What's Next for Renal Denervation? | LSI USA '25

Lisa Carmel  0:05  
Uh, so we're going to be discussing what's next for renal denervation. And I, we're going to go down the row and introduce ourselves. Howard, do you want to kick it off?

Howard Levin  0:14  
Sure. My name is Howard Levin. I'm the CEO CMO of Deerfield Catalyst, but was one of the founders of renal denervation back in the day.

Karun Naga  0:24  
Good afternoon. I'm Karun Naga. I'm a partner at the foundry, and going back many years, partnering with Howard and Marc elfend at the foundry, we coined the therapy for renal denervation through our vehicle, which was Ardian that sold to Medtronic in 2011 for about 850 million. 

Jie Wang  0:45  
I'm Jie Wang, the founder and CEO of CMAP, and we did a first cohort of five innovation rd and patients in China, Nanjing with Han Sen and Howard together.

Lisa Carmel  1:02  
My name is Lisa Carmel, and I've been on steering committees with Howard For Mayo Clinic innovation summits. The next one's the cardiology radiology Innovation Summit. So pleasure to be here. So we will jump right in. I thought I would just throw up question and and you can jump in and respond as as you like renal denervation has faced significant challenges, but appears to be turning the corner. And we want to know, do you agree, or and, or what key factors are contributing to this shift?

Howard Levin  1:41  
Well, I think that, yes, it's turning the corner. I think that's evidenced by the fact Medtronic has approval. Ricor has approval. There's a national coverage decision for insurance coming up that looks like that will open up things a lot. Jie, besides doing some of the early work with us in in real innovation, has a current company called C map, which has a new renode innovation mapping catheter. And hopefully he'll, you know, talk more about here. But my opinion is things are broadening out for practical reasons. You know the data is starting to you're really look solid and repeatable, as well as reimbursement. What do you think? 

Karun Naga  2:28  
well, absolutely. I mean, the regulatory reimbursement boxes have been checked, but now we move down to the next phase in the spectrum of risk. And I'll say market, market development is a open area. I think we presumed for many, many years now, 20 years, that the market is huge, which it is. We know hypertension is a silent killer, and there are millions of people that have it, but most of these patients are sitting with a prescriber that is trying to optimize the management, you know, through drugs and lifestyle modification, at some point, these patients need to get referred to an interventionist for a minimally invasive procedure. And I think that's, that's a big hurdle. There's a lot of work to do still to get those patients to providers that can help them with this new therapy. So, yeah, I think, I think there's been great progress, but still more work to be done. 

Jie Wang  3:23  
It's very interesting, because we thought if we change the rdn indication from heart failure to hypertension, we can have shortcut by them, but we never expect once we do hypertension, it's even more tough than heart failure. We can talk about this later. And finally, RDN, from a topic in the academic meetings to real practice in real world. What we can see here, because we start to sell our device in China is approved last year, August, Starbuck at a cell, December, 2024 and what can see the responses from the patients and also from physicians, are much more than we expected, because we see the significant drop of the Blood pressure on those patients, to our surprise is bigger than what we thought, because we believe there are three factors add up together. Number one, the placebo effects, plus the therapeutic effects. Number two, because we did mapping ablation, therefore we can further increase the responder rig. Number three actually is also very interesting. In the clinical trial, those patients already on three, four, even five drugs. Therefore you add one more therapy, you don't see much effects. But now this patient said they had 345, drugs, actually they did not have therefore they. Where you put your rdn therapy on, you'll see significant drop on their blood pressure. That's what we have learned so far.

Lisa Carmel  5:11  
I'll move move on to the another question here about, as you had mentioned, real world medicine. Real world clinical medicine, renal denervation is now entering this arena. What do you think are the primary clinical benefits driving this adoption?

Howard Levin  5:29  
Well, I think from the clinical point of view, as a cardiologist, you know, as coon said, as a silent killer, and you know, the hardest part is to get people to understand that by treating something today, in the long term, there'll be a long term significant benefit to them. You know, people want to see I had something done and you know, I'm immediately better. And the benefits of reducing blood pressure, while you may reduce blood pressure quickly, the benefits can take a long time to see. So I think more of that information is getting out, but the market, getting that market information out there and driving it and putting it out to the patients. You know, a lot of the focus has been on getting data to show it worked. Now I think we have to put more effort into, you know, getting the average clinician to understand what the potential benefit is, I don't know if you agree. Well,

Karun Naga  6:26  
yeah. I mean, I think a non implant medical device intervention to take a big bite out of chronic disease is a very big deal. And you know, Pharma has had their shot at fighting and defeating hypertension. And you know, with meds, they've been able to do fine and well, but we know, I mean, the first patients we ever treated were, you know, had refractory hypertension, and they struggled the side effects of those drugs, the combination of those drugs and those interactions. For some patients, it was incredibly debilitating. So to be able to go in take some of that burden off is a very, very big deal.

Howard Levin  7:07  
And you know, just if I remember, Jie published a paper on Houston C map approach on looking at the reduction blood pressure. I mean, you can look at it two ways, and I think this is one of the clinical adoption issues that come in. As Karen said, you know, you can either reduce blood pressure, or you can bring blood pressure, you know, maximally, or you can bring blood pressure down to what's an acceptable cut off and reduce the drugs. And so I think Jie's trial was the first one to show that that that actually occurred, is that true or correct?

Jie Wang  7:46  
Once you introduce rdn to a patient, he must ask two questions. Number one is, how much my blood pressure will draw, and also after therapy, should I take off my drug? Therefore those two questions clinically the same, equivalent, important. Therefore we design our study use combined primary outcomes, which is the control rate of blood pressure and also the reduction in the drug burden. There's another very critical reason we designed the study like this, because no matter recro study or spiral study at six months, they don't see the drop in blood pressure between a shame and treated group. In other words, the primary outcomes failed. The reason for that because there is no way you can control patients, particularly from shame group, do not take anti hypertensive drugs because they have high blood pressure. So once they take drug, the differences between these two groups abolished. Therefore our trial is we force physicians after the therapy, justify their anti appendix drugs in order to reduce blood pressure less than 140 and then we made a comparison between the two groups in terms of drug burden. Therefore we can see the differences between the two groups at the first time we suggest this concept the people laughing at bars, but now it's become standard in the practice we have to look at drug burden.

Lisa Carmel  9:51  
Well, I think you may have answered my next question so telepathically. But here we were going to talk about the CMAPs clinic. Trial and how it different, differs versus previous studies.

Howard Levin  10:04  
So I wanted to make one comment on that, because, you know, maybe Karen thought of it. I certainly didn't think of it at the time. What the smart study, which I think was the name Jie's Jie study, was, did something a little different than your average simplicity or ReCore approach. It it mapped. And as soon as I say, map, I get really nervous, because I think, and I think a lot of people think that it's going to take forever, you know, you spend a lot of time mapping this, and then whatever, in reality, because of the way they do it and the device that they use, which is integrated into the ablation, it reduces the number of ablations from 40 in RF to four. And there's a couple other things that I just want to say that hopefully Jie will comment on. So number one, the reason it reduces from 40 to four is they don't have to do the side branches. They found that in the main renal artery, there are three types of spots, hot spot, which, if you ablated blood pressure, goes down. Cold spot, which is if you ablated, blood pressure goes up, and neutral spot, which means it doesn't do anything, but you've taken the time to ablate it, and you have the risk of stenosis or other problems from the ablation. So and they found that if you ablate a hot spot. Sometimes you have to ablate it twice. This is one of the big problems that we had originally with renal the innovation is the technical success thing. So not only does this give ability to do better therapy, it gives the ability to have some technical success. Last thing I want to say is ultrasound is nice, but when you blade, you blade everything, including the cold spots. And I think that's why there's a difference in efficacy. Jie,

Jie Wang  12:12  
okay, let's look at the data first. Let's look at the data from Sparrow study and also from Maria core study, no matter how many spots or ablation sites you do, men plus branch and branch only or men only, the responder rate is around 60, 65% the reason for that because around the renal artery, as Harvard said, three different types of the renal nerves, sympathetic, parasympathetic and the sensory. The percentage of sympathetic is about 70% parasympathetic, about 20% sensory, about 10% therefore, if you do blind ablation, the probability to get sympathetic nerve is around 60. 65% is the beauty explanation or reflection of the basic science to clinical practice. That's why, if you look at those unmapped clinical results, 30% of the patients either are non responders or their blood pressure went up after the therapy. Therefore, we believe mapping is unmatched, urging the clinical need in the renal denervation field, any therapy you need, diagnostic and treatment, just like in the PCI in the past, we do not have FFR. Now, today, we have FFR. That's equivalent our mapping selective denervation. Based on this anatomy and physiology, we designed this catheter which can do both stimulation and ablation. We put a catheter into the renal artery all the way to the distal we deliver an electronic stimulation if we see increase in the blood pressure. We name that hot spot. It's replanting sympathetic nerves. We ablate. After ablation, we deliver the electronic stimulation again. If you need not see increased blood pressure, we know is effective ablation. So it gave the physician the feedback during the procedure, if we still see the increase in the blood pressure, we do a second ablation. So we use this mapping ablation confirmation approach, start from distal to proximal to treat the entire D. Renal men artery,

Karun Naga  15:02  
yeah, I think diagnostic guided thermal ablation denervation is critically important because if you're flying blind, then it's very simple. You know, you're ablating tissue, you're destroying tissue. There's an SAE profile with that. But the extent of your denervation is usually tied to the extent of tissue destruction and ablation. So your safety and your efficacy are kind of at odds with one another, unless you can be smarter about it, and so having a diagnostic that can help you be more selective of the tissue that you ablate is one way to do it. We looked at during the Ardian days had many different modalities for how you can denerve it. Our first, actually preferred modality was what we call irreversible, irreversible electroporation. Now that's called today, pulse field ablation. And we thought, hey, we could pulse nervous tissue selectively so that we could preferentially ablate that tissue and spare the vessel wall from unnecessary damage. Very elegant approach. We struggled to make it work, and so then defaulted to thermal ablation. But within thermal ablation, there are many different modalities, from RF to ultrasound, microwave, cryo, and each one has its pros and cons.

Lisa Carmel  16:27  
So I think this we're all this is flowing right into the next question about the choice of technology platform, and does it significantly impact the effectiveness in the adoption of renal denervation, and what are the pros and cons of the currently approved energy platforms?

Karun Naga  16:48  
Sure. Well, I mean, obviously right now we have simplicity and re cor simplicity is, you know, RF electrodes to generate heat that through conduction is going to penetrate through the renal artery wall to hit the renal sympathetic nerves and achieve denervation that way, ricor it's it's ultrasound. So in theory, the the energy waves are penetrating and being thrown outside of the vessel wall, so that more of the energy that you're communicating to the tissue is hitting the nerves and that tissue outside of the vessel wall. So these are both through the clinical trials that have been performed. Are very effective and safe ways to go. There may be better, more elegant approaches. And then again, I think to Jie's point, you know, once we have better tools to understand what are the best targets for ablation, then it's going to become a little bit clearer what might be the best modality. I know there are drug delivery companies, at least one company, infusing alcohol into the annular space where outside of the renal artery, where the the nerve fibers reside. So I think there's a lot of very interesting approaches, but we have to see, really, at the end of the day, how do you optimize both safety and efficacy, and that, there's still some work to do here to figure out what's optimal,

Jie Wang  18:18  
right? It's not. Is not only the alcohol also people try Korea and however, as far as as I can see, that any devices design have to base on the anatomy and the physiology the renal nerve around the renal artery. Therefore, whether we should do branch or branch plus my artery or mental artery only is not really the question physiology or anatomy basis preference is really the combination of anatomy, physiology and the device designed, preference,

Audience Question  19:08  
please. I don't think there are many of us here. And I also treat the resistant hypertension in a major hospital. I'm not ready for you guys. I want to see the outcomes. I want to see the statistics. I want to see survival. I want to see the Kaplan mayor. And I think what you guys are doing is a very blessed but there's a long way to go until a guy like me is going to say, Mr. Jones, you're going to have an ablation. I want to see more, more statistics, but congrats on the day, on the I think, seminal work that you mentioned identify what fibers do, what Wow. It's a big deal to put that in practice. 

Howard Levin  19:50  
So really appreciate that. Thank you for those comments. Certainly you know you always. Would like more data before clinically you're going to put people to a certain thing, and there's always a bell curve of early adopters and late adopters. But to address your question, I think there are now three year data on certainly showing no complications and showing reduction in maintaining of the reduction blood pressure out that long. So one could argue, Hypertension is a chronic disease. We'd like to see, you know longer data and certainly so. But you know, if you have somebody with very high blood pressure who are not responding to meds and actually taking them, there may be a role for doing an intervention earlier in that particular group, as opposed to, you know, your average person who's doing okay on some meds and stuff like that. I mean, one of the things that I used to hear, and I don't know if you guys have heard the same thing people. There are some people who say, given the choice of taking pills or having a one time procedure, if, if it got me off all my pills, magically, I would really like to do that. And you know, then there's the people that are very high and want to come down, even if they have to stay on pills. So I think there's a big potential opportunity, if one could prove it, to try and get people off meds. So I don't know if, from your market research, you sort of same thing, or

Karun Naga  21:40  
Yeah, I honestly Howard, I think it's a TBD. And this goes back to the point on market development. I think, I think there are segments of the patient population that will find this very appealing, and whether it's a compliance adherence burden or challenge versus, you know, a need to really definitively address the risk, downstream risk associated with this chronic disease. But I don't think we know yet, you know, and I've had, I mean, in the early market development days, you know, we talked to, you know, these diagnosing, prescribing physicians who we want to become referring physicians, and they say, What? What do I as a referring physician have to conclude for me to refer a patient for a surgery when, if the patient does what they're supposed to do, take the meds on time, make the lifestyle modifications, they they'll be fine. And so it's a high bar, in my view, but there are many other areas of medicine where that bar has been met, and there is a very robust market. It's just time will tell

Jie Wang  22:50  
to answer this gentleman's question. The data already showed, after 10 years of the therapy in small group of patients, 100, 200 patients, they still benefit from the procedure. Okay, 10 years, and also Medtronic, they have another program is follow 5000 patients for five years to look at the safety and efficacy of the therapy. So that's data number one, their data number two is if you have reduction in the blood pressure by five or 10 millimeter mercury, even for one or two years, you are you mobility and mortality, for instance, heart failure, stroke, decreased by 30, 20% okay, that's number two. Number three, the survey showed most interestingly across the board, no matter their age How many pills they take, about 30% of patients want to have a surgery. Okay, particularly people come to the physician's office the first time they never take any pill. This group of people, they have most willing to take procedure 57% so you can see the demanding from the patients and the clinical practice they really need. Okay, I don't know whether I answer your question or not.

Lisa Carmel  24:35  
How about we I'm keeping an eye on the clock, so I'm task master, so I'll move along here. Thank you so much. No, thank you so much for your question. We look forward to more questions at the end here too. So do we want to discuss practical advantages of mapping versus non mapping approaches in addressing unmet clinical needs in renal denervation?

Howard Levin  24:57  
Sure. I mean, I think Jie is the one to. To to talk about it. But the thing that I took away, and I was a questionable believer in the need for mapping, and the fact that it would add time, you know, my concern that it would add time to the procedure, whatever, but with the finding that there are hot and cold spots, and with the finding that if you map, it takes the same amount of time, same amount of contrast, and you end up getting as good or better results, you know, I become a believer in that. I mean, more, of course, data needs to be done, but you know, it's, I think it's, it really behooves us to look seriously at at this question,

Jie Wang  25:56  
data must speak in the self. Let's look at the data. Medtronic, they need to ablate all the branches. So they do 4050, even 70 ablations. Therefore they need to shoot a contrast to identify all these branches. However, once you do renal artery ablation because you only do the my artery, therefore the time is very comparable to Medtronic branches plus my artery ablations. Medtronic data showed the per procedure needed about 99 minutes our mapping selected innovation is about 70 to 80 minutes. Once you look at the record, data, record only tell you the part of a story. They said once they put a catheter in, you need only eight seconds. But however, they have seven different sizes of the catheter. In order to put a proper catheter in the proper location, you need to switch the catheter all the time. Therefore their procedure time is also about 70 minutes. So if you look at the time, it's very comfortable. However, we use much less contrast. Medtronic study used about 200 CC contrast. We use about 70 CC contrast. That's the data.

Karun Naga  27:34  
You know, obviously the goal here is to optimize clinical outcomes. But as we think about real world and what's scalable, have to think about the call point the interventional cardiologist is not quite an electrophysiologist. We know that in cardiac ablation treatments for atrial fibrillation, for example, there's a great deal of patients and time invest in these procedures. But Jie, you mentioned like PCI, right? We know that you know interventions in the heart, they're pretty straightforward in that, okay, you have a hemodynamically significant occlusion, and you need to resolve that. You go in, you do it, and you have confirmation that you've had success, and then you can move forward. I think that's the quintessential procedure for an interventional cardiologist, but now, when you're asking them to do many ablations, and, you know, add five times, 10 times to the procedure time compared to what they're normally doing, that's going to be quite challenging, and it's going to impact adoption. So we'll have to see exactly which types of cardiologists are willing to have the patience to move forward with with this type of procedure, which is a little bit different than what they're used to. 

Lisa Carmel  28:44  
Jie, you know, think about in follow on to what you're just saying in real world practice, how important are clinician skill level and patient anatomical differences in achieving successful renal denervation outcomes

Jie Wang  29:03  
without map, without mapping, and which is, which is a, basically a blind procedure, okay? Basically, you look at the renal arteries, you find all the branches. You blame them all, and then you ask them. You said, What did you do today? So I don't know. Let's wait. Let's see tomorrow. Let's see the week after tomorrow. Let's see, you know, two or three months wait from now, therefore that is no feedback procedure. If you have mapping, you have feedback during the procedure. You know you did effective ablation or not effective ablation. Interestingly, so far, because the therapy already in clinical practice, we clearly see with mapping, the reduction in blood pressure is almost immediate. You can see the reduction in the blood pressure de. Day two, day three, a week after procedure. But however, without mapping most of the patients, you have to wait to see the reduction in the blood pressure. That's a huge difference between mapping and mapping. So physician love to have something they can assess their procedure results,

Howard Levin  30:28  
I agree with Jie. 

Lisa Carmel  30:29  
Okay, so what currently matters most to clinicians and patients in the real world setting, are outcomes more focused on reducing medication burden, or are there other factors that are equally important? IE, you know, is reducing the drug burden enough to be for this to be an accepted therapy?

Jie Wang  30:50  
You know, ideal world, if I'm a patient, I would like to have my blood pressure control and also take my pill away. Okay, that's an ideal war, but however, is very hard to achieve that. From our study, we can see about 42% of the patients after therapy, they can take their drug away, but not totally. They can take one or two drugs away, but still have the blood pressure control, then less 140 that's the data we have.

Lisa Carmel  31:31  
Karun or Howard, let's talk reimbursement. What's the current reimbursement landscape for renal denervation? And what do you see are some of the challenges and opportunities that exist for broader adoption.

Howard Levin  31:44  
I think that one of the big problems was the fact that it was on a case by, you know, state by state, you know, group by group basis. And if this national current coverage decision comes through, I think it opens up markedly the the opportunity for people to use this more. You know, across the board, what do you think?

Karun Naga  32:07  
Yeah. I mean, you know, Hypertension is well known as, again, we say Silent Killer, not because you necessarily die of hypertension, but a downstream consequence of that, heart failure, stroke, etc, etc. And so reducing blood pressure as a proxy or surrogate for the downstream cardiovascular events, I think, is critically important buy in for making that coverage determination. I think reducing burden on drugs when most of those drugs are off patent and don't cost anything, is a very more difficult and strained argument. So I think we just have to double down on, you know, the belief expectation that reducing blood pressure over time, and you do take the compliance burden away leads you to more reliable incomes and outcomes in the long run.

Lisa Carmel  33:07  
Okay, well, let's see. We've got around five minutes left, and I thought we could do a quick what? What do you think we do? A quick last question, and then take some questions from the audience. Is that good? So now looking ahead, what do you see? Are the new directions or potential indications that could expand clinical applications of renal denervation beyond hypertension?

Howard Levin  33:34  
I mean, we originally started with heart failure, and if I have the story right, and Karun can probably tell me if I have the story right here. You know, we, the original patients, were hypertensive, because one of the options we thought could be was that it could reduce hypertension. And so in order for safety reasons, we took people who were a little higher with blood pressure, you know, and had heart failure, we were looking for diuresis and stuff like that. And strangely enough, there were these huge reductions in blood pressure. And the board made a decision to move towards the hypertension rather than heart failure. But I still believe we can treat heart failure, and I think there's some data out there to support it. I still think we can treat chronic renal failure, or nephrologist colleague in the audience will have a seizure over this. Thank you very much. And but I think there are other things that people have done, reducing autonomic tone in general, to treat reduce the risk of afib, things like that. Are also other opportunities. And, you know, Medtronic, I believe, has said former what was, what was mentioned earlier is that, you know, they're looking at multi organ, or thinking about multi organ de innervation as a way to do it. So I think we're. Still early and at the forefront of many of this, many of these things, and a lot of work needs to be done, but we've certainly made huge steps and have answered a bunch of the important questions.

Karun Naga  35:13  
Yeah, you know, we're 20 years in now, and there's still a lot to figure out, just within renal generation is love, as Howard said, I mean, heart, kidneys, Central, sympathetic tone that could impact insulin resistance, so maybe could modulate metabolic disorder. At one point, we said, maybe we'll call this company panacea, because they can touch everything. But we had to focus on one indication, and we're still working to get there and defeat that one. But I think it's opened up a lot of people's eyes on the impact that you can have by modulating nerves from inside a body lumen without an implant. And so it's inspired other companies to be formed to do lung denervation, hepatic artery denervation,

Howard Levin  36:06  
set point, not innervation, but stimulation. Yeah.

Karun Naga  36:10  
So I think, I think, you know, this is part of the discovery process. Is you find a niche to scratch, you keep scratching, and then you see what else comes a bit. So I think one thing that I am very proud of what we did at Ardian was a great commitment to science, doing the research, contributing heavily to thought leadership, to inspire more more ideas. And I think there's a lot more to come.

Jie Wang  36:38  
People may or may not realize renal denervation is very specific case in the device therapy to treat cardiovascular diseases. Most of the devices treat diseases by physics, but however, renal denervation is treated diseases through pharmacological or physiological pathway. It's a very unique case. Therefore, any diseases with high sympathetic tone as pathogenesis could be treated by renal denervation. That's my point of view. And however, on the other hand, renal denervation still in the very early stage, just like drug eluted. Stand before drug eluted, stand is a bare metal stand Money, money issues have now been addressed. Money, Money questions have now been answered. So we are facing a great challenge still.

Lisa Carmel  37:37  
Okay, well, we have time, I think, for one question. Does anyone else have a question they'd like to ask? Sure, come on,

Audience Question 2  37:50  
Just maybe a clinical question that you guys can answer three consensus on which class of drugs can or should come up first, if you have a positive

Howard Levin  38:05  
That that's a really good question. I can tell you. The only data I know of actually came out of in this particular situation, came out of Jie's smart study, where they prescribed which class of drugs would go on in which order and be taken off in which order? Whether that's the only order you can do it, I don't think anybody knows. But Jie, what was the order? 

Jie Wang  38:31  
Yeah, they in the clinical practice, they call ABC, okay, A is car American because they use a, R, B, always first. B is, you know, beta blocker. The people like use the beta blocker first, and the C is calcium blocker. Okay, so this also depends upon the habit of the physician, but in the clinical guideline, you say to use a, always first, and then you use C, and then we lose speed.

Lisa Carmel  39:09  
Any other comments, okay, well, I think that's a wrap. Thank you so much to our most esteemed panel. 

Jie Wang  39:15  
Thank you. 

Howard Levin  39:16  
Thank you.