Join us for an invigorating chat with Dr. Howard Levin.

Howard is an MD and together with his friend and professional colleague, Mark Gelfand has created some of the landmark medical device companies in cardiology. Between them, they have created 10 companies via their incubator, Coridea and are inventor-founders of Ardian, Cibiem, Respicardia and Axon Therapies.

Recently, they joined hands with Deerfield Management to found a Medtech incubator called Deerfield Catalyst.

Join us for a conversation with one of the true pioneers in the field of neuromodulation, outside the brain and spinal cord. 


Arun Sridhar: 0:00

Neuromodulation is a science of modulating nerves for therapeutic benefit. It has strong roots in neurology and neurosurgery. As a result, it is not surprising that the bulk of today’s revenue generators are spinal cord stimulation devices and deep brain stimulation devices. Both of these technological innovations evolved incrementally from pacemakers through technological innovation led by engineers. As a result, it appears to me that people always run around with the hammer – the technological solution, looking for a nail – the biological problem. Today on SKRAPS we are lucky to have Dr. Howard Levin. Howard and his friend Mark Gelfand have silently, yet surely led the area of modulating nerves in cardiology, and also led the field of neuromodulation into disease indications beyond the traditional neurological disorders. They’ve taken a biology focused innovation approach and in line with my thinking, and sometimes I evangelise about it by saying that the biggest opportunity for the future lies outside the brain and spinal cord and not in it. That’s not to say that things cannot be improved in these areas. But one does not open up new markets by modulating nerve structures in the brain and spinal cord. The two of them Howard and Mark, have founded some of the significant companies that explore the role of nerves in modulating cardio, renal and cardio respiratory disorders. They first founded ardian, the renal innovation company, along with foundry, the West Coast incubator, rescue cardio sought to develop treatment for central sleep apnea. It was a first device for this purpose. CBM was the next company that was founded out of Korea. And that company looked at carotid body modulation. And now more recently, they started axon therapies to develop treatments or device based treatment for a massively unmet heart failure population. I got to know them when they were setting up axon therapies and it was wonderful insight into how they work. Recently, they joined forces with DFL management, who was an investor in their axon therapies company to start a med tech incubator called Deerfield catalyst. It is a pleasure to welcome Harvard to the show. First of all, congratulations on this amazing news.

Howard Levin: 3:01

Well, that thank you very much Arun. And you know, really appreciate the opportunity to be part of your podcast, you know, as as you were saying we were lucky to be working with now Deerfield management to be able to make a joint venture between different management and karidian to start a company called Deerfield catalyst. Previously, Deerfield management had started a West Coast incubator called NXT biomedical, Stan Rowe’s leading it who’s, you know, giant in the field, having done PVT and everything else. And so we’ve been lucky to start an East Coast incubator called DFcatalyst.

Arun Sridhar: 3:53

That’s fantastic. And Stan, when he kind of came on our podcast, he shared with us briefly about how the deal was structured and what he was trying to do in terms of the cardiac valve innovation, and potentially his goal to spin out kind of five companies in the next few years from the incubator that is running with a commitment for $250 million of which a large proportion or is set aside for future investments, but most of it is for or a small proportion is for early stage investments in terms of operating costs, etc. So can you share with us anything with respect to the deal terms, etc? How it?

Howard Levin: 4:39

Sure we have a very similar overall approach. Your numbers are slightly different, but they’re all basically the same concept. We have an operating budget on which we run it and do some internal evaluation and then once we find things that are looked like they could become series A candidates. If you were able to answer a few more questions basically a seed phase, then we can get additional money for different seed projects, which we then evaluate them to get to and that justify series A, the benefit of that is that it provides better vetted deal flow for Deerfield, who is, you know, will be the early investor, but also provides everybody including ourselves with a better opportunity to have a better chance to win. Because, you know, you can now take out the earlier issues earlier and take out a lot of the risk earlier than you normally would be able to.

Arun Sridhar: 5:56

Yeah, that’s fantastic. So one of the follow up questions that kind of comes to my mind really is, how is this model of innovation that you that you will be working on over the next few years now, with Deerfield, through the DFcatalyst, different from the the previous models of setting up companies through Coridea work, like, for example, I think I kind of quoted Ardian, Respicardia, Cibiem, and Axon. I was kind of involved during the setup of Axon as you as you know. And so can you just walk us through how this is slightly different, because I think there is a reason why you probably opted for this particular model, compared to the traditional VC funding model, which has worked incredibly well, for you in the past as well. So it’s not as if you moved from a model that did not work for you, you’ve actually been extremely successful in that arena. But what what kind of prompted the discussions around around setting up this type of model,

Unknown: 6:56

on average, it’s a time savings for us in a significant way, let me explain why. It’s, you know, even though we’re pitching to one VC, essentially, Deerfield management. You know, and they’re still, you got to prove that it’s a real project that, you know, like, just like any other project, it has to meet the criteria for VC investment. The difference is, is that you save a lot of time. And there are two types of time. One type of time is the time it takes you to convince any individual VC to invest. So you know, every VC slightly different, they have slightly different needs, because their funds are different places, or, you know, they’ve got portfolio management that they want to do and be able to have more in one area or another area or whatever. But second, more important for us is that, without this, I’d spend 50% of my time raising money. And this now allows me to go to 10% of my time raising money, you know, which is a time where we’re pitching and I can spend a significant amount more time actually working on things. That’s real difference.

Arun Sridhar: 8:17

Yeah, that’s fantastic. And I think that is something where working on things is where you guys, you folks have been incredibly productive. So just to give a flavour to our audience on the various technologies that you’ve actually developed, can we actually go back to the very beginning, and I know this is a story that you and Mark, have said it many times. But I think it’d be fantastic to kind of really understand how the professional marriage between you and Mark kind of came to be, etc. Can you just tell us about those early days, then we’ll go from there into into you’re setting up your first company Ardian and others? So I’m old. That’s the first thing and what that meant. What that means is that in the late 80s, I was a fellow at Johns Hopkins and cardiology and Mark was a engineer in the lab and we shared a desk I want to call it’s actually a lab bench. We call it a desk because it sounds better to call it a desk and then said we were given a lab bench to sit out. And, you know, we worked on a lot of academic projects together is really great. We enjoyed working together a lot and found that we both had entrepreneurial sort of interests. So after I left Hopkins, I went to Columbia and clinically I was a heart failure cardiologist was running the mechanical cardiacs supports service and Mark actually then went out After a couple more years, he went out left Hopkins in their first spin up the first one out that Hopkins did in a company called cardiologic. And that device now is sold by zol. Is the auto pulse. He then you know, spend some time doing that when to mallinckrodt, pierron. And Bennett did some time in a strategic for yourself. Yeah. And then in 1999, we got back together again, to start a company called CHF solutions. CHF solutions was a device to treat heart failure, which was sort of, you know, our area of interest and expertise, and got sold to gambro. We moved on right before the sale to start ardian. And we were able to do you know, preclinical work and some very early clinical work, before the foundry took it over. And ran, went and did an amazing job. And the whole ardian team did an amazing job to get it through approval. So, after ardian, when we left ardian, we founded a company called respa cardia, which is about to be hopefully, in the next reasonable amount of time I acquired it, I think it met its hopefully met his three year sales goals. Fantastic.

Unknown: 11:52

Yes. So hopefully, that will be true. And we also did a number of other companies Cibiem, Renoguard, Repreive. And one you’re very familiar with having been involved with it, which was Axon Therapies through APVC and GSK being the early investors. So you know, we’ve sold a bunch of patents to other companies, etc. Yeah, so it, that’s, it’s been a lot of fun. We’ve really enjoyed it. You know, certainly we’ve had a lot of help from different people that we’ve worked with. And that’s how we got here.

Arun Sridhar: 12:41

Yeah, that’s fantastic. So can I just pick a couple of few examples here, and you can just walk me through the rationale, because I think a lot of our audiences all predominantly in the neuromodulation and, and, and med tech world. So I think they will, they will really appreciate and also a lot of academia, as well. So if we just pick up the first example, right after CHF solutions, which was ardian, which is a is a very funky way of saying renal innovation, which is rb, and literally the three letters of the alphabet. And so, and that is something that you partner with foundry to be able to do that early stage ideation, etc. And this is the states back to your working model that Coridea as well as like, as soon as you have an idea, you figured out a way to partner with smart investors who understand what this is, and then ultimately, are willing to take the project forward to still understand your kind of long term ambitions in terms of moving on to other projects that are willing to kind of establish teams and take the project forward, etc. So, talk to us a bit about the idea for why renal innovation would be extremely important at the time, did you start off with hypertension? Or did you straightaway think about heart failure, etc. Because I think that also had a bit of a knock on effect, from what I understand in terms of the strategy some of your competitors took as well, because knowing that you were a bit ahead in hypertension. At this stage, I think CVRx basically decided to focus on a different indication. So you just want to tell us a bit about that as well, in terms of what sure innovation does, so

Unknown: 14:23

Renal denervation came out of the the idea that we were trying to find a better way to remove volume from patients. And in order to do that you have to make the kidney believe that there’s a reason for it, not to retain salt and water and not to release neural hormones that cause problems. So it turns out that the same approach could have treated hypertension heart failure and chronic renal failure the originally we went after the heart failure approach and did a handful of patients with a percutaneous approach to block the renal nerves actually under ct guidance and then when the foundry took it over and got into humans with the with their device the initial idea was basically more or less still heart failure but start with people that higher had higher blood pressures because we knew a potential side effect of it was that you could drop blood pressure and then they saw a significant reduction in blood pressure retargeted towards hypertension and the rest is history so that’s that’s actually how it got there now that’s my memory being old and decrepit it may not be exactly correct you can ask Hanson and Mark Deamon, Andrew and you know those guys they can tell you better but

Arun Sridhar: 16:17

yeah no it’s fantastic and i think the fact that you you folks are able to able to understand a critical problem which leads to fluid accumulation and end stage heart failure and then ultimately understand that that is the way in which most of the ace inhibitors work as a mechanism or even the opposite is true in terms of worsening of disease and then you would die trying to target the real the real nerves that would ultimately lead to kind of tricking the kidney into believing that everything is okay and therefore we could release all the salt and water out would be was a great way and i think you sold that company to medtronic for a query sizable amount and i think they kind of botched up the pivotal trials a bit in terms of patient selection but it looks like it’s actually making a renaissance again in terms of some of the trials being run and also by i did attend that recent seminar that you had with the d chf group where there were some new evidence that was being presented in af and looking at me led innovation in a tribulation etc which is fantastic to see that that’s actually still running within within medtronic at this point of time so from there you actually moved into a very different kind of not necessarily heart failure but looking at a very important complication of heart failure end stage heart failure which is central sleep apnea with your recipe cardia system and i know there were a lot of other companies that you that you mentioned at the beginning but let’s actually take respite earlier because what really excites me about recipe cardia is again the news that you said but also more importantly from a scientific point of view the manner in which you were addressing a very critical part of cardio respiratory issue that actually happens in end stage heart failure so tell us a bit more about what the issue is and what did Respicardia do to overcome that.

Unknown: 18:19

Respircardia was founded to look at, as you said central sleep apnea which is different than obstructive sleep apnea. They’re actually on a continuum but central sleep apnea is due to a most people believe in imbalance between cardiac output and the time due to that cardiac output that the change in a blood gas is expected to be seen by the sensors in your brain and peripherally and that adjust your breathing rate and your breathing pattern; so to make a long story short what we tried to do was to adjust the breathing pattern in such a way originally we tried we’re trying to take over the breathing pattern and give credit to Mark Gelfand. As he’s trained as a controlled system engineer, we looked at this as control system and he realised that we don’t have to take over what we can do is again in train or fake the the brain into believing it should breathe in this pattern rather than that pattern than this abnormal pattern and was able to have mark reductions in in the Central sleep apnea apnea hypopnea index, which now looking at the longer term data that’s coming out about heart failure looks like it has a significant benefit in improving the heart failure state. So, you know, that’s, that’s actually nice to see that it’s not just a respiratory change, but that the hope for change in heart failure actually occurred. Also, you know, none of these things, what, no matter what project, it is, I’ve never seen, maybe there are people, but I’ve never seen where the first assumption you make for a particular Physiology or approach to therapy, turns out to be 100%. Correct. And, you know, Mark spent a lot of nights in, in, you know, sleep, doing sleep studies, with different stimulation patterns and stuff like that, to find out the right way to do it. So, you know, that was a tonne of work. No, I’m, again,

Arun Sridhar: 21:10

I think I was when I kind of came to know about Respicardia around the time that you were, you were doing your clinical studies at the time. I mean, I was, I always grew up in my cardiology, and cardiac surgical training, knowing about kind of Cheyne-Stokes breathing, and what happens in end stage heart failure with respect to activation of the central chemo receptors, and in the brain, that leads to a build up of CO2 because his heart is not able to pump enough blood and that leads to a depression of breathing, and therefore patients will actually stop breathing. And then they would, sometimes they would come up, and sometimes they would just end up into into arrest, etc. So the fact that we are, you’re able to kind of provide a big reason to stay ventilated, because of the stimulation of the diaphragmatic, or the phrenic. nerve to, again by a percutaneous. Well, I think I think the device solution here is extremely novel and super innovative. I think the way you folks actually figured out a way to get to the phrenic nerve and being able to stimulate that it’s fantastic. I mean, I think I think, which is why I say it’s a true source of inspiration in terms of how you folks have thought and I think you folks will almost one of the first ones, although the the influence of autonomic nerves, etc, has been described in the past in cardiology for many, many years. I mean, this dates back decades, right. But I think apart from the cardiac pacemakers, I think you folks have demonstrated the value of modulating nerves to treat cardiovascular disorders with some of your portfolio companies, which I think is, is incredible, because that actually led to a change in the view of how for an industry and interventionalist were very much focused towards pacemakers and defibrillators and ICD devices, to moving them on to kind of neuromodulation and by electronic medicine, I think your work the two of you, between you and Mark has been such such an inspiration for for people like myself, to be honest. So from there, moving on to Cibiem, which, again, looks at chemo receptors, but this time, you actually, were not looking at hypertension, you were not looking at end stage heart failure, as was the case with ardian. And with with rescue cardia, you actually had a very significant hypothesis to look at heart failure for a very specific hypothesis, look at heart failure. So tell us a bit more about Cibiem, because I followed a lot of those clinical studies, in my early days of of my industrial work or experience, about how you kind of went about the hypothesis and testing that.

Howard Levin: 23:54

Sure. So well, you know, Cibiem was an interesting thing in the sense that there was a obstructive sleep apnea interestingly. Okay, let’s take a step back. The sympathetic hyperactivity is the cornerstone of the problems with heart failure. Many other disease states but especially in heart failure. And all of the treatments or the majority of the pharmacological treatments are aimed towards dealing with the complications or sec with a of that autonomic hyperactivity. One of the we found one of the roots of hyperactivity was something called the carotid body. Now most people think when you hear credibly, they actually think carotid sinus, which, again is actually ruffling. same place in the neck and but is that mccann that’s americana receptor that measures stretch or blood pressure where the carotid body is like a grain of rice size structure between the two carotids that is a chemo sensor and can sense oxygenation level co2 can sense blood flow to some degree which is why it has some activation in heart failure etc but low flow and heart failure obstructive sleep apnea central sleep apnea all activate the carotid body when you activate the carotid body it causes an increase in sympathetic hyperactivity so we said okay well that’s bad let’s try and get rid of it and that’s how we came up with the idea for carotid body modulation – CBM (Cibiem)

Arun Sridhar: 26:04

yeah which is again an interesting word play on the three letters of the alphabet that you picked up right just like rd so in the case of Cibiem, you had the clinical study that was done with, if i remember correctly in poland with with with with Peter Ponikowski and then i saw i think i saw just one review. So what happened to Cibiem, i mean i think you did publish the clinical study that was done, correct and then what happened to the company

Unknown: 26:38

so what happened was the heart failure stuff it was being done in HFrEF and we did like 10 patients but similarly they found that there was a reduction in blood pressure and the board decided to go after hypertension as a different essentially as a competitor to the mechanisms a different mechanism a different target than Ardian and when simplicity-3 trial results came in or didn’t come in (as expected) there was funding issues for everybody (in that hypertension) and i guess the company could have pivoted towards heart failure maybe a little earlier maybe not who knows but in the end it went on holdArun Sridhar: 27:26

yeah which i think it still has utility and heart failure right based on some of the data that was published

Unknown: 27:32

you might want to revisit and restart at some point there’s something for you to do, yeah in your spare time you can do that

Arun Sridhar: 27:40

yeah i think you’ve also definitely left left that space for me to do i will they will definitely look that up and and we’ll catch up offline is about that then finally i think the one that is super cool in my opinion but also rather than focusing on the traditional heart failure which is the head friend for heart failure with preserved reduced ejection fraction you folks decided to go with a completely different type of heart failure patients with axon therapies and i think especially i just wanted to point out this in i think this is probably where while have passed with which has preserved ejection fraction heart failure preserved ejection fraction has been there on load more i think that has received more attention in the in the in the last year or so just because of the COVID sequelae because i think some of the college athletes who actually tested COVID positive i think 15% of them end up having a large scale diastolic dysfunction if i remember correctly a lot of it started at OSU which is my alma mater an alumni of and i think it kind of has spread and it has been confirmed that at a few other college athletes from other universities as well so it’s definitely very timely and it looks like that company is doing fantastically well we had Juan-Pablo (Mas) on the podcast last year and he kind of explained it. We kind of gave him a hard time at that time just so that just like the way he gives puts you folks through the paces he and Imran i think we are talking through all of the other companies. So tell us a bit more about axon therapies because i think the way you went about testing the hypothesis here as well i think i think it’s very important for for young innovators to actually know which i think is a really point to the podcast so tell us a bit about the hypothesis and then how you went about de risking that idea to then developing your own proprietary device system for which you’re you’re just starting your clinical trials if i’m correct or maybe i have that wrong in terms of maybe have already started or maybe so yeah just want to tell us a bit more about that

Unknown: 29:56

sure and you know everybody does things their own way, this is the way we do it. But you know, it’s worked for us and hopefully it worked for some of your, your listeners, you know, the you can tell we have a physiological bent towards our the things we try and work on. And again, this was part of that and and originally when axon was started, it was started as funding from APVC, GSK as part of the bioelectronic medicine initiative were looking for electric vehicles are a way to use the patterns of nerve activation or to treat disease. One of the things we looked at was that there was a specific nerve called the greater splanchnic nerve which controlled the spank neck, or the origins of the abdominal organs, the vasculature of the abdominal organs. And then, specifically, the venous vino dilation, and found that we could treat syncope or fainting by trying to activate that nerve and move more blood out of the strengthening bed into the central veins, which would increase cardiac output and prevent people from fainting. It’s actually a normal mechanism that the body has in order to respond to haemorrhage or other things where the body needs a lot of blood quickly. But we found that blocking that nerve allowed you to pause vino dilation or pool more blood at a lower pressure. And that obviously is sort of one of the goals of treatment of heart failure. So we said okay, let’s let’s look at this in terms of heart failure. Well with that separately from us, Dan birkhoff and others looked at and found that there seem to be a mal-distribution and inappropriate redistribution of blood at rest and with exercise in patients is both with HFrEF but more more so and have HFpEF and that it you know, we hypothesise that that may occur due to excess sympathetic hyper activity, which is carried to splanchnic bed on that particular nerve. And that ablation of it would work. So we said, okay, well, how are we going to do it. And again, this is one of the things that we purchase, we take, there’s no reason to raise a lot of money and spend a lot of money on building the perfect device. If you don’t know if it works physiologically or clinically. So we found a surgical approach to ablate that nerve in patients with HFpEF and we chose HFpEF because there is zero therapies out there essentially approved therapies for HFpEF where there are many, many for HFrEF. So both from the commercial clinical point of view made sense to go after HFrEF. Since HFpEF is at least 50% of heart failure maybe more now. So we then said okay, and did a surgical study, follow patients up for a year found that they had marked improvements in physiological and clinical outcomes, then raise the money to develop a endovascular approach, we did a lot of work to understand what the right approach would be built a device did first inhuman with the Invesco approach in 11 patients nd now have an IDE in the US where we are just enrolled our first patient about a month ago.

Arun Sridhar: 33:59

Yeah. And I think that that, again is fantastic. Because I had known just around the time that you folks that were just in discussions, or we were all discussing at the time about the creation of Axon. I also knew that there was a previous company which had excellent called Leptos Biomedical which had actually stimulated the greater planchnic nerve for treatment of obesity because they wanted to regulate gut hormones, etc. And one of the side effects when they actually tried to do that, from what I understand, was tha they saw an increase in bloo pressure when they stimulated the greater splanchinic nerve ecause it basically causes al of the constriction of the bl od vessels in the gut and there ore, it was emptying it was em tying into the inferior vena ca a. Pretty much the same hypothe is that you describe for syncope where you just want to redistr bute the amount of blood back to the heart so that the brain g ts supply and you will treat yncope. So that is again, I thin , Because I knew that becau e the Chief Scientific Offic r of Leptos, at the time had j st moved to GSK. And, and a yea , a year before we we start d interacting around Axon, I had a conversation with him. And h kind of described this, and w ich is when I think there s opportunity kind of came up. I think it the opposite alway seemed like the right way to ap roach it. But syncope, again is a great indication, I think it just speaks to the perce tage of people who have have et versus it could be and I thi k as, as innovators, I know nd I know thatHoward Levin: 35:35

we’re not giving, we’re not giving up on

Arun Sridhar: 35:38

I know, it’s a very important work. And and and it’s also something t at I believe is is important o me personally, as well, beca se I think my father passed away because of syncope, I bel eve, because of aortic stenos s. So therefore. Yeah, s it’s definitely kind of impo tant. And I think that is som thing that’s, that’s there. And also do know, a few peop e who actually suffer from fro bots and have is illegal synco e, as well, as a result of th t. So no, that’s that’s defi itely something that’s worth pur uing. And hopefully, you will ursue that as part of the DF ca alyst here, and many more to come. That’s fantastic. How rd, I think so with all of th se, I think are you going to be there is always a flavour to k nd of heart failure, and cardiol gy to the word care. So thro gh df catalyst, are you going to be focusing again, on you core expertise of your exper ence, etc, in in this area? Or a e you also planning to kind of v nture out into other therapy ar as as My guess is it’s gonna remain cardiovascular, respiratory renal, sort of as an overall focus. Yeah. You know, that’s where we know things and I probably wouldn’t be no good at ophthalmology. But at the same time, I think

Unknown: 37:05

No, that’s really rue. I can guarantee you I will e no good.Arun Sridhar: 37:09

You folks are masters at applying the knowledge and effectively converting that into products that will help patients so thank you so much for doing this. I would really, really appreciate it. Oh, this has been a lot of fun, really appreciate the opportunity. And, you know, if you ever give up your day job, we’re always looking for people, so please don’t hesitate. Yeah, definitely. Definitely. Thanks for listening. Please share the love by sharing the stories you heard, but more importantly, spreading the word about where you heard this information and recommending that your friends and family listened to this podcast. All interviews and soundtracks you heard belong to scraps, a brand jointly owned by Jojo Platt and Arun Sridhar. Our soundtrack was digger by acid dad. And you can find the collections on all the music apps. Remember to share this podcast it scraps with the K and sparks spelled backwards.