Vulnerable Plaque Heats Up

Vulnerable plaque is the hottest cardiovascular device opportunity in years. But in shifting thinking about coronary disease from structural to biological processes, it challenges what it means to be a device company. As more evidence suggests vulnerable plaque is a systemic rather than local problem and as the underlying assumptions about coronary disease shift from a structural view to a biological one, conventional device approaches are challenged.

Vulnerable plaque is the hottest cardiovascular device opportunity in years. But in shifting thinking about coronary disease from structural to biological processes, it challenges what it means to be a device company.

by David Cassak

The first of a two-part series.

• Work in unstable or vulnerable plaque may explain why so many heart attack victims have less than highly occluded arteries and may represent the next huge opportunity in cardiovascular devices.

• There are many different ways to detect vulnerable plaque, but the bet being placed by some early device companies is on thermography, which has an edge over imaging approaches because it measures function.

• Many questions remain unanswered about vulnerable plaque—not the least of which concern effective therapies—but that's why thermography companies are betting not on a single technology, but on an industry.

• As more evidence suggests vulnerable plaque is a systemic rather than local problem and as the underlying assumptions about coronary disease shift from a structural view to a biological one, conventional device approaches are challenged.

They say that, as a boy, Alexander the Great wept when his father Phillip of Macedonia came home after his final battle, for fear that there were no more worlds to conquer.

Not so interventional cardiologists, who no sooner have in hand the technology, drug-eluting stents, to solve one of cardiology's most intractable problems, restenosis, than they begin looking for their next major clinical breakthrough. And by all accounts that next breakthrough is vulnerable or unstable plaque, a phenomenon in which friable or loose plaque in coronary arteries breaks away from the artery wall, drifting downstream until a thrombus of sufficient size is formed to cause an acute myocardial infarction (AMI), or heart attack.

What's so fascinating about vulnerable plaque and its growing army of adherents is that it turns on its head 50 years or more of conventional thinking about what causes AMIs and how to detect and treat at-risk patients. In effect, no sooner has interventional cardiology solved a long-vexing and critical clinical challenge than it sets out in search of new clinical problems to solve, and in doing so, embraces an entirely new paradigm about how coronary artery disease works, replacing today's mechanical and structural approaches to treating artery disease with new biological ones. It's as if the Boston Red Sox won the World Series one year and decided to play football the next.

For medical device companies, the temptation to follow their customers into what is likely to be interventional cardiology's most promising area is irresistible. Indeed, early estimates suggest that the vulnerable plaque market may be as large as $10 billion annually; more to the point, if vulnerable plaque changes the paradigm in interventional cardiology, from structure to biology, not to do so would be suicide by irrelevance.

But the pursuit of vulnerable plaque opportunities, like vulnerable plaque itself, masks some hidden pitfalls. For one thing, while everyone, physicians and device executives alike, agree that vulnerable plaque is a hot new area, no one yet knows precisely what approach will work best, both in diagnosing the disease and treating it. That's why virtually every company pursuing vulnerable plaque is keen on the clinical space but less certain they've found precisely the right technology. Indeed, there are nearly as many approaches to vulnerable plaque as there are companies working in the area, and many companies are pursuing multiple technology platforms. It's beyond the scope of this article to assess which new approach will become the preferred one for cardiologists or even, within one technology to identify which company is likely to win. Instead, in this two-part series, we look at four companies, Mountain View, CA-based Imetrx Inc. , Laguna Hills, CA-based Volcano Therapeutics Inc. , UK-based Thermocore Medical Systems NV , and Switzerland-based Medispes SW AG, each of which is pursuing just one of the myriad approaches to vulnerable plaque, thermography.

In addition, while vulnerable plaque's new paradigm is winning over interventional cardiologists at an impressive clip, basing success in medical devices on new treatment paradigms and practice patterns is always a risky business as dozens of start-ups can attest.

Finally, virtually everyone agrees that today's technology, which features interventional-based devices will have to give way to entirely different technology approaches, featuring non-invasive and/or systemic approaches to both diagnosis and treatment, if vulnerable plaque is to live up to its full potential. As the science of vulnerable plaque evolves, that evolution raises questions about the future relevance of a whole generation of tools to serve interventional cardiology.

Indeed, vulnerable plaque changes the paradigm for interventional cardiology, and thus catheter- and guide wire-based device companies at this early stage have to hold two different thoughts in their mind: the benefits of conforming to existing approaches in interventional cardiology and the likelihood that vulnerable plaque will change the underlying assumptions of interventional cardiology. In the process, it will also change the assumptions about the tools that will be needed to diagnose and treat. As such, one early advantage that thermography companies are counting on—the similarity of their devices to traditional cath lab tools—could, in time, become a limitation as thinking about vulnerable plaque evolves and changes.

And it is changing. At this year's TCT meeting in Washington, Peter Libby, MD, one of vulnerable plaque's pioneers and author of several key articles, noted that "we have to stop thinking about vulnerable plaque" and start thinking about vulnerable arteries, vulnerable arterial beds, and, even more fundamentally, "the vulnerable patient." As studies indicate that 80% of patients with acute coronary syndrome have more than one plaque rupture, he went on, "local therapies that target vulnerable plaque may leave a lot of problems untreated."

The view that vulnerable plaque is a systemic, rather than focal problem fundamentally challenges the device start-ups that hope to capitalize on their early lead in detection. No one's arguing that device-based solutions won't be part of the armamentarium of cardiologists treating vulnerable plaque. Still, the more evidence there is that vulnerable plaque is a systemic, multi-focal disease, the more difficult it will be for device companies with focal, catheter-based devices to take and hold the lead in treatment of vulnerable plaque.

That's why executives at thermography companies talk about investing in "a disease" or "an industry," rather than a technology and why they've begun even at this early stage to talk with both large cardiovascular players and even drug companies about possible collaborations. In the end, the challenge for these early device leaders isn't just that the technology to diagnose and treat vulnerable plaque is evolving rapidly, but that in changing the paradigm of coronary disease—from one with root causes in mechanical or structural obstruction to one rooted in biology—vulnerable plaque is leading to a similar shift—from structure to biology—in the tools cardiologists will require. In the process, vulnerable plaque, for all of its opportunity, may change as well the fundamental assumptions about what it means to be a medical device company.

Fast Adopters

Launched in February of 2001, Volcano Therapeutics was the brainchild of venture capitalist and medical technology incubator Olav Bergheim, a general partner of Domain Associates Inc., who notes that the first discussions of vulnerable plaque as a clinical problem came around a decade ago, in work done at the Texas Heart Institute (THI) by James Willerson, MD, and S. Ward Casscells, MD, both Volcano founders. "At the time, however," Bergheim notes, "most people weren't really paying much attention to vulnerable plaque."

But Bergheim was, and he continued to track development of the concept of vulnerable plaque through papers presented at clinical congresses such as the American Heart Association (AHA) and the American College of Cardiology (ACC) for the next couple of years. "It was at the AHA meeting in Anaheim two years ago where much of this started to come to the surface and I began to send out feelers to physicians that we, Domain, were interested in doing something in this area," he says.

Scott Huennekens, a former Baxter Edwards (now Edwards Life Sciences Corp.) executive and most recently CEO of Digirad Corp. , a developer of nuclear cardiology imaging equipment, joined Volcano as its first full-time CEO in April of this year. "Vulnerable plaque has the potential to be a complete paradigm shift in interventional cardiology," he notes. "Every year, over one million people in the US have a heart attack and half of them die." Billions of dollars are spent on diagnostic catheterizations and therapeutic devices, such as coronary stents, he goes on, "but they're just treating hemodynamic issues. They don't address why people die from heart attacks." Describing the paradigm shift, he notes, "Leading interventional cardiologists have told me that vulnerable plaque gives them the opportunity to move from being plumbers, managing symptoms, to actually saving people's lives."

Huennekens, who had known Bergheim from the days when both worked at Baxter, says the opportunity to be CEO of Volcano was "compelling." "On the one hand, if we can figure out what causes these heart attacks, we can save millions of people," he says. "At the same time, we know this is a market which already spends billions of dollars on products, and interventional cardiologists are fast adopters and progressive implementers of new technology."

Though Huennekens was impressed with the thermography technology Volcano had acquired early on, he says, "I told Olav that if this were just a thermography company, I wouldn't be interested in joining it. What appealed to me was the broader vision of Volcano as a vulnerable plaque company, one that was going to aggressively pursue diagnostic and treatment platforms, starting with thermography, but building on that by looking at and going after other therapies as well." Indeed, Volcano differs from Domain's other incubator plays in that its bet in vulnerable plaque is less on an early stage technology, than on the field itself.

Thus, even as it has built up its thermography platform, Volcano has also been investing in and developing IP by in-licensing technology from other sources. In addition to the thermography device licensed from Casscells work at THI, Domain also made an early investment in Imetrx, which at the time was working on a different approach to the detection of vulnerable plaque. Volcano has also looked at technologies in everything from OCT (optical coherence tomography) to spectroscopy and has some patents around near infrared technology. (See "Growing Companies—Part 1" IN VIVO, January 2002 (Also see "Growing Companies--Part 1" - In Vivo, 1 Jan, 2002.).)

(Originally working on a kind of Geiger counter approach to vulnerable plaque, Imetrx represented an early diversification play for Domain. But when Imetrx switched its focus to thermography, Domain officials saw a potential conflict with what Volcano was trying to do. Plans to fold Imetrx into Volcano never evolved past the discussion stage, and Domain and Imetrx are now going their separate ways. See next month's IN VIVO.)

If anything, Volcano's approach has been to be as technology neutral as possible, paradoxical as that sounds in a technology start-up, recognizing the potential of a winning position in vulnerable plaque and thus the importance of casting its net widely in order not to place the wrong bet on any single technology. "I think the important thing in starting up a platform company like this is not to start with a device and build a company around it," says Bergheim.

Bergheim likens his approach to the difference between "building a cathedral and operating a cement mixer." You can have a lot of cement mixers and, if you're lucky, they'll pour enough cement to make a cathedral, he says. But the only way to guarantee that you'll build a cathedral is to have a vision of one when you begin. "If you have that, the kind of cement mixer you have is much less important," he says. For Bergheim, "Vulnerable plaque is the cathedral—you need to have the vision of what you're going after. We know there's a clinical problem, however, we may not know exactly how to diagnose or treat it," he says. "But I don't really worry much about whether we have this cement mixer or that cement mixer, I just know we want to be able to diagnose and treat vulnerable plaque."

Focusing On a Strategy, Not a Technology

Indeed, Volcano's second financing round raised $24 million, much more than the typical $8-10 million a device company might have sought on its Series B, Bergheim notes, because the company wanted capital both to develop its current technology and to acquire other promising technology beyond thermography [See Deal]. "Don't get me wrong, we're very serious about thermography," he says. "But we didn't dare to put all of our eggs in one basket." If Volcano's thermography technology proves not to be the best approach, he goes on, "we'll find it [i.e., the best approach]."

Volcano believes it can justify a large early round, even though it raises the hurdle for raising money at reasonable valuations in future rounds, because its approach trades focus for reach as clinical data about the science and technology of vulnerable plaque evolves. Even Bergheim concedes that, "In today's market especially, $24 million is a lot of money." But, he explains, "we felt that if we can seed $1 or $2 million into an interesting vulnerable plaque initiative, it's worth it, even if they all don't hit. Because the value coming back is going to be so enormous, any miss is dwarfed by the big picture." Scott Huennekens agrees, "We're going to continue to expand our diagnostic platform because I would rather place five bets and write off three of them than not make those bets and find out later that one of those was the one we should have been betting on."

Indeed, Bergheim notes, some of the start-ups that have tried to tackle vulnerable plaque have already run aground, testimony to the difficulty of technology development in a fast moving space. "This isn't about having the nicest new catheter, and that's what too many companies are focusing on—they're simply trying to adapt tools to be used in vulnerable plaque," he says. At Volcano, he goes on, "we're focused not on a device, but on a strategy."

Central to that strategy is a fundamental change in the way people with coronary artery disease are treated. The statistics are compelling. In 2001, 1.1 million Americans suffered a heart attack, and 650,000 of those were first-time attacks, 75% of which were asymptomatic. By some estimates, 80% of those attacks are due to vulnerable plaque, and the consequences are dire: 50% of heart attack victims die, figuring out to 10,000 deaths per week or one every minute.

Until recently, cardiologists focused on the build-up of plaque as the cause of AMIs—patients with arteries occluded 70% were deemed to be at much greater risk than those whose arteries are 20% occluded. But recent studies have shown that a large number of heart attack victims, 86%, had arteries that were less than 70% occluded—nearly three-quarters had lesions less than 50% occluded. The premise behind vulnerable plaque is that it is the plaque's friability or volatility, not the size of the occlusion that is most important—a coronary artery that is 20% occluded may be at greater risk than one 70% occluded if the plaque in the former is about to rupture.

That means that vulnerable plaque leads cardiologists to think differently about coronary artery disease. "Historically, people viewed atherosclerosis as a passive artery disease," says Huennekens. "The artery was passive; lipids built up slowly on the artery until the vessel was occluded. But now, we have a better understanding of the disease. We know that lipids actually go into the wall of the coronary artery where they're trapped and attract macrophages." As macrophages build up, a cascade of inflammation occurs that eventually leads to the breakdown of the cells in the fibrous cap that sits over the lipid pool; when the cap erodes far enough, a rupture occurs that releases thrombus into the bloodstream.

It is that thrombus, rather than the plaque build-up, that causes heart attacks, which is why heart attacks can occur in people with relatively unclogged arteries. "It's now clear that heart attacks are not primarily caused by lesions that are 70% occluded," he goes on. In fact, "those are patients whose vulnerable plaque has already ruptured and is now stable. The main concern is some hemodynamic problems." Indeed, one of the things that makes vulnerable plaque so hard to detect is that it is hemodynamically insignificant, variable in size, and usually not calcified: a traditional angiography identifying lesions within coronary arteries becomes largely irrelevant, as are newer imaging modalities that simply flag calcification.

Combining Diagnosis and Therapy

There are still questions about how vulnerable plaque works: for example, we know that high levels of stress trigger more heart attacks, but is that because stress accelerates inflammation or macrophage activity? Still, the concept is catching on. And as it does, it brings a huge paradigm shift for interventional cardiologists—and, by extension, device companies. Diagnosis—and, by implications, therapy—which focuses on structure misses the point: vulnerable plaque has to be identified biologically. Huennekens draws an analogy to a patient whose cancer advances from their organs to their bones, causing the bones to become brittle. "You can take an x-ray and see where the bone in his arm is broken," he says. "But unless you do a nuclear scan, you're going to miss the fact that there's cancer there."

Volcano executives draw on the same argument to make their case for thermography over any of a number of other diagnostic imaging modalities—including OCT, intravascular ultrasound (IVUS), infrared spectroscopy, and MRI—that have also been mentioned as tools for detecting vulnerable plaque. "Structurally, a lot of arteries look the same," says Huennekens. "What you need to find is the one with a lot of macrophage activity. That's why our first play is in thermography. By measuring temperature, we're indirectly measuring macrophage activity."

Key to vulnerable plaque, says Huennekens, is the ability not just to identify vulnerable plaque but also to "risk stratify it," assessing which vulnerable plaque is prone to eruption. And that entails much more than simply measuring the degree of inflammation. Risk stratification takes into account things such as physiological and structural factors, as well as patient demographics. "There are about eight different factors," he notes. "We plan to build them into a software package that will, at the push of a button, tell the interventional cardiologist, ‘This is vulnerable plaque—and for these reasons.'"

Even more important is the ability to combine diagnosis and therapy. "Many companies are focused on finding a better way of identifying vulnerable plaque," says Olav Bergheim. "But this isn't about diagnosis of vulnerable plaque anymore. That's where the focus was two years ago. We now have ways of finding vulnerable plaque, the question is, what are we going to do about it?" Adds Huennekens, "Volcano was founded not as a diagnosis company or a therapeutic company or even a thermography company, but as a vulnerable plaque company."

Currently in clinical trials, Volcano's technology is an over-the-wire catheter-based device, 3.3 French in size, with a nitinol basket on the end that has five thermocouples to detect inflammation-based heat in vessel walls. After threading the catheter into the coronary vessel, the interventionalist pulls the device back, in effect, taking the temperature of the lumen as well as the blood, tracking any difference. (Volcano calls its catheters "atraumatic" and says they apply about the same pressure as an IVUS catheter, with no damage to the lumen.) The end result is a kind of real-time thermal mapping of the entire coronary artery that can be done in a minute or two, one of the real benefits of its device, say Volcano officials.

Key to Volcano's technology portfolio is a package of spectral analysis software, licensed from The Cleveland Clinic, that uses a radio-frequency (RF) back scatter signal from IVUS to create automatic boundaries and geometry of the vessel and allows for plaque characterization through what Volcano calls pseudo-histology, further enabling real-time diagnosis of vulnerable plaque. Providing color-coded images of the artery interior, such software represents an enhancement over IVUS alone in that it helps interventionalists not just to see plaque build up, but to understand what kinds of plaque—fibrous, calcified necrotic, fibrolipidic, or calcified—are present at any given time. The interventionalist "can then overlay this on an angiogram and integrate the IVUS images with the thermal map and know exactly what's going on," says Huennekens.

Like a Powder Keg Going Off

Perhaps most surprisingly for vulnerable plaque companies is the speed with which clinicians are picking up on the concept. While significant clinical data remains to be collected and questions to be answered, interventionalists are embracing the science behind vulnerable plaque to an amazing degree, particularly given the way vulnerable plaque turns historic thinking about AMIs on its head.

Scientific validity aside, one reason interventionalists are beginning to embrace vulnerable plaque as a diagnostic and therapeutic option is that it really doesn't threaten their practice to the degree one might imagine—just the opposite. Scott Huennekens points out that interventionalists "are still going to treat lesions that are 70% stenotic." But new therapies in vulnerable plaque should also open up enormous new patient populations among those less than 70% stenotic, patients interventionalists have never really treated before.

Moreover, the advent of drug-eluting stents, while eagerly welcomed by interventionalists in the short term, poses a longer-term threat since lower restenosis rates mean fewer repeat revascularizations. Some interventionalists might actually see a decline in procedure volume with the success of drug-eluting stents, and vulnerable plaque therapies will help by expanding the current patient pool.

And easing the adoption process: the technology being developed, such as Volcano's thermography catheter, is familiar and easy-to-use for most physicians, with a relatively easy training course needed. That's why Huennekens believes vulnerable plaque's adoption will be "like a powder keg going off" and doubts Volcano will run into any of the kind of training or adoption issues that sometimes plague companies developing new technologies in new fields. Drawing an analogy with the early days of minimally invasive surgery, Huennekens notes, "I was at an endoscopy company during the hay day of laparoscopic cholecystectomy and spent every weekend for a year in hotel rooms training surgeons how to do them." With a half-day's training, surgeons quickly picked up the new procedure. The same should be true with thermography devices used in vulnerable plaque, he says. "This is a lot like laparoscopic surgery, but even better because the physician is using the same tools they already use: a catheter that's fed into the artery, much as they do with an IVUS catheter. There's no training or uptake issue." <<t1 And Huennekens believes Volcano can capitalize with a relatively small sales force, at least initially. "We think there's going to be so much interest in this, we can get by with a limited sales force calling on around 500 high volume centers in the US," he says.

But before there's widespread adoption, physicians will need clinical data that testifies to the value of vulnerable plaque detection and treatment. That's why Volcano is investing in databases and clinical trials. "We need to get through these next two years of clinical data to show that we can diagnose vulnerable plaque and that the therapies are going to be effective," he says. Once that happens, Volcano predicts that the vulnerable plaque market could be anywhere from $2 billion annually, looking only at the catheter device and related products, to $10 billion, if aggressive adoption of new drug regimens and diagnostic markers are taken into account.

Taking Blood's Temperature

To date, Volcano has done a host of safety studies in animals, again with results similar to IVUS in terms of minor focal endothelial loss, and began human trials this May. It has done a nine-patient study in New Zealand and currently has trials underway at two centers in Europe, one in Essen, Germany under Raimund Erbel, MD, and one in Milan, under Antonio Colombo, MD, to be completed this October, for a combined total of more than 30 patients. It will then begin in the first quarter of 2003 a five-center European study on more than 100 unstable angina patients and a post-market correlative natural history study on over 900 patients at approximately 30 centers in the US, Canada, Europe, and Brazil, tracking vulnerable plaque profiles to incidence of major adverse cardiac events (MACE) over a 12-24 month period. The multi-center study will be under the direction of Martin Leon, MD, of New York's Lenox Hill Hospital, Raimund Erbel, and William Wijns, MD, of Aalst, Belgium. Volcano hopes to have FDA approval in the first or second quarter of 2003.

Volcano's approach differs from that of other thermography companies in that it tracks the difference in blood and lumen temperature, rather than simply differences in lumen temperature, though whether one is more valuable or what kinds of temperature differences clinicians ought to be looking for is too early to call. Is a 0.2-degree Celsius difference meaningful? 0.3-degree? "We don't know," says Huennekens. "We have some hypotheses, but at this point, it's just guesswork. That's what we need to figure out."

Indeed, the early New Zealand data showed what he calls "a high degree of heterogeneity of temperature," suggesting that temperature variation is significant; the 900-patient correlative trial to be started soon will attempt to match plaque temperature to MACE in an effort to determine precisely how elevated a temperature had to become in order to trigger an adverse event. "We'll measure their temperatures and then, once they have an event, correlate back," he goes on. "If you had a 0.5 degree elevation, did you have a 50% event rate within 6 months? Within 12 months? What temperatures are clinically important? Which ones should we try to treat and which ones not?"

Is Screening An Option?

Such uncertainty about temperature measurement doesn't mean that Volcano isn't committed to thermography—the company points to 11 patents and more than 20 pending in the technology, including several broad method patents with full allowance of claims. "We feel we have the US market locked up from an IP standpoint for any device that measures vessel wall temperature in the coronary arteries," says Huennekens. But the field is evolving so rapidly that being too committed runs the risk of missing out on critical shifts, both in technology and clinical thinking.

Moreover, if, as noted, some 75% of all first-time heart attacks are asymptomatic, part of both the challenge and opportunity for vulnerable plaque companies lies in pushing adoption of the technology as far as possible, trying to reach patients who haven't yet begun to show signs of coronary artery disease. And with some 60 million people in the US alone suffering from some form of heart disease, the potential screening market is enormous.

In the past, however, efforts to promote extensive screening of asymptomatic patients have fallen flat—witness the plight of electron beam tomography company Imatron Inc. , now part of General Electric Co. 's GE Medical Systems , who tried to make a case for screening—trying to establish an intuitive connection between early treatment of calcified lesions, before arteries become significantly occluded, and later reduction of MACE—but was routinely opposed by cost-conscious payers and resisted by unmotivated consumers. Even vulnerable plaque's strongest supporters believe the diagnosis of asymptomatic patients will be a long time in coming. "I think there will be a progression over time," says Scott Huennekens. "But in the beginning, we'll only treat symptomatic patients," i.e., those patients who are already in the cath lab for one reason or another.

That will broaden as current and future clinical studies in vulnerable plaque should identify specific patient populations—diabetics, for example, or heavy smokers or people with a family history of heart disease—who would be good candidates for asymptomatic diagnosis. In fact, Volcano is developing a proprietary database of 1,000 patients, tracking key criteria such as diabetes, elevated CRP (C-reactive protein), and other factors, hoping to identify people likely to have an elevated thermography score, says Huennekens. "We'll be able to say, that person's score is so high, we ought to do an invasive diagnostic on him." Still, widespread screening of people off the street is likely a long way off, largely for reasons of cost, both of diagnostics and therapies.

An Achilles' Heel for Device Companies

Vulnerable plaque's advocates insist that screening can, in fact, be cost effective: by identifying patients with vulnerable plaque and beginning appropriate therapy earlier, we may be able to prevent more expensive interventions later. Further down the road, "three to five years," says Huennekens, "we're going to detect vulnerable plaque either with non-invasive imaging or [biological] markers," that make systemic rather than focal identification of plaque. (A currently available blood test measuring for CRP has attracted a lot of interest, but isn't completely accurate, putting companies in search of new tests.) Hence the importance for Volcano of focusing not on thermography per se, but on a wide range of technologies to detect and treat vulnerable plaque. "That's when we'll start getting more people diagnosed for vulnerable plaque," he concludes.

Volcano is already preparing for that day, with alliances with several major device and pharmaceutical companies currently in the discussion stage. Huennekens says Volcano is very close to signing an agreement with "a Fortune 500 company in the diagnostic and non-invasive area" (he won't say who it is) and is in discussions with several others. Nor will Volcano always necessarily develop new vulnerable plaque technology itself: arrangements with diagnostic companies might generate royalty payments for Volcano if the company develops valuable new markers based on the data it is compiling. In addition, collaboration with statin companies can create interesting new therapies for vulnerable plaque that are outside Volcano's core competence but generate revenues nonetheless. Notes Huennekens, "There are still a lot of unknowns—that's why we're collecting all of this data on vulnerable plaque. And we want to be able to monetize that through partnering opportunities."

: In addition, beginning early next year, Volcano will embark on two more clinical studies, one in collaboration with a drug-eluting stent company, the other focusing on systemic drugs, both looking at the role of vulnerable plaque detection with different therapeutic approaches. Not surprisingly, vulnerable plaque is particularly of interest to makers of statins and anti-inflammatory drugs, notes Huennekens: "If we can measure a person's vulnerable plaque and then put him on a six-month regimen of statins that lowers his plaque temperature, we'll have data to submit to the FDA for a whole new claim with a huge market opportunity."

Such studies, which will be funded not by Volcano, but by its device and drug partners, illustrate nicely how continuing research into vulnerable plaque has implications not just for thermography companies, but for a much wider network of interventional device and cardiovascular drug companies. Moreover, as products are developed to identify plaque systemically, clinical and market opportunities will also become apparent in neurological and peripheral vessels—thus expanding even further a market that, large as it is, today is focused exclusively on cardiovascular opportunities.

Indeed, many cardiovascular device executives argue that as vulnerable plaque catches on, thermography catheters and other devices will become part of and enhance the armamentarium of the cath lab to the benefit of all who sell products into it. Drug-eluting stents, for example, will get an even greater boost—as if they really needed one—from research into vulnerable plaque, they argue, because stents that deliver pharmacological agents to suppress inflammation or reduce macrophage activity will be in high demand among interventionalists, particularly as they treat the kind of marginally stenotic lesions that currently don't call for stenting.

But there's a potential Achilles' heel for drug-eluting stent companies: as vulnerable plaque shifts the therapeutic paradigm from structure to biology, drug-eluting stents become valuable not for their structural features—i.e., their ability to prop open occluded arteries—but rather for their ability to deliver drugs to local lesions. And in that way, they become vulnerable to other drug delivery mechanisms. It's a lesson for all device companies for the way vulnerable plaque could potentially change the rules of the game in the cath lab, particularly for adjunct technologies.

Pulling, Not Pushing the Rope

Companies like Abbott Laboratories Inc. and Johnson & Johnson , the latter an investor in Volcano, illustrate how wide ranging the impact could be. J&J's Cordis Corp. , the current leader in drug-eluting stents, will obviously be affected as practice patterns adjust to deal with vulnerable plaque. But so too will operating companies such as Ortho Diagnostic Systems Inc. (diagnostic markers), Centocor Inc. (with its IIb/IIIa inhibitor ReoPro) and possibly other drug businesses, and Alza Corp. (drug delivery). Abbott as well, with strong diagnostic and pharmaceutical businesses and a growing interventional cardiology group, will feel vulnerable plaque's impact broadly.

One bonus for vulnerable plaque's potential partners and, in particular, its investors: an extremely fast regulatory path, particularly for a device with true breakthrough potential. As noted, Volcano hopes to have US approval within a year, possible because thermography catheters are considered Class II devices, with IVUS as the predicate. "We're not claiming we can detect vulnerable plaque, just that we're measuring temperature in the coronary arteries to provide physicians with additional information to manage the patient," says Huennekens. It's like a tympanic thermometer, he goes on, which measures body temperature but doesn't explicitly diagnose flu or some other condition.

As Volcano draws closer to launching its first platform in vulnerable plaque, Scott Huennekens underscores the company's challenge. "Engineering 101 says that you first understand the problem and then develop a solution for it. But here, we're trying to develop solutions at the same time that we don't completely understand the problem. That dictates that we place a number of bets as we learn more and understand vulnerable plaque better in order to maintain our first mover advantage." It also makes Volcano's strategy at once complex and simple. It will start with easy-to-use and readily adopted thermography systems to diagnose plaque, while at the same time, continuing to expand its diagnostic platform, compile the data from clinical trials to demonstrate clinical value, and partner with others to "participate in the therapeutic platform," as Huennekens puts it. But at heart, all of that comes down to a simple principle: to keep an open enough mind and have enough resources to own, to the degree possible, the space in vulnerable plaque, no matter where the technology goes.

Indeed, while many venture investors worry whether they're investing in a product or a company, Olav Bergheim insists that Domain's investment in Volcano is in an entire industry. "That's what I love about this: it's really a strategic play. It's a strategic investment in a space where there are already too many single-product initiatives," he says. Volcano's early and aggressive push, Bergheim goes on, "has positioned us as the leader in vulnerable plaque," and he points as evidence to Volcano's successful Series B round, which raised $24 million—but could, say some industry executives, have gotten $40 million more—at a pre-money valuation of $24 million and attracted large corporate investors, J&J and Medtronic Inc. (Domain also funded by itself a Series A financing of $2.5 million.) Being a leader in a field in which, by Volcano's own admission, the technology is far from certain might seem a questionable value at best. But Bergheim claims that Volcano's aggressive stance has tangible benefits. "When people look at you as a leader, you pull all of the other things with you, like attracting physicians and buying other companies," he says. "If you're just another device company, all you can do is push the rope."

A Serendipitous Find

If Volcano's impressive financing helps to make it the fastest of the thermography companies out of the gate, by all accounts, the first out with a commercially available product will likely be Belgium-based Thermocore, which was founded in April of 2000 by a team of interventional cardiologists working out of the Thoraxcentre in Rotterdam. Thermocore's CEO, John Yianni, who joined shortly after the company's launch, is a cardiovascular device industry veteran who had, most recently, risen from development scientist to become a Vice President of Biocompatibles International PLC , the UK-based device company. As one of two executives to launch Biocompatibles cardiovascular business, Yianni had built extensive networks in the European and US cardiovascular communities, where he troweled for new technology. (For example, Yianni was instrumental in Biocompatibles' acquisition of Divisio, which brought the company its drug-coated stent.) Yianni left Biocompatibles three years ago, just before the company sold its cardiovascular business to Abbott Laboratories, and began working with a Munich-based investor group, conducting due diligence on device investments.

In the fall of 1999, Yianni was visiting with Patrick Serruys, one of Europe's leading interventional cardiologists, whom he had known from his days at Biocompatibles, asking his opinion of a piece of technology this his investor group was interested in. "Patrick said to me, ‘Forget about that. Let me tell you about something really interesting,'" Yianni recalls. A few months earlier, Serruys had taken on a Greek cardiologist, Leo Diamantopoulos, MD, who had worked in Athens with Christodoulos Stefanadis, MD, one of the pioneers in vulnerable plaque, as a fellow in his Rotterdam-based cath lab.

As Yianni sat in his office, Serruys picked up the phone and asked Diamantopoulos to come in and show Yianni a new catheter he had developed with a couple of colleagues. Though THI's Casscells and Willerson had done some temperature measurement in carotid arteries using a probe with a very sensitive thermometer at the tip, by all accounts, the catheter Yianni was introduced to, designed by the team in Rotterdam, was the first developed specifically for the mapping of temperature variations in complete coronary arteries.

In fact, Yianni argues, despite Casscells' and Willerson's early work, the concept of using temperature measurement to detect vulnerable plaque didn't really begin to catch on in interventionalist circles until the thermographic studies of the Athens group were published in a Circulation article in 2000. "Stefandis really got this going with a clinical study he did with a catheter that had a single temperature sensor on it," he notes. "But [the catheter] had a lot of limitations, and when Leo [Diamantopoulos] came to Rotterdam, his aim was to build something that was better than what they had used in Athens."

A week after that initial meeting, Yianni was back in Serruys' lab, doing due diligence for the Munich investor group on Thermocore, which Diamantopoulos and his colleagues has formed just a month earlier to commercialize their catheter design. When the Munich investors proved reluctant to invest in Thermocore because it didn't have any experienced management, Yianni was invited to join as CEO.

Ironically, even with Yianni now serving as its chief executive, Thermocore and the Munich fund couldn't in the end come to terms on an investment. (A large fund, the group wanted to put in 10.5 million euros and take 70% of the company; Thermocore eventually wound up raising half of that with a group of private investors and a venture capital group, Bank of Cypress Ventures, in exchange for 35% of its equity.) By the end of 2000, Thermocore's initial financing was in place. "The key was to move forward quickly and protect our intellectual property," Yianni recalls. "Even though Leo had been working on vulnerable plaque for four or five years, we knew others would jump on the bandwagon, trying to come up with different devices and catheter configurations to measure temperature inside arteries."

First to Clinic, First to Market

Indeed, notes Yianni, between June of 1999, when he joined Thermocore, and mid-2000, when he was arranging the company's first financing, interest in vulnerable plaque among investors and cardiovascular companies was taking off. "When I first started going around with this technology two years ago, the response I got was ‘vulnerable what?'" he says. "Now it's on everyone's lips. But we knew from the beginning how hot this area would become and we also knew that we'd have to move fast.

"We've seen this before," says Yianni, "an area where there are leaders, and then a number of start-ups come along as followers when the light bulb suddenly goes on and everyone realizes how important the area is going to be." Thermocore officials "knew we had a technological lead and the only way to keep that lead was to move things forward quickly," he goes on. "So we began to put the right people in place to develop the device, produce the electronics, and do everything we needed to do to be first in clinic and first to market. And we were the first in the clinic."

In fact, while the catheter technology Diamantopoulos developed in the Rotterdam cath lab was an important start, "it's gone through considerable refinement and a number of iterations since," notes Yianni. More to the point, Thermocore outsourced much of its early device development to a UK consulting firm. "We used a virtual approach and subcontracted the development," he goes on. "We didn't go out and hire engineers and set up labs—it would have taken too long and we wouldn't be where we are now if we had tried to do it ourselves."

As with an early mover advantage in any device segment, the benefits of being first lay not in creating a definitive technology per se, but in establishing a presence in the space. "If you're there in the beginning, you're more likely to get the best people to work with you, especially in terms of opinion leaders," he says, pointing to Patrick Serruys, who has been a guiding influence on Thermocore. At the same time, he goes on, "we're creating a new industry here," and having other companies play in the same area helps, too, particularly in things such as establishing regulatory paths and winning over payers.

Fast and Easy To Use

For physicians like Serruys, vulnerable plaque turns conventional thinking about coronary artery disease on its head. "When I was training in cardiology," Serruys notes, "everything was a matter of a fixed narrowing in the vessel and the amount of blood flow there. That's how we were taught." But discoveries in other areas of cardiology, most notably the fact that a significant number of AMI patients don't have high stenotic rates, have forced cardiologists to re-think their views of coronary disease. "We discovered that a large portion of our patients, up to 60%, did not necessarily have a severe narrowing," he goes on, "leading us to start thinking that perhaps the fragility of plaque could be the root cause of a lot of trouble."

Even so, Serruys notes, it was only recently that vulnerable plaque has become a hot topic, so to speak, in large part because "we didn't have an instrument to detect it." Conventional angiography doesn't work "because you will see things with angiography that look like a problem, but when you examine them with more sophisticated tools, they prove to be stiff calcifications. So conventional angiography isn't the answer."

Thus, while imaging modalities, such as OCT and MRI are emerging as potential tools, the first generation of devices designed specifically to identify vulnerable plaque have tended to focus on the measurement of temperature in the vessel wall as an indicator of the presence of friable plaque. Thermocore's first device is its Thermosense catheter. Once the catheter is inserted into the coronary artery, a sheath is withdrawn, exposing four small arms that have sensors on them to measure temperature. The catheter is then attached to a motorized device that pulls it back as the arms extend outward and in contact with the vessel wall, recording its temperature. (The arms are flexible to conform to lesions on the vessel wall as they pass over them.) As the catheter moves, it records real-time data, displayed on a screen, indicating by different colors when a sensor encountered a higher temperature. The data can be overlaid on a conventional radiolgraphic angiogram to aid in localization. Says Yianni, "The simplest way to help the cardiologist interpret the data is not to use any fancy 3D maps, but to use angiograms with which every cardiologist is familiar."

In addition, says Yianni, the Thermosense catheter is relatively quick and easy to use. Comparing it to an IVUS catheter, he notes, "With IVUS, you put the catheter in, take it out and do an intervention and then put it back in. That adds quite a lot of time." The average procedure time for the Thermosense device is six to eight minutes for a single vessel.

The key to Thermosense's design, however, are the four sensors that allow it to measure temperature on the vessel wall at different locations. "You need to touch the wall at a number of points so you can measure the temperature around the circumference," says Yianni. "If you just measure the temperature at a single point, you're missing the other 359 degrees."

Applying sufficient pressure to ensure that the temperature probes touch the wall at all times is critical—otherwise the cardiologist will get what Yianni calls "flyover" and could miss important trouble spots in the plaque within the vessel wall. At the same time, the pressure has to be delicate enough that the vessel wall isn't damaged by the sensor itself—risking an iatrogenic problem where there previously was none. "We know that if you put any device into a coronary artery and touch the wall, you have an effect," he notes. If simply touching the wall exerted enough pressure to do damage, he argues, patients would be having MIs every time a guide wire is used. "We've measured the pressure on the wall created by our device against others, including IVUS catheters and traditional guide wires, and found that even guide wires being pushed forward create more damage than our device being pulled back gently with our motorized system," Yianni goes on. "We've been able to satisfy everyone that we're not causing damage," though he concedes it is the primary concern of most physicians about products of this type.

Measuring Function

Arguing for the value of thermographic measurement over more conventional imaging modalities such as angiography, Yianni notes that when a physician looks at an angiogram, "there are a number of spots where you see something that isn't right, but the question is, is it dangerous? We don't know; that's what this whole embryonic [vulnerable plaque] industry is all about—devising techniques and devices that can potentially determine what might be dangerous from what's not. And that gets down to being able to measure functionality."

But, as noted, while there seems to be clear evidence linking higher temperatures and the appearance of vulnerable plaque, other questions about vulnerable plaque, such as what level of temperature increases provoke rupture of the fibrous cap or whether there are other triggers that cause the cap to rupture, remain unanswered. "That's what we have to determine in the future," says Yianni. "Is it [i.e., the critical data point] the maximum temperature in the vessel wall? Is it the burden of temperature over a certain vessel length? Is it worse to have two spots at 0.1 degree elevation or one spot at 0.2 degree? We don't know and that's the journey we're embarking on—to map this exciting and challenging new field."

Headquartered in Guilford, England, Thermocore will soon have a US base as well. The company signed its first collaboration with one of the large interventional players—Yianni won't say whom—and did its first case in April of 2002 in Antwerp. "We missed doing [the case] in the first quarter of 2002 by one day," says Yianni, conscious of the value of maintaining a technological and clinical lead.

The data generated by Thermocore's clinical studies is critical to adoption of thermography devices, data that not only proves that the device can register temperature, but also in the future "could help demonstrate a clear link between the detection of heat and clinical events," says Yianni. Thus, Thermocore's trials will look at patients who have already had an MI and, monitoring their plaque temperature at different points, follow those patients for six months and a year to establish the correlation between high temperatures and subsequent problems.

Indeed, Yianni argues that one reason thermography will be adopted more readily than IVUS has been is that thermography companies have learned from the experience of the IVUS manufacturers. "The mistake the IVUS companies made is that they were never able to go to cardiologists and show there was a clinical benefit from using IVUS. By the time they had the data, everyone was convinced IVUS was just a research tool." And though he believes thermography will, in the beginning, be reserved for high-risk patients—diabetics and those who have a history of cardiac events, for example—Yianni argues that widespread adoption of the technology should follow—once the data is in place. "Ultimately, I think this will be very widely used because in the trials that we're going to set up, both our own and those in conjunction with partners—I think we'll demonstrate that cardiologists need this, even when they see non-significant disease in other areas," he says. Thermocore's trials will even look at systemic markers, he says, "trying to establish the correlation between temperature, vulnerable plaque events, and these markers."

A Transient Phase

To date, Thermocore has completed its clinical trials in Antwerp, which enrolled 33 patients, and has done almost a dozen in Rotterdam, with no adverse clinical events. Indeed, the company has already received its CE mark, which it got in September, on three parts of its system: the Thermosense catheter, the console, and the pullback mechanism.

That's not to say that Thermocore is complacent about its technology development efforts. As noted, Yianni points out that early diagnostic therapies fall into one of two camps—functionality-based approaches such as thermography and imaging technologies such as IVUS and OCT. "Perhaps the ultimate solution might be a combination of the two," he says. "We're starting with thermography but also looking at what can be combined with it to give us a cross correlation and additional information—the ultimate picture of what's going on." It may be that thermography alone can do that, he says, but it may also fall short, and so Thermocore is already exploring other technologies. "We expect to be a long-term player and therefore need to be thinking in terms of long-term solutions," he goes on. "If you're not thinking in terms of a pipeline, of what's coming next, you'll quickly find your technology is out of date."

Indeed, for as effective as thermography systems are at detecting temperature variations, even thermography's advocates question whether it represents a long-term technological solution to the identification of vulnerable plaque. Patrick Serruys argues that fifteen years from now, vulnerable plaque detection is likely to be done non-invasively, by sophisticated imaging equipment that enables mass screenings of asymptomatic patients. "My gut feeling is that the current invasive approaches will be a transient phase, seven or ten years," he says. "The real solution is to test patients for things like cholesterol or CRP and then do non-invasive screening."

More to the point, though its own technology is primarily a diagnostic tool, Thermocore recognizes the need to play in both therapy and diagnostics, and the company is currently working with several corporate partners on different aspects of therapy, including a cryologics-based company, whose device would, in effect, "cool" the heated plaque, and a brachytherapy company. "Drug-eluting stents wiped brachytherapy off the map, but vulnerable plaque could be very important to it," says Yianni.

Companies with drug-eluting stents could also benefit from vulnerable plaque detection, though again, more as a drug delivery vehicle than as a stent per se. "Most of the [vulnerable plaque] lesions are 20-50% stenosed," Yianni notes. "Why do you need a piece of metal in there permanently to hold the vessel open?" Patrick Serruys goes a step further, arguing that stent companies will begin to develop stents customized for specific lesions.

A Gatekeeper to Opportunity

Still, it is the diagnostic tool that leads the way in vulnerable plaque. Yianni says he agrees with people who argue that without a therapy, diagnosing the problem of vulnerable plaque is meaningless. But, he says, there already are therapies. "The interventionalist has a number of tools and therapeutics available today, and one or more of them will be applicable to vulnerable plaque," he argues. "But the only way you can start investigating those therapeutics is to identify where these plaques are and how many of them there are."

But there's a challenge for vulnerable plaque companies, particularly small device start-ups like Thermocore: the therapeutic implications of vulnerable plaque aren't simple—it's not just a matter of attaching a different probe to the end of a catheter to turn a diagnostic tool into a therapeutic one. Noting the questions that remain about the implications of higher temperatures, Yianni notes, "Before we can even start doing therapy, we need to know more about what all of this means. How could anyone do otherwise?"

Thus, if continuing research suggests that vulnerable plaque is a localized problem, present in one or two arteries in any given patient, the therapies of choice will most likely be device-based; if, on the other hand, scans of asyptomatic patients find widespread and systemic vulnerable plaque, the appropriate therapy is more likely to be pharmacological. That's why Yianni sees start-ups like Thermocore as gatekeepers to the tremendous potential that other companies may realize. "Companies like Medtronic, Cordis, or Guidant would love to turn the drug-eluting stent market from a $5 billion market into a $9 billion market, that's really why they're interested in this," he notes. Thermocore is also talking to some major pharmaceutical companies, who are trying to prove that greater use of statins is the best therapeutic approach to vulnerable plaque. "We're gatekeepers," he says. "We don't have to hang our hat on one technology because all of the big companies with therapies are coming to us."

The Mouse that Roared

For catheter-based device companies, the prospect that therapy will drift toward systemic treatment threatens to overwhelm their technology. Patrick Serruys notes there's already a pharmaceutical regimen, consisting of aspirin, clopidigrel, and statins, that can go far toward dealing with the underlying causes of vulnerable plaque. "We're already using these and they'll have an impact on stopping the disease in the patient," he says. "And I'm sure the pharmaceutical industry will be looking for even more specific therapies." But even Serruys notes that systemic approaches may not be appropriate in all cases. "If you've got restenosis in one centimeter of your coronary artery, you're not going to intoxicate the body with a drug that goes everywhere. It doesn't make sense."

That's why many early adopters in vulnerable plaque believe that the most likely therapy will be a combination of a device-based intervention and a drug regimen. To industry veteran John Yianni, there's a nice irony: in a medical device industry that has gradually separated into two camps, very large companies on the one hand and small technology start-ups on the other, vulnerable plaque may be one where "the little guys can kind of exploit the opportunity to their own benefit," he says, referring to the interest large device players are showing in this market.

Still, Yianni is realistic about the likely trajectory for a company like Thermocore. Despite vulnerable plaque's enormous potential and Thermocore's early role, he predicts a somewhat typical course of events. The days of companies like AVE, small innovators who take a new technology and leapfrog much larger competitors, are all but past, he says: The large cardiovascular giants "have such a tight grip on the market that anything that looks as though it has value is likely to be taken up very early by those companies." And, indeed, each of those companies is currently looking closely at the opportunities and potential impact of vulnerable plaque; one of the most active, Guidant has at least one clinical trial underway in Boston, covering OCT.

As with any device play, Thermocore's exit strategies include an acquisition by a large competitor or an IPO, Yianni notes, "but there aren't a lot of companies going public these days." Not that the buzz around vulnerable plaque wouldn't make Thermocore a better candidate than most start-ups for a public offering—if any device opportunity can capture public investors' imagination, it's this one.

But Thermocore is playing a much more conventional hand. Thermocore and rival Volcano are similar in many respects, not the least of which is their early focus on thermography. But in one large philosophical sense, they're taking very different approaches: where Volcano is betting the moon, raising a lot of money and hedging all bets, Thermocore is, by comparison, much more focused—on both a single technology and single approach.

That's not to say that Thermocore isn't exploring technologies in other aspects of vulnerable plaque. "We have a well thought out development program, looking at next-generation devices and other potentially complementary technologies to combine with ours," notes Yianni, who insist that Thermocore, too, is "flexible" when it comes to technology development. But it is so only in the sense that it will, as noted, continually iterate and enhance its technology design to make it as effective as possible. In all other regards, the company is, he goes on, "very focused on the first generation device in terms of getting it out there in the hand of cardiologists who are beginning to make the link between the detection of heat and clinical events."

Indeed, despite the need for flexibility, Thermocore's approach seems diametrically different from Volcano's. About the latter's recent $24 million funding round, Yianni says, "They've raised a significant amount of money and they're to be congratulated." And he denies that it puts pressure on Thermocore, even with its early technology lead, "because we're so focused," he says. If anything, Yianni goes on, Volcano's money-raising efforts "[are] actually helpful to us because it's a validation of the whole field when someone does a financing like that."

Such a validation is important to companies like Volcano and Thermocore—particularly since thermography is a technology designed specifically for vulnerable plaque—engaged, as they maintain, in building not a device, but an industry. It's an industry, however, that turns on its head many of the principles of the conventional medical device industry in which they were nurtured.

Next month: a look at Imetrx and Medispes and the paradigm shift from structure to biology.