Brad McCarty • April 19, 2018

Dr. John Simpson is a medical device innovator that you know, even if you don’t recognize his name. In 1978 he developed the first balloon angioplasty catether to use a guide wire system. His invention is credited as pioneering the field of interventional cardiology as we know it today.

Dr. Simpson has built and sold a number of companies over his career, to names like Eli Lilly, Boston Scientific, Abbott, and many more. These days he serves as the Executive Chairmain of the Board for Avinger, a company that bills itself as “radically changing the way vascular disease is treated.”

We were honored to have Dr. Simpson join us at AngelMD’s first Alpha Conference in Napa, California. During his talk on medical device innovation, Dr. Simpson discussed the history of his life of innovation, and the lessons that he has learned.

Make sure to watch for the surprise story featuring Paul Newman.

John Simpson: Wow, it’s pretty cool actually and I’m glad I came here because the first thing I’m gonna do when I leave is I’m gonna apply for a job with Billy Cohen. Wow! What he’s doing, what I’ve done pales in comparison to Billy, but you have to see his magic tricks, I don’t know if you’ve seen any of those yet. His magic tricks are just as compelling and convincing as his talk was today.

So, it’s a privilege for me, I’m gonna talk about navigating the maze of medical device development, if you believe I know anything about that I’m sorry you’re really kind of mistaken, maybe you came to the wrong talk, it’s too complex.
I can tell you about, oh great thanks, I can tell you about at least an approach to working your way through medical device development. I do need to clear up one thing though, I did not flunk out of Texas Tech, we need to get that, I think now’s the time to get that addressed. I transferred the day before I got my academic ineligibility to Ohio State, so just want to set the record straight that I’m a Red Raider let’s say, but I did not actually flunk out.

So, I think we all need to know that as we navigate through this maze that there will be surprises, and you have to stay alert and there will be things that will happen to you that will be shocking, unanticipated and as Billy said, “Our obligation is really to work through those.”

So, I just think we need to put everything in perspective, Donald Rumsfeld, you may remember him from the past, but he was kind of an intellectual kind of a guy, and he said, “Reports that say something hasn’t happened are always interesting to me because as we know there are no knowns, things we know we know.”

We also know there are known unknowns things we say we know that there’s somethings that we do not know, but most interesting of course, for sure, also they’re the unknown unknowns, the ones we don’t know we don’t know.

So, I am an example of the unknown unknowns, but I think what has separated me from some of my other colleagues is that I’m willing to do what Billy has said earlier today, “I’m willing to take a chance.” Particularly to try to meet unmet clinical needs and that’s really been sort of maybe I don’t know if that’s been my strength, but it’s something that I’ve been let’s say sort of obsessed with.

But we have a lot of doctors, I guess here in the audience, so everybody who’s a physician here raise your hand, so I can identify, who are gonna be the victims of this question. Well, so this is the histology from an autopsy and this patient that died had a normal cholesterol, had a normal blood pressure, was a non-smoker, did not have diabetes, had some plus, minus family history for vascular disease, but the histology that has been taken here would be taken from the three most important coronary arteries on the top of this patients’ heart.

Does this have a pointer here or not? Well the big one in the center on the left, all of that artery has been filled up with plaque and the little bitty hole down in the bottom right and that’s where the blood goes, so there’s no really room for very much blood.

And same thing on the that’s called a diagonal branch over on the other side, no room for blood there, and so I think we could all agree, particularly the physicians I think here would agree that this probably came from an elderly patient. Are we kind of agreeing on that? Yeah, or if not an elderly patient, than a young patient would have to had, high cholesterol, high blood pressure, would have to have a lot of risk factors for vascular disease to end up in this situation.

But I think what we can for sure agree on, universally out here, is that this could not have come from an Olympic athlete, probably somebody very sedentary in terms of their lifestyle right? Suckered you into it, really easily there, that wasn’t even very hard for the doctors here.

So, this autopsy came from Sergei Grinkov, who’s the Olympic skater who died on the ice, warming up for the what was 1996 maybe Olympics, I’ve kind of forgotten today. He was having chest pain during the warm up, and you can see why he would have chest pain, because all these arteries are almost closed, and he got shots in his shoulder because the pain radiated to his shoulder, so he was getting Lidocaine injections and steroid injections in his shoulder after each practice.

Steroid injections are not an effective therapy for coronary artery disease that have closed off all of your arteries, I mean it’s just sort of on a basic medical principle. He is a victim though of sort of accepting I don’t know kind of the standard of course, he can’t have coronary disease and I think that’s why we all need to keep sort of imagining you know, to have better solutions for these problems and he should have had a treadmill test or something, there’s a lot of ways to find out what he really was having, which those were actually ignored.

So, we’ll do what Billy did a little bit, I just want to kind of tell my story and then you can think about this, half is a little bit crazy. So, I’m at the bottom on the bottom left slide there, I’m the guy with the really white teeth and so I’ve been to the dentist. We did just get back from the tanning salon too, so we really do all look pretty good.

So, the guy on the far back corner holding his head thinking, “Oh my god,” that’s Andreas Gruentzig, and I don’t know if many of you might know the name of Andreas Gruentzig, but he’s really the father of all of vascular curcutaneous intervention in a way, so he was the first person ever to put a ballon catheter in a coronary artery in a patient and open up a coronary artery and help that patient avoid bypass surgery.

So, I had the opportunity to go to this particular conference in Zurich that time, we had a little bit of wine, which also explains maybe the red face. I thought showing the wine picture would be good, because we’re in the wine country, you see the, oh geez.

Audience: Brilliant.

John Simpson: Brilliant, yeah I thought you’d say brilliant, so Chianti, I don’t know if they do that kind of wine around here, but we formed this group and it was called the International del Tasting Society and it lasted for about a year and on January the 11th, 1978, Andreas Gruentzig signed the top of the cork with AG, I’m a cardiology fellow at Stanford at the time, so I’m pretty low on the totem pole, but he signs the top of the cork as AG as the CHBD, that would be chairman of the board, and then I signed the bottom of the cork, JBS and they didn’t know what to do with me so he has assigned me the title of keeper of the cork.

Not a particularly prestigious position and I have misplaced the cork, but I still have these pictures, so I just want you to know that I’m living up to my expectation. When I came back, I wanted to do that again, kind of what Billy said, “When I came back from this conference, I wanted to build a catheter and I wanted to test the catheter,” and we had seen Gruenzig perform one of these early balloon angioplasty procedures where you open up a coronary artery and now the patient doesn’t have to have bypass surgery, so it’s really magical.

And I don’t have any equipment, actually I don’t have a Home Depot nearby too, so that would be the thing I would really look for from now on, when you locate yourselves you need to be close to a Home Depot, I think according to Billy.

Some of the names on this, my little black book, then this would be in June of 1978, a name there is Norm Shumway, that Billy knows Norm. Norm did the first heart transplants at Stanford, not the first ones in the world. Shumway was a very supported person and the cardiac surgeon at Stanford, very supportive of my efforts to develop an angioplasty system and then I went to the Rakiem Corporation for my material.

And they did just like Billy said, he got his out of a Windex, I’m so much more sophisticated than that, Windex I mean really? I would go to Rakiem and I said, I need some tubing about this size and they said, “Well, we’re in a run now, we’re extruding all the tubing to wrap the Alaska Pipeline,” and so to divert that extrusion for what you, how many, I said, “Well I need about ten feet.” And they said, “Well, probably couldn’t really do a special extrusion for that, but why don’t we see if we have material back in our warehouse that would help you about the right size.”

So, they go back there, they find the tubing that is about the right size and we use that to make this catheter up on the top right hand side of the slide here, and that’s the first balloon angioplasty catheter which went over a guide wire that we ever used, not that one, we didn’t use that one, but that design’s the first one that we designed to be used in patients.

Now, that material, that plastic tubing came there was really cool, because it was actually the electrical insulation out of the F4 Phantom, so it happened to be just about the right size, it had been irradiated, we could blow a ballon in it, but it also had flame retardant in it, because the F4 Phantom needs that in case of a crash, but patients don’t need flame retardants in their coronary arteries so all that so it had to be taken out.

So, then we have to get the … we passed all the what do you call it biocompatibility testing, you know the flame retardants do not pass biocompatibility tests, just in case you don’t, that’s why I’m really giving you all the insights that you really need here. No flame retardants in your products.

The catheter was tested in a baboon at the NASA AMES facility down at Moffett Field. The baboon had a 40 pack year smoking history, just died of peanut butter, the baboon fibrillated while we were working on him and because the way this catheter worked and the defibrillator at NASA, did not, well it was a small defibrillator used for mostly for dogs, and it did not provide enough energy to cardiovert the baboon, the baboon died.

And the NASA really took not a very positive view about me, based on what had happened to the baboon, but we did an autopsy on the baboon and you can imagine 40 pack year smoking history and died of peanut butter continuously and that baboon had zero vascular disease.

There was not a narrowed artery anywhere in sight, so our goal was to test this and to test this concept and put the ballon in and blow it up and show how that all worked in a narrowed artery, a diseased artery, because we were sure the baboon would have them and that was not the case, a surprise right?

Also, a big surprise for NASA that the baboon did not survive, that particular now, the secret sauce in this particular catheter it moves over a guide wire, and so the guide wire is the thing that we were able to position inside an artery and the catheter then goes in over the guide wire, think of the guide wire as kind of the railroad track and the catheter would come in over that.

And I know it looks, it is, this was pretty … it grew into really elegant devices and then that company sold and then back in the 80’s, it’s called Advanced Cardiovascular Systems, sold to Eli Lilly, sold for a 110 million dollars and sort of back in the 1980 dollar range, that was pretty good.

But, after that device gets perfected then I used it in patients, a much better design of that. And here’s an example of what we could expect with balloon angioplasty. So this patient, John Smith, admitted to our hospital, Sequoia Hospital in Menlo Park, California and where the arrow is on the left panel, I feel like I’m … everybody understand? I’m used to having a pointer and I feel embarrassed that I didn’t bring a pointer, somebody must have a pointer here, JJ come on, so it’s his fault.

So, then over on the left side, that’s a narrowed coronary artery, oh look at you.

Audience: Jack of all trades.

John Simpson: My god, oh I’m going to be so smart now, see this is going to be … okay, so this is a narrowed left anterior descending, yes, who did that? Yes.

Audience: Billy.

John Simpson: Billy, you’re the man. Can I get a job? Did you decide on that yet or not?

Audience: We’ll talk later.

John Simpson: Okay, so it’s a narrow left anterior descending coronary artery and this patient developed chest pain, when his race car got up to 180 miles an hour. He was seen at Yale University and they said, you have coronary spasm and that’s a thing where you don’t have a narrowed artery, it just squeezes down on itself every now and then.

They gave him Nitroglycerin and he still got chest pain at 180 miles an hour, so he went to UCLA. UCLA said, they did a treadmill test, he dropped his blood pressure, treadmill test is a pretty common test if you’re looking for coronary disease and they said, you’re so sick you can not have an angiogram, we have to go directly to bypass surgery.

Billy I don’t know if you would go for a bypass surgery for a single vessel, LA did, this was ideal, surgeons love this kind of a patient at that time. So, he signed out of UCLA Medical Center, went to Hope Memorial Hospital down in Southern California and had an angiogram. This is the angiogram that shows this narrowed artery over here on this side.

I knew the doctor at the time, Joel Manchester and he called me up that night and said he wanted to send a patient up to have angioplasty and he didn’t want to use his name over the phone because he’s kind of a VIP. And so I said okay, I’m thinking John Smith, alright, that’s great. And anyways he said his wife will be coming wit him and he’s married and his wife will be coming and her name is Joann Woodward.

And so, I said, see some people know that, you’d be surprised at how many people do not know, the Joann Woodward connection. So, I tell my wife this, she said who was that call about last night? I said, “Well somebody, I’m gonna treat a patient tomorrow morning, Mr. Woodward,” and she said, “Who is Mr. Woodward?” And I said, “I don’t know, he’s married to Joann Woodward,” and she says, “You are a dumb shit.”

And my wife, that’s not usually the way she talks actually, but on this particular occasion, so this was two balloon inflation’s takes this artery from this to this, to this and it never recurred, without a drug, without a stint, without any of the things that we talk about, that we’re developing all the time now right?

So, I just point this out that if that’s what happened every time, then the whole industry would not have developed the way it is, but it’s really rare, because most of the time when you put a balloon in this, make it look like this it recurs, over anywhere from three to six months, maybe after a couple years.

John Smith though did come into the hospital under his name John Smith, and the scrub tech who was doing the prep and the drape, did look at Mr. Smith and say, “Hmm, wow you look like my favorite actor,” and so he said, “Well, who would that be?” I’m glad she didn’t say Robert Redford that would have been a bad … she said Paul Newman and he said, “I am,” and she I think had a cardiac arrest on site.

So anyways, the concept of making a little bitty balloon to go in to fix somebody’s coronary arteries as the way that was all worked out, is because of the unmet clinical need and that is so important for anybody at any … any angel investor and by the way all of these companies so the first company ACS and this company PerClose, we sold to Abbott Labs, made a vessel closure device here. It’s kind of a cruet here on this particular slide, but they all started with angel investors.

For really good reasons right? What kind of investor is going to be crazy enough to do this stuff, I mean you’re going to invest in a balloon, that somebody’s going to put … have they been putting balloons in coronary arteries before? No, not really, in humans, mm-hmm (affirmative), what’s gonna happen when you blow the balloon up? Patient’s gonna get a lot better.

Yeah, always, well, most of the time and it turned out that three percent of the time, we induced heart attacks in that era and we ever could’ve even evaluated that kind of technology in this current era right?

But, the need was so dramatic because the patients were having the bypass surgery, not everybody could have bypass surgery in that era, and it really contributed something that is very, very special, the problem with that technology is we’ve had to use some pretty big catheters in the groin and so they would bleed.

The puncture site would bleed and so we developed this device that sold to Abbott Labs because we needed to close off the puncture site and the pro-glide device here or the PerClose device also is used in {taver} patients, patients getting valves, percutaneous valves, so this was sort of … the advantages of this device were totally unanticipated, nobody believed that this device would be used to help patients get percutaneous valves placed.

Just to say that somebody actually developed a device and the original intent of that device maybe it’s not what’s really gonna make the difference. So, two other devices and these are all for Billy, he wanted to see really crude prototypes last night and so these are really crude prototypes.

So this device eventually the subsequent iteration of this, which actually doesn’t look like this at all, sold to EV3 for 740 million dollars and this device was predated that when it was a device that sold to Eli Lily for 120 million, these have cutters on them, so they shave out and clean up vessels and we do that in the heart and we do that also in the legs.

So, I’ll show you some examples, just to, this is almost unimaginable but the device, the foxtail device that was there on top as crude as it was, peaked out in daily sales of around 700,000 dollars a day, we had a few two million dollar sales days for that company, but that device was used primarily in the peripheralvascular space and it is a device that is shown in this, functions as a clean out device if you will, maybe call it Roto-Rooter.

So, here’s an artery that’s completely blocked off here, no flow, we fix it, below the knew, we fix it, and blood flow is really good, see I don’t know if you guys get it. So, here’s what happens with no blood flow, so this is a venous stasis ulcer and an ischemic gangrenous region in a patient that had hypertension, cholesterol, had a small stroke, atrial fibrillation, was not a diabetic but she’s 91 years old and she was bedridden on continuous IV narcotics and she was diagnosed as having profound dementia and would have to have an amputation of her leg, so we said, “No, we don’t think so, we can open it with these other technologies with these catheters,” and so we opened ’em all up, and this is after she had blood flow reestablished using the catheters and you can see all of this stuff heals.

In addition to that, her morphine drip gets terminated right? And she’s not demented at all, she is totally alert and she’s thrilled. So, she lived three years after or four years after this, was fully ambulatory and I promise you had she had an amputation, these patients don’t get the DuPont hyperflex prosthesis, they get one they never put it on, they go to bed and they die. So, it’s effectively like kind of a death sentence.

So, this is fixing a leg artery, this is fixing a coronary artery, where we clean out this spot up here at the top, then we balloon it, we kind of mess it up a little bit down here and here’s what happens to it later. It narrows down again where the balloon has been used, but where the clean out device and effectomy catheter was used it looks really pretty good, so this is really a way to look at what’s the best way to work on an artery? Clean it out or squish stuff around with the balloon, so there’s the balloon there so my position always has been, it’s better to clean it out.

However, to clean it out, you’d need better visualization that we have had historically and we can’t just rely on X-ray fluoroscopy to do that, so we decided to put on the catheter and this was the development effort that went on for a really long time, like seven or eight years to put a you could call it a camera if you wanted to. A camera on the cutter, so you could see what you were cutting and that way you would make a safer intervention.

So, this is a normal artery and this is what the OCT, optical coherence tomography is the way to image these blood vessels, you can see they have layered structure here that look very much like you’d see them on histology.

If you’re working on an artery you want to stay away from the layered structures, so I’m training you now to be an interventionist and then we’re gonna give you the tool that will allow you to do that. So, here’s the tool, this is from Avenger and that work? It’s the animation, so this device has worked 100% of the time in the animation, now you’re paying attention, so I knew you’d wake up eventually.

Alright, so here’s the device here it’s got a cutter on it, it’s got a little balloon that supports it, it’s got an imaging fiber matted inside the cutter and you can look through the wall and this is the imagine that you get to see out here. I’ll show you what it looks like here and how we use it and imagine that this imaging element the OCT element, Castle, Germany huh, that OCT imaging element encouraged a physician in Muenster, Germany to work with us, and so we go to working with him and while we’re there I want to take a picture of this sign, Castle, Germany.

Someone else in this room can tell you the story behind that, but my private driver because you need a private driver in that kind of a situation in Muenster, so my private driver is a subsequent speaker in this conference, you have to figure out who it is, he’ll probably tell you.

But these are arteries that we cleaned out using the penthatheros device and then here are all the specimens that we took out, so clean these arteries out and you get really great flow, and this is the great flow, it’s the thing that helps these patients avoid amputation or become ambulatory again as we’ve basically described.

So, let’s look and see how one of these works, and also we do have I know we have a lot of doctors here, so this is good. This is an angiogram of a below the knee, he’s the knee joint right here, below the angiogram is right here and it’s looking down here and this artery is filled up with junk. It’s a tentacle, technical term there. And you can imagine that if you go down in there and work on that artery and you wanna clean it out or do anything to it, the cleaner device, the first pass can be aimed at anything because it’s so filled up.

Oh, the doctors here would sure agree, that’s just, you can cut in any direction, when you get there right? Alright, you didn’t bite on that one, so this is what it looks like before and this is what it looks like after we clean it out and so this patient profound, we call it Critical Limb Ischemia for the non-physician group, so this patient at rest was having pain in their legs, could not sleep, and now we’re gonna show the video loop, now can we stop the video loop anywhere along the way on the next slide is that possible? Let’s see if it works, okay, stop it there.

Ah, oh good, alright great. So, this is the catheter that’s gonna work on that, that’s the one that has worked every time in the animation, it has the balloon on the back side, it’s got a cutter mounted in here and it’s gonna shave out any plaque that’s inside the artery and when you turn it on and this is the image that you get, which you only get this with OCT, this is normal artery.

So, in spite of what the angiogram showed, the interventionist, the angiogram lied, it said it’s everywhere and it’s not everywhere, it’s only on the backside, so we’re going to turn this device around, we’re gonna aim it over here, we’re gonna shave the plaque out until we get down and we see this then we’re gonna stop, so now we can just let it play.

So, here’s this in the patient, so this all normal, the cutter’s sitting right here, you don’t want to cut that, so we’re gonna turn it and aim it over here to the other side, so the layers go away so this is all just atherosclerotic disease, down here a little bit of balloon, now we advance that, we cut, we cut, cut, cut, cut, here’s the normal artery we stop, maybe stopped a hair sooner, but that’s normal.

Now, that you’ve effectively treated the patient almost like you’ve taken them back to when they were much younger. And so, what this also does, it allows us to give real tissue that the Merck and the people that do gene expression analyses and things like that, will be able to do that on a very pure atherosclerotic plaque without any normal tissue, we had a deal with Merck at one time at Fox Hollow, where we gave them a lot of tissue and the tissue actually was about half normal and half disease.

Well, this is all disease now because we know by the OCT images that we do not have any normal artery in there and that’s probably not all true here to be fair, but what the gene expression analysis, you extract messenger RNA and you put it on this chip, undulant chip, and you run it and here’s what you get, amazing huh?

Wow, that is so cool, that’s meaningless right? They say after you do some data processing, when you do the data processing, you get these heat maps and what it shows is the diabetic patients here, all the red genes are the ones that are up regulated, these are mostly the inflammatory genes that are pretty well known. The ones that are down regulated are green and those are not the inflammatory genes and there are few diabetics that have no elevation of their inflammatory profiles and there are few non-diabetics that actually do.

So, this would allow us to study this whole process and just make a whole lot more sense out of it. Okay, so the next slide is my scorecard, this is always the embarrassing slide, I hate to show it off, I think I probably get by it pretty quickly. So this is really John Simpson, totally working all by himself, he’s never had any help from anybody, it’s amazing what this guy Simpson can do, really, really talented.

So, these are the companies Advanced CardioVascular Systems, Devices for Vascular Intervention, Perclose, LuMend, FoxHollow and Avinger and these are the companies, this is what the ended up selling for, I take credit for doing this exclusively, I’m just, back to my amazing guy here, but if you add up all the numbers it turns out to close to 1.8 billion dollars in shareholder value.

All starts off with angels, eventually you outgrow the ability of the angels to do this, but Ray Williams, is my primary angel and then also my ultimate angel is my wife, Lynn Simpson, she has endured a lot, and I tell that she’s just so lucky and she says, “Nah, not really,” so thank you.

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