Medical Device's Ice Age

Medical researchers have known for more than 50 years that cold can be an important cardio- and neuroprotectant, but concerns about the side effects of deep hypothermia and sloppy, time-consuming procedures turned physicians away. Advances in device design as well as new research on the value of mild hypothermia have unlocked the potential of the therapy to function as a temperature management tool in surgery and critical care, to protect against injury from emboli in cardiac surgery, in resuscitation and trauma, and perhaps the biggest opportunities, in stroke and heart attacks.

The hottest new thing in devices is also the coolest, as a host of small companies explore the various applications of cold therapy.

by David Cassak

• Medical researchers have known for more than 50 years that cold can be an important cardio- and neuroprotectant, but concerns about side effects and sloppy, time-consuming procedures turn many physicians away.

• Advances in device design as well as new research on the value of mild hypothermia have led to renewed interest in cold therapy and provided an opportunity to a host of companies.

• Though deep hypothermia has been used in selected surgical applications, the potential for mild hypothermia is broad: as a temperature management tool in surgery and critical care, to protect against injury from emboli in cardiac surgery, in resuscitation and trauma, and, perhaps the biggest opportunities, in stroke and heart attacks.

• Despite a shared faith in the value of cold therapy, however, each of the recently launched cold therapy companies is pursuing a different target market or indication, though, in time, their paths are likely to cross.

• In the 1950s science fiction film, "The Thing," a creature frozen in an ice block in the Artic is suddenly thawed and brought back to consciousness. Though not quite a fully-functioning member of society—it is, after all, a space alien—the creature is, in virtually all other respects, physically fit.

• Closer to our own times and more clinically rigorous, physicians have, since the 1930s and 1940s, been vouching for the neuro- and cardioprotective power of cold, and lowering body temperature remains a standard of practice in selected surgeries today. But current methods to lower the body's temperature, such as using ice or cooling blankets, are slow and crude. What's been missing are sophisticated devices that can cool and reheat major body organs quickly and efficiently.

• Over the past two to three years, a number of small companies, including Cardeon Corp. , Radiant Medical Inc. , Innercool Therapies Inc. , and, in a slightly different play, Cryovascular Systems Inc. , have sprung up seeking to adapt advances in endovascular device design to new clinical findings about the value of mild hypothermia and the benefits of temperature management in a variety of clinical specialties.

Some Questions

As noted, physicians and medical researchers have been touting the value of cold therapy for more than 50 years. Indeed, for decades, deep cooling has been routine in selected cardiovascular and neurosurgical surgical procedures where slowed organ function or blood flow is considered essential.

But physicians, despite its protective powers, have largely resisted any broader application or embrace of cooling and its benefits. Today, some 20-30% of surgical patients get full body cooling, though the number is dropping. Says one company executive, "The only reason doctors would go to deep hypothermia today is that they have no other choice: you cool the patient down so far the heart stops long enough to work on it then you jolt them back to life."

But it was the accumulating body of evidence in the late 1980s and early 1990s about the value of mild hypothermia—lowering body or organ temperatures by 4-5 degrees Celsius rather than 15 degrees or so—that provides the clinical rationale for the new focus on hypothermia.

At the same time, other clinical advances have also helped to fuel interest in hypothermia. For example, Paul Yock, MD, director of the Center for Research in Cardiovascular Interventions at Stanford University and an advisor to several of the hypothermia companies, notes that researchers have begun to appreciate the importance of tissue preservation in cardiovascular care. "In angioplasty, we've been looking at TIMI flow for years and saying that if we get TIMI III flow, the patient's doing well," he says. "Well, sometimes that's not true. There are a wide range of outcomes with TIMI III flow, depending on the health of the tissue and the degree of micro-flow [of blood] in the tissue."

As such realizations take hold, the protective quality of cold therapy looms as an attractive adjunct to existing therapy. Says Yock, "What we're coming to understand is that it's not just what's going on in the major arteries that's important, it's also a matter of what's going on in the tissue and whether we can preserve the tissue." That's where cold's protective nature fits in.

To be sure, there are still questions and doubts. Yock concedes that "the micro-mechanisms are still pretty unclear, so we don't really understand [hypothermia] all that well." Moreover, there are concerns, some left over from the days of deep hypothermia, about significant side effects from cooling—side effects such as infections, pneumonia, excessive bleeding and blood clotting.

Even with mild hypothermia, concerns linger, particularly about the risk of arrhythmias—that cooling the body may disrupt the heart's normal rhythm. Even Paul Yock notes, "My biggest worry going in was arrhythmagenesis from cooling. If you're talking about the myocardial infarction application, you're in a vulnerable period anyway. The last thing you want to do is to create extra rhythm problems." Yock says that it remains to be shown that arrhythmias won't be a problem, though he notes that none of the early preclinical studies done by the hypothermia companies show any such increased risk.

And even where the patient isn't actually at risk for complications, historic approaches to cooling, most notably ice and saline flushes, are often messy, unwieldy, unpleasant, and unpredictable in practice. Says one industry official, "Talk to any ICU nurse and they hate it when patients come in with whole-body cooling because trying to manage their blood pressure is so difficult."

But those very problems give the new hypothermia companies hope: advanced endovascular device technology and new approaches to cooling therapy promise to minimize, if not eliminate most side effects, while making the procedure easy, quick, and convenient for physicians looking for new solutions to some serious clinical problems.

A Play in Stroke

Redwood City, CA-based Radiant Medical was launched in 1997 by a group of venture capitalists, led by Mark Wan of Three Arch Partners. "Mark had a vision," notes Ken Hayes, Radiant's CEO. "He wanted to start a stroke company." Three Arch, along with Alta Partners, Highland Capital Partners, and Weiss, Peck and Greer, each put in $300,000 to start Radiant without really knowing what technology they would pursue. "They knew there was a huge market with an enormous unmet clinical need," Hayes goes on, "and with no other real product solutions other than TPA." Indeed, with more than 700,000 strokes in the US each year and 1.5 million worldwide, Wan knew the potential was great.

As acting CEO, Wan's first hires were Mike Dineen, formerly of Devices for Vascular Intervention, now part of Guidant Corp. , and Target Therapeutics Inc. , a division of Boston Scientific Corp. , who is now Radiant's director of marketing and business development, and Tim Machold, Radiant's VP of R&D, who had worked at a number of device firms, from Advanced Cardiovascular Systems Inc. (now a division of Guidant) to Heartport Inc. and TransVascular Inc. Their assignment: to talk to physicians and study the literature to get a better understanding of stroke and come up with possible technological solutions.

What Dineen and Machold found was a deep body of literature, from both clinical and preclinical settings and extending as far back as the 1940s, touting the neuro- and cardioprotective qualities of hypothermia. At the same time, however, they found, says Hayes, that "the medical community lost interest because of some of the adverse events that occurred as a result of deep hypothermia."

In fact, despite the problems clinicians have had, cold therapy has routinely been used in selected procedures, most notably in the cardiopulmonary bypass (CPB) equipment used in most cardiac surgery, and by neurosurgeons in aneurysm surgery. More to the point, notes Hayes, over the last several years, "the literature on hypothermia in animals has become extensive—rats, cats, dogs, pigs, monkeys: there's a huge body of evidence to show that hypothermia is neuroprotective and there should be a role for it in medicine."

For device start-ups like Radiant, however, even more important than the clinical validation for hypothermia has been a lack of any progress in developing devices to help cool the blood. "The technology really hasn't advanced all that much over the years," Hayes goes on. "It's still the basic approach: cool the blood, protect the heart and brain, oxygenate the blood and put it back in the body." In neurosurgery, physicians typically open the skull and either pack the head in ice or pour ice-cold saline over the brain. Sometimes a cooling blanket or fan is used. When the procedure is over and the time comes to re-warm the body, warming blankets are used.

Even if such approaches works, they'd hardly qualify as elegant solutions to the challenge of hypothermia—they're extremely messy, for one thing. But the current state of the art has two principal flaws: first, controlling how cool the body becomes is extremely difficult—hence concerns about deep hypothermia. Second, current approaches are extremely slow. Cooling blankets lower the body temperature 0.5-1.0 degree Celsius every hour, with a target of a 4 or 5-degree drop. "That's just too slow," notes Hayes. "By the time the surgeon hits the target temperature, the procedure is over."

Flushing the patient with saline and increasing the amount of ice used only increases the mess without offering any more temperature control. And re-warming the patient, again at a rate of one-half to one degree an hour is also slow and cumbersome, complicated by the fact that patients can't be brought out from under anesthesia or moved to recovery until some progress is made or they'll begin to shiver uncomfortably.

Physician, Heal Thyself

"The current cooling and re-warming methods are simply outdated," notes Hayes. Still, the fact that surgeons will, in cases where neuro- or cardioprotection is critical, put up with such an approach "proves the therapy works," he goes on. What Radiant officials began looking for was a simple, elegant device solution to make wide-scale hypothermia practical. Radiant's solution: a catheter-based endovascular heat exchange system, called the SetPoint System, that provides physicians with a fast, precise, and easy-to-use method to do hypothermia.

To a large extent, they found their solution in the work of Robert Ginsburg, MD, a Stanford-trained interventional cardiologist, based in Colorado. Working in laser angioplasty in the late 1980s, Ginsburg began to explore the notion of creating endovascular catheters capable of heating and cooling. Once in Colorado, he found himself treating skiers and hikers exposed to extreme cold as a result of avalanches or other disasters, which helped deepen his understanding of hypothermia.

In time, Ginsburg wrote some patents around his endovascular catheters and built a fledgling company, called Thermocorps. For Radiant officials, the appeal of Ginsburg's work was immediate—they had begun to think about devices using very much the same principles and wanted to talk to him about licensing his technology. Ironically, when Radiant approached Ginsburg, he was recovering from a massive stroke. In early 1998, with Ginsburg unlikely to pursue his vision and with a small amount of debt on the company's books, Ginsburg's wife and business partners agreed to sell the company's assets outright to Radiant instead of simply offering a license.

Following its initial funding of $1.2 million, Radiant raised a second round of financing in October of 1998, this time for $12.9 million [See Deal].

As noted, Radiant's technology uses an endovascular heat exchanger. A venous catheter is inserted into the inferior vena cava through a small puncture in the groin. The catheter's balloon is then filled with chilled saline solution, turning it into a kind of ice pop but one that remains flexible because of the saline base. (The saline is constantly circulated at a rapid rate so that the heat absorbed from the warm blood doesn't cancel out the cooling.) "The balloon gets down to 5 degrees Celsius, and your blood's at 37 degrees," Hayes explains. "What happens is the balloon exchanges heat energy directly with the blood flowing in the vein, lowering your core body temperature." At the end of the procedure, the catheter becomes a warming tool—the saline is heated and the exchange now goes the other way, with a hot balloon warming cold blood.

Moreover, the device can cause a drop in body temperature of 4 to 6 degrees Celsius per hour and a warming of 2 to 4 degrees, thereby eliminating concerns that the process is too slow. And deals with any concerns physicians might have about the risks by providing only what Hayes calls "mild or moderate" hypothermia. "We really are only cooling the body to 32 to 34 degrees Celsius," he says. "That's deep enough to provide tissue protection but not have the complication risks."

A Shift to the Surgical Suite

Radiant's venous catheter is used for total body cooling, but it also has an arterial catheter, placed in the carotid artery, used to do regional cooling of the brain. While some physicians would prefer to do local cooling because of the complications and risks associated with deep hypothermia in total body cooling, Hayes notes that sometimes total cooling is inevitable: "If the procedure is going to take more than three hours, you're going to end up cooling the whole body unless you do something to warm the blood on the other side of the body to counteract the cooling process."

By May of 1999, Mark Wan was ready to step down as CEO and find someone to lead Radiant to the next level. In Ken Hayes, Radiant got someone with a deep, diverse background in medical devices. Hayes' most recent job had been president of Surgical Navigation Technologies (SNT), an image-guided surgery company, that was acquired by Sofamor-Danek [See Deal], which itself was later acquired by Medtronic Inc. and is now Medtronic Sofamor Danek [See Deal]. Prior to that, Hayes had worked widely in surgery and cardiovascular devices, running companies such as American Surgical Techniologies Corp., a 3-D visualization company eventually sold to Vista Medical Technologies Inc. , and the USCI Angiographic Systems business of CR Bard Inc. , before it, too, was sold to Medtronic's Arterial Vascular Engineering Inc. [See Deal]. And before Bard, Hayes got his start at Johnson & Johnson , where he worked at Ethicon Inc. before helping to launch J&J's Vistakon and Ethicon Endo-Surgery Inc. businesses.

Though it was Hayes' most recent experience at SNT, with its strong roots in the neurosurgery market, that had the most immediate appeal to Radiant, his extensive background cutting across many different surgical fields would come in handy, for the first application of Radiant's device will be not in neurology, but in surgery and critical care for managing the patient's core body temperature.

Indeed, Radiant sees wide application of its device in all forms of major surgery—the kinds of procedures in thoracic, vascular, orthopedics, GI, and gynecological surgery that typically take a long time. "Anywhere you have a large incision and a lot of exposure of tissue and organs to the air and the room is cold, managing a patient's body temperature is difficult," says Hayes. "Our device can help."

Radiant hasn't given up on the neurology/stroke application. But positioning Radiant's technology as a surgical tool helps speed commercialization—its first focus will be on surgical specialties as well as emergency medicine, where exposure is often a problem, and CCU/ICU, where fever management as well as temperature management is critical.

And Radiant is confident that, if the device is proven to be safe and efficacious, adoption hurdles will be small. Hayes, who lived through the minimally invasive surgery (MIS) boom of the early 1990s while at Ethicon Endo-Surgery and saw the training burden that brought, sees no such obstacles with Radiant's device. "Any physician who's ever placed a central venous line in the OR or emergency room or critical care setting can insert our catheter," he says. "It's very simple."

Moreover, Radiant's sales and marketing efforts will target not just surgical specialists, but also anesthesiologists, both because they spread widely over a number of different types of procedures and because body temperature could become another of a series of functions or signs that anesthesiologists monitor over the course of a procedure. "They're keeping their eye on temperature, blood pressure, cardiac output—all of those measurements—and the problem is they have devices to control all of them except temperature," says Hayes. And failure to accurately maintain temperature can have serious effects on patients—not just from unintended hypothermia, but from too much heat as well.

The Breakthrough Opportunities

In some cases, anesthesiologists will actually place the venous catheters and control the heat exchange during the procedure. But Radiant's key marketing target remains the surgeon specialist. "The surgeon's the number-one decision maker in the room, the one who decides what's used and what it's used for," says Hayes. "Anesthesiologists and nurses are part of the team and you want to train them to use the equipment, but the surgeon makes the call."

As it has grown, Radiant's business model and value proposition have changed subtly. From a company with a narrow application in a market with huge potential and significant unmet clinical needs, Radiant's device has become a kind of platform technology, reaching broadly across all surgical specialties. Stroke is an important market, but one of many markets and not necessarily the first. Says Hayes, "If you think about it, we started out as a stroke company, but now we're really an endovascular temperature management company with a platform technology."

And, in some cases, that makes getting a handle on Radiant difficult. Talking about the interest larger device players have, or might show, in Radiant, Hayes notes that Radiant isn't, narrowly speaking, a cardiovascular or neurological play; its technology resonates not just with cardiovascular companies, but with more broadly defined surgical product companies like Baxter International Inc. and Tyco International Ltd. as well, fitting with each, but in a different way. "We complement what J&J does," notes Hayes. "But we do so for five different divisions."

Longer term, applications in stroke and a closely related area, myocardial infarction, remain important because they represent what might be called breakthrough targets for Radiant—the kinds of opportunities Radiant's founders were looking for at the start. At the same time, they also pose a different clinical challenge—not the management of temperature during and after surgery, but the use of cold therapy as a neuro- and cardioprotective agent during strokes and heart attacks. (There's a similarly large opportunity in resuscitation and trauma, especially in cases where patients suffering from exposure to cold or heat need to have their body temperature brought back to normal quickly.)

Hayes notes that under the current standard of care, patients who show up at a hospital with an MI have one of four treatment options: a trip to the cath lab for an angioplasty; emergency bypass surgery; an aggressive dose of thrombolytics in the hopes of dissolving the clots; or simple conservative medical treatment if the physician thinks all of these are too aggressive and the patient's health would be compromised. "We see our device as a first line therapy for any one of those," he explains. As Radiant sees it, patients who present at an emergency room with a stroke or heart attack would immediately have a catheter inserted to bring the body temperature down and begin the cardio- or neuroprotective action of cold therapy while other adjunct treatment options are considered.

At last November's American Heart Association meeting, Radiant's VP of medical affairs, Michael Dae, MD, presented the results of studies done on pigs that showed a 95% reduction in damage to the myocardium using cold therapy during an MI. And Radiant believes cold therapy will also prove beneficial in dealing with another problem associated with stroke and MI: the injuries that can result from reperfusion. "There are now data to show that when you reestablish flow into vessels that haven't had blood for a while, there's the risk of cell damage," says Hayes. "Our studies have shown that if we can cool the vessel during the reperfusion period, we may be able to provide additional tissue protection."

Even beyond stroke and MI management, the combination of temperature management and neuro- and cardioprotection leads Radiant officials to hope that, in time, hypothermia might even be used prophylactically in some cases—helping high risk surgical cases by providing an extra measure of protection—or to make other therapies more effective—prolonging the time for a thrombolytic to work by cooling and slowing down the body's metabolic processes.

A Wake-Up Call in Surgery

If Radiant is, in some respects, a neurological company that became a general surgery play, Cardeon turns the approach around, positioning itself initially as a cardiovascular surgery company seeking to address the potential neurological problems that result from cardiac surgery, and will later leverage its technology to address other opportunities.

Cardeon was founded in 1996 by Wilfred Samson, a former executive at ACS and later Guidant, and a group of cardiac surgeons. While success in cardiac surgeries, such as coronary bypass or valve repair and replacement, is generally assessed in terms of the surgery itself—patency of the graft, for example—Samson and his colleagues realized that one important outcome of the procedure had little to do with the skill of the surgeon, i.e., the neurological state of the patient following surgery.

Stroke resulting from debris released during cardiac surgery, is only the most visible of potential problems, notes Samson, and is well documented in clinical literature. "Stroke usually manifests itself by a visual impairment, an inability to speak or focus or swallow," he notes. "But there's a large body of information that indicates that, beyond outright stroke, cognitive impairment may exist that isn't quite so evident in a normal verbal discussion [with the patient]."

Now, many patients experience some form of neuro-cognitive deficit in the days immediately following surgery, notes Michael Regan, Cardeon's COO, because of the after-effects of anesthesia or some other factor. But further out, 20-25% of patients experience residual neurological problems 30 days after their surgery; 18% are still having trouble a year later. "These problems run along a continuum," he says, "from not being able to remember a phone number or recognize a face to loss of some motor function." Moreover, many surgeons assess neurological problems with a simple reflex test, but, as Regan notes, "the patient's reflexes may be fine, but he used to be a prominent lawyer or architect, and he's just lost that part of his brain that helps him do that."

Neurological problems may also result from hypoperfusion or insufficient blood flow back to the brain because of clogged arteries, or from brain hyperthermia—as perfusionists re-warm the patient following surgery, "there is a risk of overshooting the mark and the brain gets overheated," Regan explains.

Moreover, while risk of neurological problems has always been an issue, it is, arguably, getting worse. Regan notes that there are several risk factors that make a patient more susceptible to a neurological event—pulmonary dysfunction or diabetes, for example. But two of the factors, age and previous history of coronary disease, are most important. And as more and more patients are treated first, and repeatedly, with angioplasty and stents, those patients that become surgical candidates tend to be older and sicker. As Regan explains, "By the time the patient gets to surgery these days, he or she has already been through angioplasty and stenting a couple of times, and is pretty far along in disease progression." In fact, age alone is an important consideration, he goes on, since studies show that risk of cerebral vascular events "increase exponentially when you get past the age of 75."

Warm Heart, Cool Brain

Cardeon officials recognized that while there were no specific devices to help protect the brain against surgical side effects, particularly those related to emboli, hypothermia or cooling the brain during surgery as a kind of neuroprotection was well established. "In the event that an embolus, for instance, was to get to the brain," notes Wil Samson, "if the brain is in a cool, protected state, you buy time for that embolus to resolve."

But existing hypothermia strategies have been falling into disfavor at many hospitals over the past several years. For one thing, the process of cooling the patient with ice, controlling his or her shivering, and then re-warming the body, is time-consuming. And re-warming, as noted, carries its own risk of overheating the brain in an effort to bring body temperature back to normal.

There are other complications with total body cooling—such as excessive bleeding and intestinal problems. The dilemma, as Cardeon officials saw it, was clear: "The body likes to be warm," notes Samson, "but there's protection in keeping the brain and heart cool," most notably in reducing the threat of emboli by slowing blood flow to the brain, a blood flow that often carries emboli and other debris. "The challenge was," he goes on, "could we find a way to segment the aorta, to cool the brain while keeping the body overall warm?"

Following his retirement from Guidant, Samson was introduced to a number of cardiac surgeons and together with some engineers, they began to work on a device that would provide local cooling, obviating the need for total body cooling. Combining cold therapy with circulation segmentation and prioritization, Cardeon seeks first to re-route emboli to prevent them from getting to the brain. In the event that emboli do slip through, cooling the blood helps minimize the damage they can do by slowing blood flow; finally, cold's fundamentally neuroprotective character helps further to minimize any brain damage by providing time for emboli resolution. It's a system Cardeon calls Targeted Circulatory Management. "In essence, we're offering three different levels of protection," says Mike Regan.

Cardeon is currently working on three catheter-based technology platforms, and Samson calls Cardeon's portfolio of products "evolutionary." Its first device, called CNPB(CardeoNeural Pulmonary Bypass) and introduced in March 2000 under an IDE, is based on a traditional cross-clamp procedure and utilizes a multi-lumen catheter system in place of the cannula that in typical CABG surgery would hook up to the cardiopulmonary bypass systems. Cardeon's system connects to the CPB pump but has an additional heat exchanger to control the temperature to the brain. At the beginning of a surgery, the surgeon pumps cold blood to the head and warm or normalthermic blood to the body, dropping the temperature in the brain by 3-5 degrees within minutes. Early studies by Cardeon suggest that lowering brain temperature alone diminishes cerebral blood flow requirements to one-third normal levels and can, therefore, reduce emboli flowing to the brain by as much as 50%.

One benefit of the Cardeon system is that when the procedure is over, the warm blood in the body can quickly and safely bring brain temperature back to normal. "Because it has so many micro-vessels, the brain is an excellent heat exchanger," says Wil Samson. "The body warms the brain naturally and the brain, through auto-regulation, decides what perfusion it needs. You don't run the risk of overheating the brain." And because Cardeon cools only the brain, it minimizes some of the complications of total body cooling—such as excessive bleeding and arrhythmia—while overcoming one common surgeon complaint: the length of time necessary to cool the body. Says Mike Regan, "One of the reasons fewer surgeries are done with total body cooling is economic. Hospitals have a limited number of operating rooms and have to get cases in and out in a timely manner."

The company's second product, ABC, which already has 510(k) approval—CNPBwill require PMA approval—is designed to replace the cross-clamp and arterial return cannula in traditional CABG surgery, but does not involve different brain/body temperatures. With ABC, a balloon on a cannula inflates, acting like a cross-clamp to segment the heart from the rest of the body's circulation, and the dual-lumen cannula allows for perfusion and cardioplegia delivery to the patient.

Finally, a third device, Cobra, is in humans and an IDE feasibility study is underway. Cobraprovides both local cooling of the brain and protects it from emboli, utilizing a catheter-based device that is inserted into the aorta during CABG where it separates the brain and corporeal circulation. In the process, it re-routes downstream to the corporeal circulation any emboli that may be generated either from the heart or along the ascending aorta.

Cardeon is preparing to launch its ABCdevice in the US and expects to begin selling its Cobra unit in Europe shortly. In addition to internal technology and patent development, Cardeon has worked closely with and licensed some patents, pertaining specifically to the segmentation of the aorta, from the University of Pittsburgh . The company's initial financing came from Samson himself and venture firm Mayfield Fund. It did a Series B financing, including Mayfield, Guidant's Compass group, and several angel investors. A Series C round last October was made up of different angel investors, as well as Mayfield and Compass. Company officials plan to raise a new round in Q1 2001.

Creating Surgeon Awareness

Though between 20% and 30% of all CABGs now employ some type of hypothermia, Mike Regan argues, that figure has been falling because of what he calls perceived problems with systemic hypothermia and the time required to achieve total body cooling. And Regan thinks that, initially, at least, 15-30% of total cardiac surgery cases remains a realistic target market for Cardeon. "At first, surgeons will pick a cohort of patients they feel will benefit most from the device, and that's likely to be sicker patients," he says.

But over time, Regan goes on, "if this proves to have the benefit we think it will, we believe this could become more of a standard of care." Moreover, though Cardeon is currently focusing on open surgery, new surgical approaches, most notably minimally invasive beating heart surgery, run the risk of emboli because the surgeon is rotating and manipulating the heart more during the procedure, says Wil Samson. Procedures where surgeons routinely use cross clamps or side-biting clamps also increase the risk that emboli will be released. "If you ask a surgeon what's the worst thing that can happen, it's a patient suffering a stroke," adds Mike Regan. "If we can show that we can minimize that risk, this should be widely adopted."

But Cardeon officials know that for all of the clinical evidence for hypothermia, even a device that's easy to use and not time consuming faces obstacles to adoption, if only because there's a kind of disconnect between cardiac surgery and the problems that result from neurological events. Regan recalls asking a surgeon a couple of years ago what percent of his patients experience a stroke. "He said, ‘I don't know, maybe 1%.' But then he thought some more and said, ‘It could be higher because once the patient leaves the OR, I don't always know what happens because he reverts to the care of the primary physician.' There are a lot of surgeons who know that strokes occur but think that it's the other surgeons' patients who have them."

Wil Samson agrees. "The difficulty today is that the surgeon's job pretty much ends shortly after surgery," he says. "Whether the patient gets discharged to a nursing facility for rehab, whether he or she remembers his children's names, or winds up eventually continuing a career, is pretty much secondary." Moreover, the fact that many patients suffer some degree of neuro-cognitive dysfunction and much of that can reverse within a reasonable amount of time, makes the problem secondary to the condition of the heart following surgery. Says Samson, "You really have to go back and talk to the patient, to see how many went home, how many went back to their careers."

As Radiant has found, cardiac surgeons are, of course, an important sales and marketing target for Cardeon, but so are cardiovascular anesthesiologists, notes Mike Regan, "because they're the ones managing the brain/blood barrier." But company officials are also well aware that in order to make surgeons willing to adopt their technology, they have to offer something easy to use and comfortable. "Cardiac surgeons are, by nature, conservative," Regan goes on. "When you do procedures as complex as the ones they do, it's almost got to be by rote. There are so many things they have to be aware of during the procedure, even one small change may make them reluctant to try a new product."

"Our goal was to begin with simpler products and to continue to allow them to evolve into more complex, sophisticated systems," says Wil Samson. "We've seen too many companies introduce new technologies that immediately jump to the nth iteration, where surgeons have to be sent to training centers to learn how to become surgeons all over again. We were very careful not to create with Cardeon a new, steep learning curve, but to begin with a device that's very similar to things they're using today."

Interestingly, competition for Cardeon is more likely to come not from other hypothermia companies but from emboli protection and collection companies such as PercuSurge Inc. , now part of Medtronic, AngioGuard Inc. , part of Johnson & Johnson, Embol-X Inc. , and MedNova Ltd. Mike Regan acknowledges that such companies are addressing similar clinical problems. But, he argues, the fact that those companies are targeting interventional procedures, primarily in carotid arteries and SVG, rather than bypass surgery, means Cardeon will likely face them less head-on in direct competition.

To the extent they do overlap, Cardeon's technology is better suited for surgeons doing CABGs, Regan contends. Ultimately, he goes on, hypothermia in combination with emboli control is simply a better way to deal with the problem than filters or traps. Says Regan, "With filters, if the filter is fine enough to catch what it needs to, it's likely to clog; if it doesn't clog, it's probably not fine enough." Moreover, hypothermia offers what Regan calls "global protection" against emboli. With other approaches, physicians have to anticipate where and when the embolic event is likely to take place in order to place the filter or trap; by cooling the blood to minimize flow, Cardeon's device provides a broader level of protection. "We're not trying to predict where the event is going to happen," says Regan.

Moreover, preventing or re-routing emboli per seis only part of what Cardeon is trying to do with cold therapy. Cardeon considered using a filter approach and in fact has several filter patents, says Wil Samson, but "emboli is only part of the problem. We know the brain is going to receive debris at different times during the procedure. What we want to do is to become the gatekeeper for the brain, a device that controls temperature, blood flow, oxygen content, and the redirection of emboli."

A Natural Place to Start

Granted that broader vision, Cardeon officials see significant opportunities in other clinical areas, the same ones identified by other hypothermia companies: trauma, resuscitation and, most obviously in CNS and stroke. In orthopedics, for example, hip surgery generates a lot of debris, and company officials have high hopes for trauma therapy. "Gunshot wounds, severe hemorrhaging, loss of hemodynamic control—if we're the gatekeeper to the aorta," explains Samson, "we can stop the blood from going to the descending aorta and protect the brain by cooling it so it needs less blood and prioritizing blood flow so that what blood is left goes to the brain." Moreover, given that many trauma patients also suffer heart attacks, hypothermia's cardioprotective qualities can also help to limit damage as much as possible.

Finally, in stroke, Cardeon's approach, which embraces blood flow and localized therapy, could broaden the treatment window for TPA, for example, by cooling the brain and thereby lengthening the time the drug can work. Says Samson, "We can also concentrate the solution to the neuro-circulation system rather than the whole system."

Still, given the backgrounds of Cardeon's founders, cardiovascular surgery was a natural place to start. Mike Regan notes that for start-ups, managing resources and opportunities is critical. "Stroke is a very appealing goal for us, but trying to do the proof of efficacy of the device can be difficult," he goes on. Regan believes Cardeon can eventually establish a leading position in stroke, "but we've got to get the proof of the therapy in place first. And of all of the clinical areas we could go into, we felt that cardiac surgery is the most controlled procedure, with the most recognized database and the most studied outcomes in medicine today." Indeed, a focus on stroke would require a shift of emphasis for Cardeon given its focus on re-routing of emboli since, as Regan points out, "with stroke, by the time the physician sees the patient, the embolic event has already occurred."

Wil Samson echoes the importance of focus. "There's always a delicate dance between long-term survival and short-term vision," he says. "A company has to balance the various aspects of credibility in the medical community, investor return, ability to sustain itself through the various iterations of its vision before it can embark upon the broad array of applications." Cardeon could have gone directly after stroke, he says, "but we wanted to focus first on a platform that has a high probability of proving itself."

That's fine with San Diego-based Innercool Therapies, whose play in hypothermia will in fact focus precisely on stroke and neurology. Of all of the hypothermia companies, only San Diego-based Innercool, actually has roots in cold therapy; founder John Dobak, MD, launched CryoGen Inc. in the early 1990s to develop endometrial ablation devices using cold. (A recent CryoGen spin-off, CryoCor Inc. , makes devices used in atrial fibrillation therapy [See Deal].)

But Dobak's inspiration for Innercool came not from Cryogen per se, but from a story in an airline magazine he was reading one day in 1997 on a trip home from the East Coast. "It was a story about a kid who fell into a lake, and they revived him," he recalls. "He was underwater for something like 45 minutes, and when they pulled him out and resuscitated him, he was fine. And the reason was, said the doctors, the water was so cold, hypothermia protected his brain."

Dobak reasoned that if freezing water could act as a neuroprotectant, so would a device that cooled the brain, and he bet that he could develop a device to duplicate the positive effects of cooling. Like the founders of other hypothermia companies, Dobak found, as he did more research, that the literature on cold as a neuroprotectant was rich and since the 1990s, had been accumulating in even greater volumes.

Dobak focused on the work done by a Florida-based medical researcher, Myron Ginsberg, MD, who in the early 1990s, established that even mild hypothermia—lowering the body or organ temperature by 5 degrees Celsius—could protect brain tissues, an important advance since earlier work on hypothermia had established neuroprotection with deep hypothermia but, for reasons already cited, deep hypothermia raises concerns among doctors regarding complications.

Like other hypothermia advocates, Dobak knew that the clinical value of cold therapy wasn't in doubt—the obstacles lay in the methods available to physicians to do the cooling. "I learned that the real problem was how to cool the patient," he says. "Current methods were very cumbersome and inefficient, and time is very important so the cool down rate is critical." Extracorporeal devices wouldn't work, he concluded, because of potential complications; instead, Dobak would pursue direct blood cooling using an intravascular catheter.

A New Treatment, But Not a New Procedure

Innercool's device offers total body cooling, though the company's initial efforts focused on focal cooling. Indeed, around the time that Innercool was launched, Abbott Laboratories Inc. was sponsoring a study of a therapy called PROACT, which looked at inter-arterial thrombolysis for stroke, using a procedure that combined catheter-based delivery systems and drug therapy to dissolve clots. "We saw a nice synergy between focal brain cooling in the carotid artery and inter-arterial thrombolysis," recalls Dobak. "We thought we were onto an ideal therapy: we'd park our catheter in the carotid artery and do focal cooling while removing the clots."

But when the PROACT therapy wasn't approved by the FDA, Innercool switched to total body cooling through a venous catheter. Dobak still calls focal cooling, "the ideal therapy," because of the risk of complications associated with total body cooling. But the pragmatist in him also suggested that total cooling was, for the start-up, "probably a better way to get started," he says.

That's not to say that Innercool won't also be promoting focal cooling—Dobak argues that there's a role for both. But from the very beginning, he goes on, Innercool's goal was to create a device that was close to what physicians are already comfortable using. "Placing catheters in the central venous circulation is a common procedure," he notes. "We weren't trying to invent a whole new procedure; it was a new treatment paradigm but not a new procedure."

Indeed, implementing the Innercool device is as simple, for a physician, as placing a central venous catheter. "It's a very common procedure, done on the order of a million times a year," says Dobak. "If you're going to be treating stroke patients in an acute setting, you don't want a very complicated procedure that delays implementation of the therapy. One of the big pluses for us is that this is a straightforward, standard medical procedure."

At the same time, critical to Innercool's design effort, led by Innercool co-founder, Juan Lasheras, PhD, chairman of the mechanical and aerospace engineering department at UCSD and an expert on fluid mechanics and heat transfer, was ensuring that the device would be powerful enough to cool and re-warm rapidly, using saline as a medium for heat exchange. Says Dobak, "If you look at all of the clinical requirements—rapid cooling of the patient, tight temperature control, the ability to re-warm, and ease of administration—they all are best addressed by having a powerful device."

Innercool's device, which features a novel heat exchanger on the end of a catheter, is powered by a console that was developed using existing components, allowing the development process to go more quickly and smoothly, says Dobak. "At CryoGen, not only did we have to build the front end and the disposables," he goes on, "but we also had to build a whole new technology for the back end. That's a major undertaking, and I didn't want to go through that again."

The Decade of the Brain

One important issue for hypothermia treatment will be to determine appropriate dosing levels. Current reservations about hypothermia stem primarily from complications that result from the application of cold. Dobak knows that using mild, rather than deep hypothermia, will go some way toward minimizing side effects. But he also concedes that "the side effects of hypothermia really occur when it is applied for a long time," and they get worse the longer hypothermia is administered. Innercool's goal is, he says, to shorten the length of time the hypothermia is delivered while still getting a neuroprotective result. "We think the time frames we'll develop will be reasonable enough that side effects are not going to be a major issue," he concludes.

Dobak envisions that, ultimately, the Innercool device will be used in a variety of settings in the hospital—the operating room, ICU, and even the cath lab—and in different clinical applications, including cardiovascular. But the company's initial thrust will be in neurological applications. Dobak says that acceptance within the neurological community to the concept of hypothermia has been overwhelming. "It's been used in medicine for 50 years, ever since the advent of open heart surgery," he goes on. "There's a fundamental baseline belief that hypothermia is beneficial in protecting tissue from damage." Dobak claims that hypothermia is now widely regarded by neurophysicians as "the gold standard in neuroprotection. We've interviewed hundreds of physicians and their eyebrows always go up when you tell them you can do direct blood cooling safely, easily, and rapidly in a clinical setting."

But neurological applications present a different, somewhat trickier challenge than, say emboli protection in cardiac surgery or general temperature management in the OR. While studies are clear about the neuroprotective quality of cold before a vessel is blocked—i.e., if you can cool the organ before the ischemia, the damage is significantly reduced—the question for Innercool quickly became, can you deliver hypothermia after an insult occurs and still get a benefit? And if you can, how long can you wait to deliver the hypothermia and still see a benefit?

"The sooner, the better is the general rule of thumb," says Dobak. Indeed, immediate attention is critical in both myocardial infarction and stroke, but at least in MI, or heart attack, patients often experience enough discomfort to seek medical attention immediately; stroke offers a greater challenge because they usually don't feel pain and thus delay getting to the hospital. "What you feel with a stroke is numbness, tingling, limb weakness, or vision loss," he explains. "A myocardial infarction can wake a person up from sleep; stroke won't necessarily wake them up."

But Dobak argues that public awareness of stroke can help. "In the 1970s, people ignored heart attack symptoms the way they ignore stroke symptoms now because there wasn't public awareness of those symptoms," he says. Education efforts, spearheaded by groups such as the American Heart Association, were dramatically successful in calling to people's attention the warning signs of heart attacks. "The AHA has labeled this decade the decade of the brain," Dobak goes on. "We're going to see public education campaigns referring to stroke as brain attack, helping people to recognize the similarities between brain attacks and heart attacks and the need to seek treatment immediately."

The Ischemic Penumbra

Indeed, Dobak argues that the treatment of neurologic ishemic disease is at roughly the same stage today that the treatment of cardiovascular ischemic disease was in the late 1970s. "And you know how explosively that has grown over the last 20 years," he says. "I think neuro is ready for the same growth," driven by an aggressive new group of clinicians called neurointensivists or interventional neurologists. "They're like the interventional cardiologist," he goes on. "In the 1970s, the [primary physician in cardiovascular disease] was the medical cardiologist; interventional cardiology grew with the development of angioplasty." Innercool's bet: interventional neurology will parallel that growth over the next two decades.

Innercool is counting on applications other than stroke prevention. Dobak notes that once an infarct occurs, there's a core area of dead tissue that cannot be revitalized. But, he goes on, "over the next 24 hours, it's believed that there's a spreading wave of tissue necrosis and damage that occurs," the so-called ischemic penumbra. There are a number of factors for this spreading wave—regional swelling, spreading depolarization of the cortex, toxic neurotransmitter release, blood/brain barrier leakage—but, says Dobak, "the idea is to use hypothermia to prevent the expansion of this ischemic penumbra."

Stroke and myocardial infarction are the two most obvious forms of ischemia and represent major opportunities, short- and long-term, for Innercool. But Innercool sees other potential applications, in so-called global ischemia, where blood flow to the brain is either stopped or significantly reduced following cardiac arrest, and in neurosurgery, particularly aneurysm and/or vascular tumor surgery, where surgeons need to isolate the tumor or aneurysm from a blood source. Currently, neurosurgeons apply clips around the aneurysm or tumor, and in doing so cause an ischemic injury. "They're blocking major vessels that supply blood to the brain for a period of time while they repair the aneurysm," says Dobak.

Moreover, some of these biological functions that create opportunity in the brain don't have a parallel in cardiology—the heart doesn't, for example, release the equivalent of neurotransmitters which can incite further injury. For that reason alone, neurology may be more promising an opportunity for Innercool.

That's not to say that that Innercool doesn't see promise in the cardiovascular market—MI is too important a condition and, even with direct stenting, there is as much as a 30-40% no-reflow incidence in thrombolytic therapy, says Dobak. "During that no-flow period, after you've opened up the artery following a heart attack, it could be very beneficial to use hypothermia," he says.

But Dobak cites other reasons why Innercool will begin with neurological applications. For one thing, nearly all of the research on the protective nature of hypothermia is being done in neurology. "There's a little bit of data being collected on the heart," he says. "But if you look at where the basic science research is being done, it's on the brain."

Related to that, and perhaps driving it, there are so many more therapies available to cardiologists than neurologists—from drugs to stenting to angioplasty—that cardiologists are, says Dobak, "a much more difficult sell." Cardiologists "know from 20 years of research that opening an artery with TPA or stenting or angioplasty works," he says. Approached with a new therapy, "they tend to be skeptical, whereas if you go to the neurointensivist, there's no therapy for their patients and so they're very eager for one."

Hitting Home Runs

"I don't want to diminish the market opportunity [in cardiovascular]," Dobak goes on. "It's just that cardiology is very complicated and you've got to show that your product works in a very complicated environment." Moreover, with mortality from heart attacks low and going lower with each new therapy, demonstrating enhanced efficacy for new approaches gets harder and harder. Neurology, on the other hand, represents what Dobak calls "virgin territory." "There is an opportunity in cardiac," he says. "We just believe that neuro is the right place to start."

In turn, though Innercool is targeting neurological applications before cardiovascular, Dobak argues the same type of considerations will attract the attention of large, mostly cardiovascular device companies. "My sense is they all believe neuro is the next big opportunity and would all like to make a play in this area," he says. "The cardiac market is mature and growing more slowly. Right now, they're taking the technologies they developed for the heart and applying them to the brain. But I also think they're going to be very interested in fundamental new technologies that open up the neurology market to them."

Dobak and Juan Lasheras worked on prototype designs through much of 1997 and the first half of 1998 while Dobak was still at CryoGen. He left CryoGen to join Innercool full time in mid 1998 and did a first venture financing in June of that year, raising $3 million in a round led by Kleiner, Perkins, Caufield, and Byers [See Deal] . In May of 1999, just a couple of months after doing its first preclinical study, Innercool raised a second round of financing, this time for $10 million, led by then-IVP, now Versant Ventures [See Deal]. And Innercool closed on its Series C financing at the end of 2000, raising an additional $25 million [See Deal].

Having done its first human studies in mid-2000, Innercool expects this latest round of financing to last through much of the regulatory approval process. "This is a big clinical development year for us," says Dobak. "We've gone though our animal phase and done our initial clinical trial work. This is really the clinical development stage where we will use our products in large numbers of patients and do clinical work in different areas."

Innercool's clinical trial work is particularly important, says Dobak, because creating real value in medical devices today comes not from developing elegant new devices with incremental improvements over existing products, but, rather, from demonstrating significant clinical value to physicians. "There are some market opportunities here that are singles and doubles, and there are some that are home runs," he says. "I view stroke, because of its huge patient population, as a home run, and I think any small company has to have its sights set on hitting a home run." If that means Innercool has to "bite the bullet and do the study" necessary to get a stroke indication, Dobak goes on, it's ready to do so. "We know stroke is very difficult and that there's road kill all along the boulevard of new stroke therapies," he goes on. "But the good thing is, we can learn from those past failures."

But Dobak is confident that Innercool's device will succeed where other stroke therapies haven't, even drug therapies—because while most drug compounds target one of the factors that lead to ischemia, such as a single neurotransmitter, hypothermia takes a broader view of the problem. "Ischemia initiates a very complex web of processes and biochemical reactions," he argues. "Inflammation, electrolyte fluxes into and out of the cell, changes in the blood/brain barrier, and electrical activity of the brain—all of these things are occurring and to target one single pathway is likely to be a failure. What's wonderful about hypothermia is that it addresses all of the different mechanisms that are believed to play a role in tissue death in stroke."

Using Cold to Stop Cell Growth

Though they differ in specific applications, strategic focus, and marketing targets, all three of the hypothermia companies—Cardeon, Innercool, and Radiant—share a common approach: that of using endovascular devices to cool body organs on a total or local basis to get the protective benefits of cold therapy. Quite a different approach to the application of cold is being explored by Cryovascular Systems Inc. (CVS), formerly known as Odyssey Technologies Inc., a Los Gatos, CA-based start-up that is betting that cold therapy will be the next major approach to the problem of restenosis in coronary and peripheral vessel disease.

Odyssey was launched in 1997 by Ron Williams, an engineer who had formerly worked at EndoVascular Technologies Inc. , now part of Guidant, and James Joye, DO, a Silicon Valley-based interventional physician, strong in both coronary and peripheral vasculature. Having studied the research on cold therapy in surgery, or cryosurgery, Joye began to think about its potential application in interventional procedures when he came across the work of a Buffalo, NY, physician named Andrew Gage, MD.

Gage, too, had begun to explore the effect of cold therapy in treated arteries and had gone so far as to freeze some arterial segments in dogs. Once those segments had thawed naturally, Gage found, the vessels returned to normal function relatively quickly, with no signs of damage and, in fact, a kind of benign or natural healing process began to take place. The leap for Joye: could cold therapy be used to reduce or eliminate the proliferation of cells that takes place inside an artery that has been injured?

Williams and Joye set out immediately to discover at what temperature vessels would benefit from cold therapy—too cold and necrosis would set in, not cold enough and there wouldn't be enough of a healing effect—and to see if a catheter-based system could be designed to deliver the cold. Rick Williams, an engineer (no relation to Ron), and Kristine Tatustani, PhD., a cryobiologist out of University of California, Berkeley , who had been studying temperature effects in vitroon endothelial and muscle cells, were hired to address both questions. Notes CVS CEO Rich Ferrari, "We've now done some very elegant and sophisticated thermal modeling on over 85 animals to see whether we could, in fact, induce apoptosis and at what temperature range that would take place." CVS's work shows clearly that, if cooled too much, necrosis sets into the arteries. "We also have shown, through a number of assays, that you can have a fairly significant reduction in the proliferation of cells," he says.

But Ferrari, a veteran of the interventional cardiology business—he was CEO of CVIS, before most recently running CardioThoracic Systems Inc. , now a division of Guidant—also recognized the engineering challenge of delivering cold therapy. "The trick is, how do you dispense the cold uniformly inside the balloon to achieve the temperature you want at the balloon interface?" he says. "Because the key isn't the temperature at the center of the balloon, it's the temperature at the interface and how far through different plaques we can drive that."

Moreover, the catheter not only has to deliver cold, it has to be able to move and track like a standard angioplasty balloon and it has to come in sizes interventionalists are comfortable using; if the CVS catheter is too big, it will significantly limit the type and number of procedures in which it can be used. "It actually has to embody the characteristics of a standard device," notes Ferrari, "and that's not easy." Finally, in creating a simple, elegant system, CVS also wanted to eliminate the huge bulky energy source that comes with some cold therapy devices and which is a feature of CVS' one direct competitor, Montreal-based CryoCath Technologies Inc. "You need to get it down to a small size," says Ferrari. "No one's going to buy a big box."

Making the Case for a Primary Therapy

CVS officials note that getting the temperature right in the design process is critical because it's the key to an otherwise relatively simple and elegant therapy, utilizing balloon catheters identical to those used in angioplasty. Variations in plaque composition aside—fat-laden plaque would likely present a different challenge—"all other tissues—normal, calcified, fibrotic—have the same thermal conductivity," says Meg Yoklavich, director of clinical development at CVS, "so the heat transfer issues within those tissues would be identical."

Simplicity and ease-of-use are critical—CVS's cold therapy is applied in a 30-40 second treatment—because the company would like to position cold as a primary therapy in the treatment of restenosis, first in the peripheral vasculature and eventually in coronary arteries. "We know that in about 85% of the cases where [interventional cardiologists] are putting in stents, they have to pre-dilate the vessel," says Rich Ferrari. "Our thought is that they should pre-dilate with our balloon and apply cryo, thereby reducing proliferation so that when they put in the stent, they get a different compliance and a better result overall."

Ferrari knows that positioning cryo as a primary therapy—rather than focusing on, say, in-stent restenosis as the radiation companies have done—will make the clinical trials for CVS more difficult, if only by ramping up the number of patients needed for a trial. But, if successful, the long-term benefit will more than justify the effort. Indeed, though cold therapy is years behind radiation in getting to market—both Novoste Corp. and J&J now have FDA approval for brachytherapy—it is to radiation that cold therapy is most often compared by its advocates.

CVS officials note several advantages that cryoplasty, as they call it, should have over brachytherapy if it proves clinically as effective. Perhaps the most important is the benign healing properties of cold therapy compared to concerns over radiation. Related to that, cryotherapy is easier to handle and administer, placing none of the special handling or regulatory burdens on hospitals. And unlike radiation, CVS says, there's no candy-wrapper effect in cryotherapy that occurs at the edges of the radiation treatment where the dosage falls off, resulting in cell proliferation and restenosis. As Meg Yoklavich explains, "The reason you have proliferation at the sides is that the radiation energy is too little to be therapeutic, but enough to be stimulatory. But with cold, if you don't deliver enough cold at the edges, nothing happens."

But, says Rich Ferrari, perhaps the biggest advantage is that cold therapy is, to interventionalists, so similar to basic balloon angioplasty. "We're trying to keep in mind how interventionalists actually use the technology and to eliminate complications in the procedure," he notes. By using a balloon to simultaneously dilate and apply cold therapy, the interventionalist does essentially the same procedure he or she has always done. "This is much different than going down with a dilating balloon, then deploying a stent, then applying radiation," he goes on.

Proliferating Options

In the short term, however, radiation and cold therapy may not compete at all, if only because the initial applications for radiation are targeted at in-stent restenosis whereas CVS would like cryoplasty to be a primary therapy, a de novotherapy to prevent restenosis, used virtually with all interventions—something which, if it came to pass, would create huge, almost stent-like opportunities for the company. To achieve that status, CVS would have to establish cold therapy as a prophylactic standard of care in the treatment of restenosis.

CVS is promoting cold therapy at a time when the options for treating restenosis and in-stent restenosis are themselves proliferating. Asked about potential competitors, CVS officials cite not just CryoCath and the companies playing in brachytherapy—Novoste, J&J, and Guidant, to name just the leaders—but also a host of new approaches to restenosis, from photodynamic therapy (PDT), soft X-ray to ultrasound and even drug-coated stents. "The one advantage we have," says Ferrari, "is that with the exception of the drug-coated stents, all of those tend to be used as adjunct therapies, applied after the stent is in place, not before or at the same time."

A Play in Peripherals

CVS also has its sights set on other promising new areas of interventional cardiology. It recently filed a patent—its seventh—around the detection and treatment of so-called vulnerable plaque using cold therapy, currently a diagnostic approach seeking therapeutic tools. (See "The Coming of Age of Vulnerable Plaque," START-UP, November 2000 [A#2000900196.)

In the short term, however, the company will focus on cryoplasty in peripheral arteries—in part because the regulatory path is easier, in part because, as Rich Ferrari notes, "it's a huge market and not a lot of people are focused on it. I'm very excited about it because the highest incidence of restenosis happens to be in [the superficial femoral artery in] your leg."

Indeed, the problem, called intermittent claudication, occurs in 4.5% of men over the age of 50, and peripheral arteries treated with both balloons and stents still show a 50-70% restenosis rate after six months, with pain and difficulty in walking. "Restenosis is rampant," Ferrari goes on, "and right now there isn't much they can do for you outside of exercise and therapeutic stockings. If physicians had something that really works, they'd use it all the time."

Currently CEO, Ferrari got involved in CVS early on, during the company's seed-stage financing, through Saratoga Ventures, a VC firm he had put together while at CTS. US Venture Partners also participated in the seed round. And last year, CVS raised its Series B round from US Venture Partners, Pequot Capital, and De Novo Ventures, a new fund Ferrari launched with Fred Dotzler, John Simpson, and David Mauney, MD. It was through De Novo's investment that Ferrari took over as CEO, a role he'll hold until the company's next financing round, seeking to raise $15-18 million, which is expected to take place in the first quarter of 2001.

By that time, CVS expects to have filed its 510(k), to be in humans in peripheral therapy, and to be getting ready to file its coronary IDE. Veterans of the interventional cardiology business, company officials believe ultimately that cold therapy could become a critical therapy in the treatment of restenosis. "It's simple and effective without creating any safety concerns for the user or the patient," says Meg Yoklavich. Adds Rich Ferrari, "And it's a huge market with, at least today, no real solution for dealing with the trauma that's induced when you have an interventional procedure." Add the appetite interventionalists have for new technology and, Ferrari goes on, CVS "sits right in the sweet spot, where all the vectors are aligned."

Even in today's cautious venture capital environment, Ferrari, who wears hats as both CVS' CEO and a lead investor at De Novo, doesn't think the company will have trouble raising the funding it needs to complete its early work and conduct clinical trials. And CVS officials note that, to date, none of the large interventional cardiology companies seem to have projects underway in this area. Says Ferrari, "They're all working in radiation and trying to get into coated stents." But, he goes on, if cryo works in both coronary and peripherals "they're going to have to broaden their portfolio to protect their customer base." Thus, one potential exit strategy: an acquisition by a large interventional device company looking for another tool for its customers in the armamentarium to fight restenosis.

Neither Ferrari nor Yoklavich believes that cold therapy will become the exclusive modality to fight restenosis. Talking about the wide range of technologies currently under development, from PDT to soft X-ray, Ferrari says that while some "will fall by the wayside either because of cost or complexity," he believes that "there will be a combination of therapies that will be right to dramatically reduce restenosis." That may mean cryo and stents or cryo with some other therapy, he says. "But it will likely be some combination of mechanical and biological," with cryo clearly one of the therapies if it works the way CVS envisions.

Moreover, argues Meg Yoklavich, interventionalists "will balance ease-of-use and the time required to do a procedure with the therapy's effectiveness, and the therapy that's most effective and easiest to use will win." Rich Ferrari agrees. Asked why cold therapy will, of all of the new approaches to restenosis in an ever more crowded interventional market, succeed, he notes, "I think we're going to win because [cryo] is easier, it's standard, and it can be applied as a primary therapy. The only other device that fits all three [criteria] is a coronary stent."

Intellectual Critical Mass

Precisely because the clinical value of hypothermia has been well-documented by physicians for over 50 years, it's hard to say why a handful of device companies should each, for very different reasons, spring up in a two-year period between 1996 and 1998. Some argue it was a host of new clinical literature, much of it generated in the late 1980s and early 1990s, newly touting the value of cold therapy, particularly mild hypothermia; some that the interest shown in stroke and CNS as an area of opportunity played a driving role. Add to those two the continuing evolution of device technology, which gave designers new ideas and options in delivering cold therapy, and you get a kind of intellectual critical mass that leads to serial company creation. Says Stanford's Paul Yock, "You know how these things happen—people start talking about it in the hallways and at meetings and all of a sudden it becomes clear that this is the next nut to crack." Indeed, Yock argues that "myocardial and neurologic salvage are the next great frontier."

Despite their common roots in cold therapy, however, even among the hypothermia companies, differences stand out almost as strongly as similarities. All, of course, promote the value of cold as a protective agent and all mention the same clinical areas—cardiovascular, neurology/stroke, trauma and resuscitation—as potential targets, in either the long- or short-term.

But each company is clearly focused in the short term on narrower and, for the most part, distinct opportunities: Radiant in general surgery, Cardeon in cardiovascular surgery, Innercool in stroke, and CVS in restenosis. With different clinical problems to solve and different marketing targets, the various hypothermia start-ups are likely to cross paths in the marketplace less than one might expect, at least in the short term. Indeed, as noted, Cardeon's initial competition is likely to come less from Radiant or Innercool than from emboli protection and collection companies like PercuSurge and AngioGuard. "It's going to be interesting to see how each of these technologies carve out their specific markets," says Wil Samson. "Each has its pros and cons, and while I think we're all going to overlap in some markets, stroke and maybe head trauma and neurosurgery, we're all going to have different approaches."

Even Radiant and Innercool, the two most similar, take very different approaches to the market: where Radiant shifted focus from an early neurological focus to a broader play in temperature management, Innercool has gone in the exact opposite direction. Says John Dobak, "General temperature management is a market that everybody's got their eye on." But while Innercool's product works well in cooling and maintaining a low temperature, "general temperature management, or normalthermia, is a totally different ball game."

Proving the Value of Cold Therapy

Of course, in time, Radiant's pitch to neurosurgeons and cardiologists will sound very much like Innercool's, and Cardeon and Radiant will make similar appeals for their devices' application in MI. But for now, sorting out winners from losers is difficult because it's simply too early and the paths each company is taking are sufficiently different to say which company is ahead. Says Radiant's Ken Hayes, "At this stage, its so early for all of us. This is a marathon and we're just at the starting line."

Just as intriguing as the current differences are potential synergies between the various approaches. CVS officials, for example, foresee the day when they'll link CVS' cryoplasty with an anti-embolism device similar to the approach being pursued by Cardeon—and note a common ground all of the cold therapy companies inhabit. "In a broader sense, both technologies [i.e., cryoplasty and hypothermia] are looking at the same biological process," notes Meg Yoklavich. As part of therapy, she goes on, "cold has been used for centuries.." If doctors begin to aggressively embrace cold therapy in all of its forms and to push research forward, each company could experience a tide that lifts all boats, just as advances in interventional therapy or minimally invasive surgery expanded exponentially as companies and physicians searched for new applications.

And there are other synergies. As Cardeon sets out to raise its next round of financing, Wil Samson believes the success Radiant and Innercool had will only work to Cardeon's advantage. "Even before the last rounds, the four of us had raised over $100 million, and that's climbing fast."

Samson knows that Cardeon's biggest challenge will be one that all of the hypothermia companies face together: proving the value of cold therapy. "One of the things we hear all the time from doctors is that they know hypothermia is beneficial, but before they adopt it as a standard of care, they want to see some data. If we can produce the data, they won't be able not to use it."

All of which speaks to a growing confidence in hypothermia as an important approach to therapy. Ken Hayes argues that, in time, hypothermia will evolve from a tool used only when there's no other choice to a standard of care, used widely to afford an extra measure of protection. "If you provide a tool that's simple to use, with no adverse side effects, there will be no reason not to use it," he says, echoing Samson.

It seems a bet investors, at least, are willing to make. Hayes notes that Radiant had relatively little trouble raising money for its most recent round, from both existing investors and new ones. "I originally was only going to raise $15 million, but there was a lot of interest," he says. "I think people appreciated the potential of this technology and the very large markets. We actually turned away people who wanted to invest because there wasn't enough room."

And hypothermia advocates believe that enthusiasm will only continue. Noting the fund-raising success of Radiant and Innercool, Cardeon's Wil Samson says, "That's only good news because I think it's going to tell the world that hypothermia is a good thing, it's protective, and we're all going to work hard to convince the medical community that these technologies have value to the patient."