plasty and stent carotid first. If we had concern and that we aspirate aggressively, if we are concerned there may be still a [indiscernible], we can do IVUS. But we typically do directly deflate the balloon, go through the stent with the balloon guide, inflate it on the other side and do what we need to do intracranially to get good results. So here's a quick video to show you that this is a critical carotid. You can see there is very, very slow flow. It's not going up north It looks like a pseudo-occlusion. So -- and this is an older case, and I'll show you this is a MoMa device. This is something that Chris really brought to our attention, along with Nick. And what you can see is we get the carotid open, but there is intracranial occlusion up north in a very slow fashion. So we inflate the balloon in the external, we inflate the balloon in the common and bring in a stent and go ahead, deploy the stent. And once the stent is in place, we still have the occlusion. So we now switch around and deflate, and we put the guide catheter through. So this is why I switched away from MoMa, Chris, because it requires me to switch the guide around. So with the Walrus, I don't need to do that. So you can see, I still don't have intracranial flow because there's a thrombus. So now, what I do is I go up with my aspiration catheter up top and cross into the middle cerebral artery. And then once I have that there, I'm deploying a stent retriever right there. And once the stent retriever is deployed, I aspirate back, and I pull this back together and there is our run, and we have completely restored flow. And this is the final run. It shows complete restoration of flow. And almost always, you can guarantee when you see this that you're going to have, and there's your carotid, cervical run. So -- and I'm going to sort of skip this to just show you -- make the point that the problem in this case is when you have a case like a tandem occlusion. You don't have enough time to put patients on long-term dual antiplatelet therapy. By the way, here's another case of perfusion defect in the middle cerebral artery. This is the person who has got reduced flow, volume is up. You don't open them up now. He's going to have a lot of dead brain. There's a CTA showing you the MCA occlusion. And there's critical stenosis of the carotid as well. So what do we do? We go ahead, stent the carotid. We use a distal filter in this particular instance because we have a clear lumen that we can see. The stent is being deployed. So we snap the thrombus in its location. Imagine if we had a stent that would actually trap the thrombus completely rather than have it protrude through the tines. The stent is being plastied. And once we have that, then we again aspirate through. And there is the MCA occlusion. We go across. There is the microcatheter being placed in the middle cerebral artery. And once we have that, we put a stent retriever. And once we have this stent retriever in place, we pull it back, and we get complete recanalization of the middle cerebral artery, before and after. So the big challenge with devices here when it's acute stroke is, what are we going to do about dual antiplatelet therapy? Number one. And number two, how are we going to protect this ruptured plaque from continuing to send plaque up north? And I think both those issues are very well addressed with the CGuard device because it's an open cell, low-metal surface area device, so you don't need as aggressive antiplatelet therapy as with a higher-metal density device. And second, the mesh allows a lot better plaque prolapse after the procedure. So again, I look forward, and hopefully, Marvin will be convinced that stroke is something that he needs to pursue. And I hope you guys will help them go in that direction. Thank you.

So I think I'm next. So hopefully, everybody can hear me. I'm Sean Lyden, I'm the Chairman of Vascular Surgery at the Cleveland Clinic. Can I get my next slide? These are my disclosures. Next slide. So I'm a surgeon. I do both TCAR. I do carotid endarterectomy, carotid stenting. I trained at University of Rochester, where Charles Rob came after he did -- done one of the first carotids in England. And so he was on the wall there. So I've trained at an institution where really carotid disease was developed in the United States. Next slide. Here's just an operative picture. This, I took from Norm Hertzer, who was the chair 15 years ago here at the Cleveland Clinic, and we still do it in exactly the same way now as we did then. So we may or may not put a shunt in. We scrape all the plaque out. Next slide. Once we're done, we may or may not tack down the end point. You can see how clean it looks. And then we patch the artery to restore it to normal size, or we'll divide it and evert it and complete as an eversion endarterectomy. But for the most part, carotid surgery is identical to the way we've done it for almost 30 years. We do more people under the local. But -- and we have better anesthesia techniques using narcotic-based anesthesia. And so the outcomes have improved, but the surgical technical aspects are pretty much unchanged. Next slide. So what are the advantages of surgery? Well, we can deal with really dense calcium. If it's a really tortuous arch, we can deal with that. What we can do, people awake or asleep. When I first got to the Cleveland Clinic, and we were leading in carotid stent technology, we had a summit with CEOs from everywhere, and I remember I get asked when I do a live case. Jay Yadav was doing a carotid stent on one camera. I was doing an endarterectomy on the other camera. And he goes, "No, look, my patient's awake. Kind of great this is." And everybody goes, "Ooh," "Aah." And I said, "Hey, wait, look my patient's awake, too. Look how awesome this is." So you can do it either way. And it's got great long-term data. What are the downsides? Well, there is definitely a higher heart attack risk. When we first saw that, when we first started doing the carotid stent trials with the SAPPHIRE trial, and we know patients do have cranial nerve injuries. When we look at registry studies, they say they're 2% to 4%, but you get independent neurology evaluation, they're definitely higher. Next slide. So TCAR's come along. And TCAR, basically, is a small cut down in the neck. So it's still surgery. It can be done under local or general anesthesia. And interestingly, most of it in the United States is still done under general anesthesia. And the difference is instead of now cleaning out the artery, you're getting a basically the equivalent of [ 11 French ] sheet then, and then drawing blood out of that sheet and then returning it through a femoral venous sheet. We're basically using passive reversal flow for protection. Next slide. So TCAR has really gained the huge interest of the vascular surgeons. And I hope none of the investors are vascular surgeons. But what I'll sit there and tell you, I think it has enabled the non-skilled interventionalists to do carotid stenting. Because one of the riskier parts when you're learning [ endo ] carotid stenting is coming from the groin and getting into the carotid safely without producing a stroke. In the original carotid trials, the ACAS and NASCET trial, the angiogram alone produced about 1% of the strokes. And right now, if you're involved in the Vascular Quality Initiative registry, you can do TCAR in patients. And so that registry is allowing the treatment of 40,000 patients in that registry, and it has grown leaps and bounds. The early results would suggest it's about as good as surgery. However, it's not a randomized study. So there are patients who you can't treat with surgery that you can treat with TCAR, and there's patients you can't treat with TCAR that you can with surgery. However, there's still cranial nerve injury. It's still an incision, and you can cause damage to the common carotid artery. So it is a great adjunct to what we have, but I don't think it's going to replace surgery in the long run. And I think most patients, if they had their choice and didn't have to have an incision in their neck, still would want. Next slide. So what are the advantages of TCAR? Well, it's covered if you're involved in the Vascular Quality Initiative registry. If you're not, you still can't do it. It avoids the arch. And someone for bad arch, that's awesome. I think it clearly allows easier access for less skilled interventionalists. And if you have a really tortuous internal carotid with a loop-the-loop, you don't need that distal filter. I would also say that Dr. Metzger, Dr. Siddiqui and I, myself, would also say that that's where the moment comes in. But it has been shown to have a very low learning curve. And so unlike carotid stenting, when we first started in the early 2000s, where there was a pretty steep learning curve, TCAR has been adopted pretty quickly with not a large learning curve. Some limitations. You need at least 5 centimeters from the clavicle to the internal carotid origin to be able to get that TCAR sheet in safely. You can have a big disease common carotid artery. You can cause some dissections in the common carotid. You still need an incision, and you still have cranial nerve injury. And my other job in life is I was the [ medical officer ] supply chain for the Cleveland Clinic, and I'm still the Chief Medical Officer for our GPO, Excelerate, and it's expensive. And so it costs a lot more than stenting or surgery. Next slide. So carotid stenting, well, we all likely do it, and we waited forever to get it in the U.S. The problem was in the early 2000s, there was a huge fear of use and abuse. And the surgeon, which I'm part of, we're terrified that it was going to take over one of our last bastions of things that we own and control. So because of the dispute between the surgical and interventional community, it was limited by Medicare to only approved trials and for approved devices. And we've all seen how this has limited the use of the technology and the dissemination of this technology. Next slide. So in 2005, it was really the first time CMS, to my knowledge, really, had a global noncoverage policy. So it really limits the carotid stent IDE trials and it limited to 70% symptomatic stenosis in high-risk patients with approved devices. So you can still be in a category B trial, but you had to be a site that had approved competency in carotid stenting, and we had to report our outcomes. Next slide. So you can only do it with approved stents, approved devices, cleared embolic protection systems. And if you couldn't get embolic protection system in, TMS doesn't pay you. Now maybe some institutions is not a big deal. This is a big deal to Cleveland Clinic. They're not really excited when we do things for free. And so if patients don't meet those coverage policies, we either have to get them to sign an Advance Beneficiary Notice saying they're going to pay the whole bill or we don't do it. Next slide. Can we get the next slide, Tara? So CMS has said, what is high risk? And so I'm not going to go through this, but you basically have to have a bad heart, bad lungs, a high lesion or low lesion or prior surgery, and you have to be symptomatic with a non-disabling stroke. So that sounds like not too big a deal, right? Next slide. The difference is it limits to what we do. And in my practice at the Cleveland Clinic, it's about 5% to 8% of our patients who qualify. Now in 2007, industry and physician leaders wanted them to add asymptomatic greater than 80%, high risk to coverage. We also offered mandating a surgeon evaluation and no coverage for those above 80% when the early CREST data suggested that maybe the older patients wouldn't do as well. And no coverage if no protection device is used. But really, CMS sort of rejected all that. They basically said, "You still have to use embolic protection," and rejected all those other suggestions. Next slide. So where do we sit today in 2022? Amazingly, no different than we were in 2005. About 10% of my patients qualify. It's the only disease process I do, where once I decide the best way to treat my patient, I have to look down the sheet and see what they have for coverage. And so if they're private carriers, some of them will mirror Medicare. Some of them will mirror the FDA labeling. And some just say it's all experimental, don't cover it at all. And the route this -- what this has done, it's stifled innovation in this space. Next slide. But what's changed? Carotid stenting, despite that, has undergone the most scrutiny of pretty much any therapy I know. And the difference is, since the last time we asked to change the coverage decision in 2007, there's been 4 large multicenter randomized trials with almost 7,000 patients showing equivalence to carotid endarterectomy in both procedure outcomes, long-term stroke prevention and durability. And I think we also have gotten really good as physicians in knowing who best to apply the technology on. Next slide. If you look at, over time, of all these trials, you can see the trials from the early 2000s to now, you can see that the procedural stroke and death rate has continued to improve because we're getting better and better as figuring out who to use this technology on. Next slide. We spent forever trying to talk about closed cell and open cell. And as Chris and Adnan talked about, closed cell has better area of coverage. So there's not as much area that the plaque can come through. Whereas open cell tend to have a bigger area, and it allows for better conformability to the wall. So in closed cell, all the cells are connected. They're smaller cells, but it tends to be stiff. So -- and a tortuous army doesn't work well. And then an open cell design, some of the cells are connected. Those are larger cells so they have the ability to prolapse, and they're more flexible. So most of us have gone to say, well, some of the data suggest close cell designs are better for stroke prevention. And so we generally use that any time we can or in straight anatomy. In open cell, that can -- has tortuous anatomy. And unfortunately, there's no ideal stent, and there's been this debate going on for 15-plus years. Next slide. So my opinion, and many experts', is that carotid stenting now should be not just for high-risk patients. From the CREST outcomes, stratified by symptoms, we know that for greater than 50% symptomatic and 70% asymptomatic patients, there was no difference between carotid stenting and carotid endarterectomy for the primary end point of death, stroke, myocardial infarction in either subgroup who was 5.2% versus 4.5%, with a hazard ratio of 1.18. And you can see the confidence in general. And there was almost 1,400 patients that were symptomatic and almost 1,200 asymptomatic patients. So a humongous trial that has reported outcomes. Next slide. Since that last update, there's a bunch of new trials. So the difference is now we have the really long-term actions from CREST. ACT I, which was a randomized trial, surgery versus stenting, really, once again, showing no difference. The SPACE-2 trial, carotid endarterectomy versus carotid stenting and medical management, no difference. And the ACST-2 trial just reported last year with almost -- over 1,800 patients in both arms was once again, through late outcomes, no different. Next slide. So if you look at that, we now knew ACT I data to 5 years. And you can see that any procedural stroke for carotid endarterectomy, carotid stenting, no difference in the p-value; SPACE-2 through a year, no difference; ACST-2 through 5 years, no difference. Next slide. So what do we know now? We know that if we look at their arch, if it's really that the artery comes off at the top of the arch, it's easy to get into. So the far left screen would be a type 1 arch, the far -- middle screen would be at -- more of a type 2, where the far right, as we knew, would be a type 3. So this would be one that only someone with a lot of skill might undertake, where you might be able to do surgery on this patient or TCAR. Next slide. We also know that there's clot in the arch. Or if there's a bad arch, you can still stent people, but it's a lot harder. You're going to have a lot more difficult risk. You can see in this patient that the sheet has kinked. Now the delivery of any of your protection devices can be much more difficult with a higher risk. Next slide. The other thing we know is that what are your landing zones. So you can see a patient here where the external carotid is out. So then using the MoMa, where trying to get your sheet in is a little bit more difficult, but not undoable. If the patient has a very straight landing zone, that's also great. But if there's a loop-the-loop or tortuosity, then trying to place your filter in that is going to be more difficult with more fraught complications. Next slide. And we also know that if it's densely calcified, like this picture on the left, if it has ulcerations like the middle picture, or if it's really, really tight like the picture on the right, that pertains to a higher risk of adverse events with carotid stenting. And skilled -- and still, it can be done safely, but higher risk. Next slide. So what's the advantage of carotid stenting? Definitely, there's a lower MI rate. I'm a surgeon, but it doesn't take anybody to commit to the patient. No scar or a scar, percutaneous is better. It has equivalent risk of stroke and death the carotid endarterectomy. It has an equivalent risk of restenosis to carotid endarterectomy. And the best types in -- of anatomy to treat, I think, are well defined. For much better, both distal and proximal embolic protection works. We also know that still densely calcified lesions aren't perfect. Transversing arch isn't perfect. And what we talked about, you heard from Dr. Metzger and Dr. Siddiqui, we know that we can have post dilatation to get the artery open. But that's the time of most embolization and that plaque starts to protrude through the stent, but that embolic risk continues, as Chris showed you, for some time afterwards. And we know that it leads to both silent brain region -- lesions by MRI that are higher than carotid endarterectomy. And the problem is that up until about a couple of years ago, in the United States, there's been no real development. Next slide. So if we look at some of the approved devices, whether open cell or closed cell, and you look at the area for a piece of plaque to go through, you can see that if you were a circle plaque, they're all about the same. But that's in a straight artery. If you start having a bending artery for an open-cell design, that plaque starts to -- we have a bigger area to go through. But there's not a big difference in the large inscribed circle between the closed cells to the open cells. But if you start having some tortuosity, that can make a difference. Next slide. So what's got me excited? It's the micromesh stent technology. There's been 3 versions that have come out, but they're not all the same. So some of them elongate and then have to force shorten when you place them and don't necessarily appose the plaque really well. Some of them have had higher thrombosis risk. And I'm not going to go through the same data that either Marvin showed you or Chris or Adnan showed you, but this micromesh from the CGuard from InspireMD is -- it has the largest amount of data set up. Next slide. So we've heard that -- from CREST that surgery is equivalent to stent. But amazingly, they've even spent time trying to study their stent, the CGuard stent, against the Acculink stent, which was the stent used in the CREST trial. And so if you look here, when people had CGuard or Acculink in a randomized study, there was much less event rate in it. And so not only do you say, well, we have a registry comparing one to the other. This was actually a trial looking at the two. This was just published last year in JACC: Interventions. And I think this is one of those studies that really got me excited. And I think this is where this company is very well positioned because, hopefully, we'll have this stent approved the United States soon. Chris is a national PI, both Adnan and I are sites. I've used this clinically. It works really well. I've seen the data from Europe. It is very strong and powerful. But the advantage to me of the micromesh stent in this design, in particular, it conforms to the vessel because it's basically an open-cell stent design. It's going to stop plaque protrusion, not only at the time of post dilatation but outside of that because of how tight the weave is. Next stent -- next slide. There are other technologies out there, one is the Neuroguard protection device. And so that puts a second filter in, and then you deploy the stent, and you can post dilate the stent. That will help protect any emboli while you're ballooning and placing your stent. But as Chris showed, a lot of those events happen later in that. So although this is a new technology, hopefully, to address some of those needs, I don't think it's going to have the impact that the micromesh stents do because it's only going to help stop issues right at the time of stent deployment and post dilatation. Next slide. So where are we at? I think carotid endarterectomy and carotid stenting has matured. I agree with Chris, there's a lot more enthusiasm for carotid stenting now. And I believe, and we're pushing to get CMS to relook at the NCD to cover for both greater than 50% symptomatic and greater than 70% asymptomatic patients, just like they do for carotid endarterectomy. I think we've really spent a lot of time defining who best to use carotid stent technology over the last 20 years. TCAR is a great approach. It does have a role. I'm not a huge TCAR enthusiast, but a lot of my vascular surgery friends use it almost more than surgery. And so, I guess, part is this stent technology can be used there, too. And we've clearly seen, now in the last year with this company, advances in stent and protection strategies. And I think that's going to continue to improve our outcomes. And so we definitely now know that the micromesh and some versions are better than the standard stents. And I can say the 3 of us are all excited to hopefully have this in our hands to use as we want, how we want in the United States soon. Thank you.

Great. Thank you all. Thanks. Those were terrific presentations. So I think we'll jump to some questions now, if that sounds okay to the LifeSci folks. Tara, is that your expectation?

Yes. That sounds good. Thanks, Marvin. At this time, we'll be conducting our question-and-answer session with our speakers, that will be moderated by Chuck Padala of LifeSci Advisors. [Operator Instructions] Please go ahead, Chuck.

I think I'm going to steal the microphone from Chuck here, Tara, if that's okay. So let's take a step back into the economics here. Each of you -- each of the physicians on the call have been a part of this multidisciplinary group advocating broader coverage for carotid stenting. And CMS seems to feel -- seems to be favorable in the idea. And I think that's a big change, as you pointed out, Dr. Lyden for many years. How do you see the impact on this progress for broader use of stents with standard-risk CEA patients? And how do you feel, since you've been through this a number of years, that this is progressing? Do you think it's imminent? And once it does, how will that impact more stenting?

So the last time in 2009, when CMS last put it out there, they said they wanted more data. They wanted long-term data. So we have more data. We have long-term data. We have equivalence data. There's a huge push with health disparities, and these things affect patients of lesser means more than patients who could just say, "I have the money. I can pay. Give me what I want." I think it's really -- right now, we know who should do carotid stenting, how to do carotid stenting, the best ways to do carotid stenting. And I think it's time to take it out of a National Coverage Decision and put it in the hands of clinicians and hospitals for credentialing committees to look at outcomes to say, "Can you do it? Should you keep doing it?" And I believe CMS, because of the data we have, will be responsive to that.

Okay. Yes, I would briefly echo that, Marvin. I think that now, when they ask for data and now it's provided, and you have 4 carefully done published randomized trials directly comparing carotid endarterectomy to carotid stenting, in all 4 of their equivalent strategies, there has never been in the history of American Medicine a mandate to get to more invasive procedure when the less invasive procedure may be preferred by their patients and subsidiaries and where there's equivalent. So I think, faced with this data, they now -- and there's like more and more folks are wanting carotid stenting, even the surgeons are embracing it. I think that we'll -- you can never predict governmental agency, but I believe that they're well intentioned. And I think that I'm very optimistic, let's put it that way. And if so, Marvin, in answer to your question, what will that do to access? Now, all of a sudden, those that weren't doing it because of some things that Sean talked about, will now have the choice. And given the choice, I think a lot of operators are going to choose carotid stenting. And I can tell you, from a long career, there's patients, given the choice, if either 1 is equal, out of 99 or 100 times, they're going to choose a stent. So if both options are there, I think that this will really change the technologies we use in the reimbursement in a number of folks being treated with the strategy.

Great. I think we have Dr. Siddiqui still on. There was a question specific to that area of acute stroke. So if he's there, I'll see if I can ask this question on behalf of the author here. So in this field of addressing acute stroke and specifically this tandem lesion indication, if you can share your thoughts a bit more on the possibilities of how CGuard fits into that setting and also the future indication. But more importantly, do you feel that this will unpin some additional growth with transfemoral stenting with this indication? Obviously, it's a transfemoral approach if you have thoughts on that, if we still have Dr. Siddiqui. If not, I can jump to another question. Okay. we'll hold that one then for a moment. This one comes from some of the analysts. Why will carotid stenting really take off with only equivalent rates of stroke, death and revascularization? So that's to the broader group.

So as a surgeon, I'll sit there and say that patients are afraid of surgery. And even a surgeon, if you see a surgeon claiming it works really well. If you look at what's happened and then the vascular [ and tissue ] repair, when you could fix it through punctures percutaneously, we've seen a shift with equivalence of early outcomes with even still maybe inferior late outcomes, 85% the world market is done with endovascular needs. If you now have equivalent outcomes for carotid stenting, I agree with Chris. I believe they have an equivalent choice. I'm pretty sure most of my patients will choose stenting over surgery. I get so frustrated. I have to look at their insurance, instead of saying, "Oh, I got to cascade it. No, you're really calcified. You're going to go have a surgery. Or you have a type 3 arch, you're not going to be great with a transfemoral approach, then I can do a TCAR or surgery. And I think it really -- it should be up to the skill set of the physician you see because not every physician will be able to do all 3 options. If -- Chris is probably one of the most amazing carotid stenters I've ever seen. And if he said I was a good candidate for carotid stent, I would let him carotid stent me. I mean, I think that's the difference. When patients can have a say in what they get and the surgeon or interventionalist feels it's an adequate therapy in their hands, we should be able to do it.

So Sean, first of all, I'd gladly stent your carotid, just so you know. Thanks for the nice word. But I would almost turn the question around, Marvin. If they're both equivalent, why wouldn't you choose the less invasive? You don't need -- so just not just the procedure. Remember, there are cranial nerve injuries and others go along with surgery. There's anesthesia and anesthesia risk. There's a time, the length of hospitalization and so on. So if both therapies are absolutely equivalent, not just short term, but long term, we have 10-year plus data, that's their equivalent, okay? Why would you choose a more invasive, unless there's an advantage to the more invasive? Sean and I and Adnan, all would say, if there's heavy calcium, as a chronic stenting enthusiast, I would still be the first to call the surgeon. And Sean, just so you know, if I've got calcium up here, you can do my endarterectomy, okay? But I mean, honestly, if there are equivalent therapies, most people are going to choose the less invasive, and that has been shown time and time and time again. We're talking about leg interventions, as Sean said, aneurysm, even the surgeons are choosing it 85% of the time. If they're equivalent, everyone will migrate more towards the less invasive, going home sooner with less comorbidities on.

Great. So this is another question from one of the analysts out there. It's kind of a 3-parter, but maybe you can comment on all 3. Is there another situation that you're aware of where a device that has not yet gained regulatory clearance was included in a major study like CREST II? Obviously, referring to our recent announcement with CGuard. Why do you think the investigators sought or are willing to use and include it? And what's your view of the likelihood of a favorable NCD, given study results? And finally, in your practice, what portion of patients could be candidates for CAS? So we want to chew on there, but if you could...

So in terms of CREST, TCAR got added to CREST as well. It's not also approved. And so the CREST investigators have done a really good job making sure that for CREST-2, we're using what we would consider up-to-date good technology. And it's not like there's not any data with the CGuard device. As we saw, there's been 1,600 patients in clinical research trials studied over a long period of time, just not in the United States. And so I think the -- I can't thank Tom Brott and the people running CREST-2 enough that they've allowed -- so we can sit there and say, "Oh, it's done now. But we're using all that old stuff that's not as good if we use the new stuff, it'd be much better." And so the trial has done this before, and they've really kept up to date to make sure we're not seen as completing a trial that's well past its prime with meeting old technology.

I would take a slight, slight exception at that. The only thing about differences about TCAR, TCAR is FDA approved, okay? So Marvin, I would say that this is unprecedented, what they've done for the trial. In other words, they've taken something that is not -- that's going through the PMA trial, the IDE trial. And before that result is out there. they believe that the technology is favorable enough based on the European data that Sean just mentioned. And the technology that they made, as far as I know, an unprecedented decision to say, yes, it can be included even before it's FDA approved because we believe in the technology. So I think that part is a really strong statement on behalf of. I think you're right, Sean, they're trying to do everything they can to make sure that any really good technology is offered as part of the trial, whatever the arm is. But I think that this is unprecedented in terms of a non-FDA-approved device that they've chosen to allow.

Great. So we're rolling up to the top of the hour here. I guess, for the purposes of time, we'll leave it at that. I don't see any other questions that we didn't cover, which is great. I just want to thank you, gentlemen, again, for participating today. It's a pleasure working with you day to day. And it's been our pleasure to have you on board to make sure that there's a full understanding and education of what's happening in the carotid market. We're building a company specifically to address this market. And so we have a lot on the line, and we think it's a very good bet to place because it's time for major standard of care change. So I just want to thank everyone for their participation today, and best of luck.

It's a pleasure. Thanks, Marvin, and everyone.

Thank you all.