Evalve: Leading the Valve Revolution

Full-scale commercialization of percutaneous heart valve technology is still years away, but Evalve’s new approach to mitral repair is closest to the clinic.

by Stephen Levin

Heart valve repair and replacement are among the few remaining areas of cardiovascular therapy that remain the province of surgeons.

The question, however, is when, not if, interventional cardiologists will begin treating heart valve conditions, with many new products in the works.

Percutaneous heart valve start-ups have been among the hottest areas for medical device investors over the last few years, but technology development is slow in this complex area.

Evalve, the first company formed by The Foundry incubator, is developing an interventional system to treat mitral valve regurgitation.

The company appears to be the farthest along in this space, reporting positive early clinical results, and currently conducting its pivotal trial.

One of the most successful formulas for success in medical device start-ups has been to develop a percutaneous alternative for a procedure previously performed exclusively using traditional open surgery. That model has proven particularly successful in cardiovascular therapy with the most obvious example being the growth of angioplasty as an alternative to coronary artery bypass graft procedures. Similar trends appear to be emerging on the short-term horizon in both carotid and peripheral vascular treatment.

Longer-term, venture investors and major device companies are betting that the same transition will take place in heart valve therapy. Beginning in the late 1990s, percutaneous heart valve start-ups have been among the hottest technologies in attracting the attention and financing of both venture capitalists and big companies, even with the understanding that this is a complex technology area that will require a lengthy product development cycle.

Menlo Park, CA-based Evalve Inc. was among the first wave of interventional heart valve companies when it was formed in 1999. The start-up’s growing pains were compounded by the fact that Evalve was the first company launched by The Foundry device incubator, which itself was in the process of getting started. (Also see "St. Paul and the Foundry Team Up" - Medtech Insight, 1 Jan, 2003.) (Also see "Growing Companies" - Medtech Insight, 1 Dec, 2001.) Indeed, The Foundry had declined to pursue the original idea for a percutaneous valve technology that interventional cardiologist Fred St. Goar, MD, had presented to them, before he came back with the idea for Evalve’s system to treat mitral valve regurgitation (MR).

Second Time’s the Charm

Fred St. Goar is among the cadre of interventional cardiologists in the San Francisco area who are as involved in new technology development as they are in treating patients. St. Goar and his partner, James Joye, DO, head the Cardiovascular Institute at El Camino Hospital in Mountain View, CA. St. Goar has been involved in the early days of seminal device start-ups such as CVIS (cardiovascular ultrasound, acquired by Boston Scientific Corp. ) and Stanford Surgical Technology (SST), which became Heartport (now part of Johnson & Johnson ), a pioneer in minimally invasive cardiac surgery (MIS).

Heartport generated such controversy around its MIS technology that few recall that the company’s original product idea was to develop a percutaneous aortic valve replacement, based on having rights to the Andersen patents, which are important pieces of intellectual property (IP) for interventional valve replacement technology. (Those rights subsequently were licensed to Percutaneous Valve Technologies (PVT), another interventional valve start-up that is now part of Edwards LifeSciences Inc.). St. Goar’s interest in developing percutaneous valve technology was what attracted him to Heartport.

While at SST/Heartport, St. Goar recruited a talented engineer named Hanson Gifford, who later left Heartport to form a medical device incubator called The Foundry. So it was only logical that after leaving Heartport, St. Goar approached The Foundry with the valve replacement technology idea. Gifford’s partner at The Foundry was Allan Will, a veteran medical device executive now with the venture firm Split Rock Partners. Will had previously headed, among other companies, interventional pioneer Devices for Vascular Intervention (DVI), subsequently acquired by Guidant Corp. and AneuRx, an abdominal aortic aneurysm (AAA) company acquired by Medtronic Inc. Gifford and Will turned down St. Goar’s initial proposal because they thought it would take too long to develop.

In October 1998, one of St. Goar’s cardiology patients underwent heart valve surgery at Stanford University Medical Center . The surgeon was trying to repair, rather than replace, the valve because the patient was young. Replacement would call for the use of a longer-lasting mechanical (rather than tissue) valve and an accompanying lifelong warfarin (Coumadin) regimen. The surgeon called St. Goar after the operation to tell him that the surgery had been difficult and he couldn’t perform the repair using traditional techniques, so he employed what at that time was a little-known procedure called the Alfieri edge-to-edge stitch to repair the patient’s mitral valve. "I had never heard of the procedure before, but when the surgeon described it to me it sounded so simple and elegant that I immediately thought there was the potential to develop a percutaneous way of doing this," St. Goar recalls.

The Alfieri approach was developed in the early 1990s by Ottavio R. Alfieri, MD, PhD, a cardiac surgeon at the Ospedale San Raffaele in Milan, Italy. St. Goar immediately began researching this technique and found that Alfieri published his first article on it in 1995 and then did a follow-up article in 1998. Both appeared in the European Journal of Cardiology, and they didn’t attract widespread attention, particularly in the US.

After gaining a better understanding of the Alfieri technique, St. Goar designed a system that could perform the same mitral valve repair using a catheter-based procedure, rather than surgery. After vetting the idea with an experienced patent lawyer, St. Goar again approached The Foundry several months after their first meeting, and this time Gifford and Will liked the concept. "This idea was less dependent on a valve design, and more dependent on developing a catheter system, which was technologically more along the lines of products we were familiar with," Will says.

In addition to the specific details of St. Goar’s product design, Allan Will points out that there were other factors that spurred The Foundry to do this deal. First was that the business strategy followed the well-accepted device industry model of developing a percutaneous alternative to an existing surgical procedure. "The fact that we had a successful surgical predicate—the Alfieri approach—helped eliminate a significant amount of clinical or therapeutic risk from the technology development process because we didn’t need to pioneer a new therapy; we needed to pioneer a new way of performing the therapy," Will explains. There already were published data on more than 1,000 patients, with up to 11 year follow-up, showing that Alfieri’s technique was safe and efficacious for all types of MR patients.

The timing was also right, as device entrepreneurs and investors were becoming more aware of new ways of treating structural heart disease. The last several years have witnessed the emergence of treatments for all types of structural heart disease including valve disease, with repair and replacement, and annuloplasty procedures, and PFOs and left atrial appendages, which are now treated with occlusion devices. "We were really at the forefront of this whole movement to treat structural heart disease," Will says.

The result: St. Goar, Gifford, and Will agreed to form Evalve, the first Foundry company, in February 1999. The terms of the deal, including dividing the founders’ equity, were agreed on with a handshake, Will recalls. The deal was done quickly and amicably because the parties all knew one another and had previously worked together.

These existing relationships established a level of trust in a deal that also included an additional element of risk for Evalve. Not only was The Foundry an unknown entity, but, in 1999, device incubators generally were not seen as favorable vehicles for launching companies. The widely held view was that, rather than adding value, incubators actually diluted a start-up’s valuation. And at that time, incubators had not yet established the track record that they have today of being able to launch successful start-ups and add value.

Turning Risks into Benefits

Allan Will initially assumed the role of Evalve’s president and CEO, while Hanson Gifford focused on the engineering and technology, and Fred St. Goar effectively served as the company’s medical director (and is a major shareholder). Gifford quickly uncovered what would become Evalve’s first major challenge—the existence of potentially competitive IP that was owned by Columbia University , based on work done there by noted cardiac surgeon Mehmet Oz, MD, along with some additional IP in this space that was the property of French cardiologist Jacques Seguin, MD, who founded another percutaneous valve company, CoreValve SA , and Devax Inc. , a bifurcated stent start-up.

For a newly launched start-up, the discovery of potentially competing IP could pose a significant obstacle and cause a change in strategy. However, Allan Will says that Evalve chose to view this situation as an opportunity, rather than a threat. In Will’s view, "When you’re founding a company, how often do you get the opportunity to add important IP? The answer is not often, so we recognized that the additional IP could be a tremendous asset for Evalve and set out to obtain the rights."

Hanson Gifford conducted the negotiations with Columbia, which proved to be more complex than they originally appeared. Oz’s IP also attracted the attention of other device companies, but Evalve eventually acquired the rights from Columbia, and it did the same with Seguin. Evalve now had access to a stronger IP portfolio to support its strategy of developing a percutaneous system and technique to accomplish what the surgical Alfieri approach did for mitral regurgitation.

Allan Will recognized that among his first responsibilities as the company’s president and CEO was to find his eventual replacement. Will needed to split his time between running Evalve and The Foundry, which had an initial goal of launching two companies each year. Will’s strategy was to run Evalve in the beginning, and hire someone he could mentor to take his place, with the understanding that Will would then become the company’s chairman, which is his current position.

Again, past working relationships proved important as Will tapped Ferolyn Powell to serve as Evalve’s general manager. Although Powell had never run a device company, she and Will had successfully worked together in several previous positions. Powell had been director of R&D at DVI where Will had been CEO, and she later served as VP of R&D at Adjacent Surgical, a small start-up that Will headed, having co-founded the company with noted surgeon and device entrepreneur, Thomas J. Fogarty, MD. Adjacent wound up being merged into General Surgical Innovations (GSI), another Fogarty company, where Powell had become VP of operations. When GSI was acquired by Tyco Healthcare Group , Allan Will wanted to hire Powell for a senior position in one of The Foundry’s start-ups.

Once Evalve was up and running, Will and Gifford recognized that the company’s next challenge would be technology development, which is Powell’s strength, so they offered her the job as Evalve’s general manager. "Since she had never run a company, we hired her in the hope that she would be the president and CEO, but that if things didn’t work out, she could still lead the company’s R&D efforts," Will recalls. Within six months, Powell was named Evalve’s president, and about a year after that, she also became CEO. "In addition to being smart and focused, Ferolyn and I work well together," Will says. "It’s one of those active chairman roles that you yearn for, where the CEO is eager and learns quickly, which has made my job easy." Seven years later, Powell is still running Evalve, reflecting unusual management stability for a device start-up.

For Powell, Evalve seemed to have the perfect combination of attributes that a prospective CEO would look for. "There are four big issues that a start-up company needs to address: IP, market, technology, and people," she says. "Evalve had three out of the four, and the missing piece was the clinical application of the technology, which is a strength of mine, so I believed that, with the beginnings of the great team we had, we could make this work."

A Clip, Not a Stitch, in Time

Evalve is the classic example of a device start-up built on a concept, not on a particular technology. For although Fred St. Goar initially had plans to use a stitch-driven system (as opposed to the clip that was ultimately developed), the real value behind the company was in the conversion of a surgical to an interventional approach, rather than in a particular product design. "I have to give credit to our early investors, particularly NEA and Three Arch, because they were investing in the overall concept, not in the specifics of the approach," St. Goar acknowledges.

Indeed, when Ferolyn Powell joined Evalve, no device design had yet been agreed upon. She hired Troy Thornton, who had previously been with Guidant’s predecessor, Advanced Cardiovascular Systems (ACS), and with WL Gore & Associates Inc. , as VP/R&D, and she hired Jan Komtebedde, a veterinary cardiac surgeon with whom St. Goar had worked at Heartport, to be VP/marketing and business development. Together with the R&D team, they worked on coming up with a viable product design and prototype.

Unlike the surgical approach, which is performed on a stopped heart using a cardiopulmonary bypass pump, Evalve’s technique is done on a beating heart, thereby obviating the need for the CPB pump and a sternotomy. "When I joined the company, our biggest challenge was figuring out how to reliably grasp the mitral valve’s leaflets, which are moving pieces of tissue," Thornton explains.

Mitral valve regurgitation occurs when the leaflets of the valve do not close properly. The mitral valve is a one-way valve—sometimes referred to as a set of swinging doors--that separates the left atrium, the chamber in the heart that collects blood, from the left ventricle, the chamber that pumps blood. For patients with MR, blood flows back into the left atrium with each heartbeat, which decreases cardiac output, meaning less blood flowing throughout the body. The more severe the MR, the harder the left ventricle has to pump to provide sufficient bloodflow. Also, the chronic backflow resulting from MR can cause a number of other heart problems including dilatation of the left atrium and ventricle, progressive myocardial damage (weakening the heart muscle), congestive heart failure (CHF), atrial fibrillation (AF), and sudden cardiac death.

In cases where traditional surgical techniques were unsuccessful in stopping the mitral valve leakage, and where the surgeon did not want to replace the valve, Ottavio Alfieri came up with the idea of attaching a segment of one valve leaflet to the other in order to close the leaflets and stop the leakage, thereby reducing MR. The technique involves suturing a portion of the anterior leaflet to a corresponding portion of the posterior leaflet, permanently joining the leaflets at that point. This creates two channels, one on each side of the sutures that allows for sufficient bloodflow from the left atrium to the left ventricle, while also assuring effective valve closure when blood is pumped to the rest of the body.

But this is not the primary surgical approach for treating MR patients. "The Alfieri technique was initially only being used as a bail-out procedure by surgeons in situations where traditional repair techniques didn’t work, leaving them faced with an irreparable valve that they did not want to replace," Ferolyn Powell explains. "In these instances, the only way to avoid replacement and complete the repair was with the edge-to-edge approach."

Fred St. Goar had worked with Perclose (now part of Abbott Laboratories Inc. ) on designing a suture-based femoral artery closure catheter device, and he thought that the same type of approach could be used to develop an interventional edge-to-edge system. Indeed, Evalve’s IP covers suture-based systems, which is an approach being employed by Edwards, the only other company working on developing a percutaneous edge-to-edge device.

But a funny thing happened in the course of developing the device needed to grasp the leaflets—Evalve’s engineers demonstrated that simply grasping the leaflets resolved the mitral regurgitation, obviating any need for sutures and leading to the clip design. "This was a major breakthrough in our product development," St. Goar recalls. Indeed, Powell points out that the device’s current design is basically the same as an early clip prototype. "Our development team hit on some key concepts early on that have resulted in a very stable product design," she says.

Evalve’s percutaneous mitral valve repair system consists of three components: a steerable guide catheter, a clip delivery catheter, and an implantable clip, the MitraClip. The guide catheter is inserted into the femoral vein and steered to the mitral valve. The delivery catheter is then used to grasp the leaflets and deploy the clip on the beating heart.

Powell notes that the clip functions much like a retractor. Using fluoroscopy and echocardiography, the physician places the clip, stabilizes the leaflets, closes the clip, and evaluates the MR. If the physician isn’t satisfied that the placement of the clip decreases the leakage sufficiently, he or she can re-open and re-position the same clip at a different point on the leaflets without damaging the tissue. Multiple MitraClips can also be employed. (In the pivotal study, to date, up to two clips have been used on patients.) The clip is covered with a biocompatible, polyester fabric that quickly becomes completely endothelialized and incorporated into the valve’s tissue, minimizing the risk of migration and stroke.

Complex Valve, Complex Disease

The elegance of the MitraClip system belies the complexity of any type of mitral valve intervention. Anatomically, the mitral valve is a complicated, highly irregular structure. Interfering with the valve’s operation while it is beating without causing hemodynamic or anatomic damage is a significant challenge that Evalve’s approach appears to have met.

The procedure is made more difficult because there is no direct route a physician can take to access the mitral valve. Indeed, most of the intracardiac approaches to mitral repair require navigating into the left atrium, which requires a transseptal puncture—a procedure that most interventional cardiologists are unaccustomed to performing, largely because no common percutaneous procedure currently requires such skills.

Indeed, Allan Will notes that, for Evalve, the difficulty in accessing and observing the mitral valve meant that navigation and manipulation of the catheter were going to be important challenges. "The physician must be comfortable simultaneously using both fluoro and echo to perform the procedure," he says, noting that most interventionalists are only accustomed to using fluoro in the cath lab. To achieve the level of navigability required for mitral intervention, Evalve’s catheters can be steered much more precisely than most others used in standard cardiology and electrophysiology procedures.

In addition to the mitral valve’s anatomic complexity, mitral valve regurgitation is not a monolithic disease. There are two subsets of MR patients, each with different etiologies and surgical treatments. Degenerative MR largely comprises patients with mitral prolapse where the leaflets are structurally abnormal. The other patient group is categorized as functional MR, and includes heart failure patients and those with ischemic disease generally resulting from a heart attack. Degenerative MR is surgically treated by removing excess leaflet tissue and performing an annuloplasty (implanting a ring to relieve stress on the leaflets and to decrease the size of the mitral annulus). Annuloplasty is also the primary surgical treatment for functional MR patients, but Evalve’s co-principal investigator for its EVEREST (Endovascular Edge-to-Edge Repair Study) clinical trials, Ted Feldman, MD, director of the cardiac catheterization laboratory at Evanston (IL) Hospital, and professor at the Northwestern University School of Medicine, points out that this therapy is of limited value because the sickest heart failure patients are often not surgical candidates, and the clinical results for ischemic patients are not very good.

Ferolyn Powell notes that one constant across all MR patient subsets is that patients improve when regurgitation is reduced—their symptoms get better and their outcomes improve. Given the complexity of the disease and the variety of surgical repair techniques, it is not surprising that there are a number of companies developing different therapeutic approaches to accomplishing that goal. "There is not going to be one percutaneous device that is going to be the answer for all patients with mitral regurgitation," says Ted Feldman, a pioneer in percutaneous MR treatment, who is on the clinical advisory boards of several of the interventional companies in this space. (Feldman groups them into several categories: leaflet repair, which includes Evalve and Edwards; two annuloplasty approaches—indirect via the coronary sinus, which is Cardiac Dimensions Inc. , Viacor Inc. , and Edwards, and direct annuloplasty, which includes Mitralign Inc. ; chamber remodeling, which is the approach being developed by Myocor Inc. ; and a combination of annuloplasty and chamber remodeling, which describes the work of Ample Medical Inc.)

No matter what the cause of MR, Ferolyn Powell points out that it is a chronic progressive condition that ultimately leads to heart failure, primarily because the constant overload takes its toll on the left ventricle, causing it to dilate and remodel (lose its shape and strength). Powell notes that, according to the literature, annular dilatation itself is rarely the cause of MR; the ventricle and atrium first dilate while the fibrous annulus is maintained. Once the ventricle becomes extremely dilated, there may not be sufficient leaflet tissue to perform an edge-to-edge repair. However, Powell says that more than 85% of patients annually diagnosed with significant MR have sufficient leaflet coaptation to undergo the MitraClip procedure.

In addition to surgery, there are medical regimens for treating MR. Typically these include ACE inhibitors, beta blockers, and diuretics, but medical therapy does not improve patient outcomes. "Drugs simply treat the symptoms, but the regurgitation and resulting volume overload and the disease progression remain," Powell explains. As a result, the annual mortality for heart failure patients with MR treated only with medical therapy can be as high as 40%.

How Successful is Surgery?

The lack of success with medical therapy means that surgery is really the only effective treatment for mitral regurgitation. Therefore, surgery is what Evalve’s procedure will be measured against in terms of safety and efficacy. The question then for the company and clinicians becomes: how successful is surgery? According to Ted Feldman, "The broad answer is that surgery is generally very successful, but the more careful answer is we really don’t have a clear understanding of how the success of surgery is measured, and this is an important discussion in terms of what’s going to be involved in demonstrating whether Evalve and the other percutaneous therapies work."

Feldman points out that, for valve repair surgery, there have been no prospective randomized trials and no "intention to treat" trials. This is due, in part, to the nature of surgery, where procedures tend to be studied through single-center, self-reported observational trials, which have limitations. But also, as he notes, "Valve repair surgery has been the most effective therapy for nearly 30 years; why would you study it that carefully when there really are no other options?"

This lack of clinical data hinders an understanding of the success of MR surgery. For example, Feldman points out that, because there have been no "intention to treat" trials, the proportion of MR patients who are taken for valve repair surgery but instead get their mitral valve replaced because the repair procedure is not going well in the OR is unknown. "Most surgeons say that they repair 85% to 95% of mitral valves, but the STS [Society of Thoracic Surgeons] database says more than half of these patients have their mitral valves replaced. There’s something wrong with the math here," he suggests.

Indeed, Ferolyn Powell points out that, in much the same way, some surgeons are critical of the Alfieri approach because the reported clinical outcomes are not as good as those of traditional valve repair techniques. That is not an apples-to-apples comparison, she notes, because surgeons typically use the edge-to-edge approach in the most complex cases as a last ditch effort to repair the valve and avoid replacement.

Feldman is not arguing that surgeons are being disingenuous in reporting their procedure numbers. Rather, his point is that this kind of inconsistency reveals how much we don’t know about the success rates of mitral valve surgery. And that makes it difficult to use surgery as the standard of care against which interventional procedures will be judged. "The utility of the percutaneous therapies will depend heavily on what the alternative is," he points out.

Currently, mitral valve surgery is the second leading valve surgery performed in the US (behind aortic valve procedures), with approximately 50,000 operations performed annually, most of them for MR. More than 40% of these patients are 65 or older. The mortality rate overall ranges from 2% to 6%, but for CHF patients and those over 80, the rate goes up to 10% to 20%. "Mitral valve repair is complex, which is why not all surgeons regularly perform the procedure. The average is about ten per year for those who do the surgery, and as a result, there can be tremendous variations in operator experience and outcomes," Jan Komtebedde observes. In the hands of a less experienced surgeon, the risk that a patient will need additional surgery increases, and for re-operations, the mortality rate increases fourfold.

Mitral valve regurgitation in the US extends to far more than the 50,000 patients treated surgically each year. There are an estimated 250,000 new cases of MR diagnosed each year in the US, and the 200,000 who are not surgically treated go into a prevalence pool that is currently estimated to be around four million patients with significant MR and another seven million with mild MR just in the US. Based only on the annual number of new MR patients, Powell estimates the potential US market opportunity at greater than $2.5 billion, which explains why there are roughly 14 companies currently working in the mitral valve space.

In Whose Hands?

Evalve believes that any near-term concerns that surgeons may have about percutaneous procedures driving patients away from surgeons to interventional cardiologists are largely exaggerated. In fact, the opposite may be true. Ferolyn Powell sees the growth of percutaneous mitral valve therapies as the classic example of how a rising tide can raise all boats. "Improved and alternative treatment options will increase awareness, and that’s going to drive growth in both surgical and percutaneous procedures," she argues. Indeed, Christopher Dauer, SVP/sales and marketing, notes, "Our clinical sites that are actively enrolling patients are seeing their surgical volumes increase."

In terms of where the percutaneous patients are going to come from, Ted Feldman believes they will be drawn from both ends of the MR spectrum. "Patients who are older and sicker are not ideal surgical candidates, so the most obvious place for interventional therapy to expand is in this higher surgical risk group. But this treatment could also be very attractive for those patients at earlier stages of MR, and for whom this approach could help prevent or delay the progression of the natural history of the disease," he suggests.

Evalve’s percutaneous approach also offers the advantage of delaying surgery without adding complications to any subsequent procedures that may be necessary. "It was an important goal of ours that treating patients with the MitraClip not alter their surgical options," Powell explains. "We didn’t want to ‘burn any bridges’ if we didn’t successfully reduce MR."

Although Evalve is confident that percutaneous procedures will expand the MR market broadly for both cardiologists and surgeons, the company is not under any illusions when it comes to determining which clinicians will be their primary customers: it will be the interventionalists. "When we founded the company, we thought our focus would be on the interventional cardiologist, and really only a subset of all interventionalists, and that remains the case because this is a demanding percutaneous procedure," says Allan Will. "I will be surprised if any surgeons adopt this approach."

Ted Feldman takes a similar view. "There are going to be very few surgeons who will be able to adopt the Evalve percutaneous technique because it is a complex catheter procedure and takes well-developed interventional skills to perform," he explains. In that way, he distinguishes the percutaneous edge-to-edge approach from other interventional mitral valve approaches, such as coronary sinus annuloplasty, which may be easier for surgeons to adopt. In his view, the group of surgeons who will learn these percutaneous techniques is very small because it will be limited to those who have finished their cardiovascular surgical training and have then done a year or more of training in the cath lab, and there are literally only a handful of those people now around the country.

The bigger question for Feldman is how many interventionalists will adopt this technique because it requires a set of skills not currently employed by most cardiologists, being used primarily by interventionalists with experience in treating structural heart disease. "It takes a fair amount of time and substantial commitment to learn this approach," he says.

Feldman estimates that it would take several cases for cardiologists to become basically familiar with the Evalve technique, and five-to-ten cases before they can perform these cases smoothly and quickly. "And that is presuming that the physician has had an interest in valvular or structural heart disease, and is facile with performing a transseptal puncture," he adds. Initial MitraClip procedures took anywhere from three-to-six hours to complete, but the average time is now running under two hours, Feldman estimates. "I’m one of the more experienced operators in the clinical trial, and my last few cases have been done in less than 90 minutes," he says. Evalve patients do receive general anesthesia, yet the average hospital length of stay is just over two days, much shorter than the five-to-ten days following traditional valve surgery, primarily because the patient does not need to recover from a sternotomy and the CPB pump.

Although Evalve is focused initially on developing the MitraClip system for interventionalists, Troy Thornton points out that "The technology we have is very amenable to being adapted for use in a surgical setting," which the company doesn’t rule out as a possible future application. Fred St. Goar believes surgeons represent not only a future opportunity, but also that there will be some who will adopt the percutaneous approach. "I’ve believed strongly from the beginning that Evalve should also be developing a surgical device, and I’m confident that we will," he says.

St. Goar has a different view than Feldman and Will when it comes to surgeons adopting the interventional technique. "I don’t think the MitraClip requires extremely sophisticated catheter skills, but it does require advanced three-dimensional imaging and visualization abilities because this is clearly an echo-driven procedure," he says. St. Goar points out that younger cardiologists who have had more trans-esophageal echo (TEE) training tend to adapt more easily to this approach than more experienced interventionalists who lack TEE experience. "That’s why I’m sure that there are young surgeons who will also have no problem learning this procedure. The big question for any operator will be the volume of cases they perform because you have to do a certain number of procedures to keep up your skills," he points out.

It’s All in the Data

When it comes to selling products to interventional cardiologists, the primary driver of adoption is always the clinical data. Interventionalists are probably the physician specialty most influenced by evidence-based medicine, which is why the results of Evalve’s ongoing EVEREST clinical study are likely to determine the ultimate success of the MitraClip system. The company successfully completed its EVEREST I feasibility study, which served as the basis for the FDA approving Evalve’s pivotal trial design. The company’s clinical trial work is directed by Liz McDermott, VP of regulatory and clinical affairs and quality assurance, who is another veteran of ACS.

"We worked with the FDA for almost two years to get approval for our pivotal study, EVEREST II, with the goal being to provide data that allows the clinicians to determine which patients should be receiving the percutaneous therapy and which should be having surgery," McDermott explains. The risk/benefit trade-off will be demonstrated through superiority in safety, and effectiveness will be shown with non-inferiority, randomized against surgery.

The EVEREST II pivotal trial is a prospective, randomized, multi-center study of 280 patients at 31 sites in the US and Canada. Powell points out that Evalve is using a core lab to validate the trial data, which has not been done in previous mitral valve studies. The company has already enrolled 145 patients in the combined EVEREST trials and expects to complete pivotal trial enrollment in the second half of next year. Evalve is the only company in the percutaneous mitral valve space currently conducting a pivotal trial. Indeed, several patients have been followed for more than three years with positive results.

To date, Evalve has raised a total of approximately $57.5 million in three funding rounds, which Powell anticipates will be sufficient to carry the company into Q4 of 2007. Evalve expects to receive CE mark approval in the second half of 2007, and has set late 2009 as its goal for approval of its PMA by the FDA.

After The Foundry provided Evalve’s seed financing, Allan Will and Hanson Gifford led the effort to raise the Series A round. NEA and Kleiner Perkins get first look at all Foundry deals as part of their investment in the incubator, and NEA chose to lead the $6.5 million Series A financing in November 1999 and has participated in each of the company’s additional financing rounds. Also investing were Three Arch Partners, ABS Capital Partners, and John Simpson, MD, PhD (investing on his own).

Fred St. Goar says that "One of the most memorable weeks of my life in terms of getting positive feedback from people I highly respect was when we did this first fundraising." Over the course of three days, St. Goar and Gifford had separate breakfasts with Simpson and Thomas J. Fogarty, MD (who is an Evalve board member) looking to raise money. "We went to John Simpson’s house, and he was feeling pretty flush because he had just sold Perclose the week before. We got halfway through the presentation, and John said, ‘You guys can stop right now; I want to invest my own money in this company.’ And then we met with Tom Fogarty and not only did Three Arch invest but Tom agreed to work with our engineers on a regular basis, which enabled him to be actively involved early on."

In December 2001, Evalve raised $15.9 million in its Series B round, where NEA, Three Arch, and ABS were joined by Delphi Ventures, St. Paul Ventures, and Cutlass Capital. And in 2004, Guidant led Evalve’s $35 million Series C round, with all of the previous investors also participating. [See Deal] The Series C financing consisted of an initial closing of $20 million, with three milestone closings of $5 million each (two of which have been achieved). Guidant’s recent acquisition by Boston Scientific and Abbott raised a question about what would happen to its stake in Evalve. The resolution was that Boston Scientific and Abbott split the equity and Abbott retained all other rights and obligations, including a final milestone investment of $5 million.

Evalve has the financial wherewithal to carry the company through to completion of clinical trial enrollment, at which point they will seek additional funding to reach their next milestones, which include completing the EVEREST II study. As the first company with a percutaneous device in pivotal trials, Evalve is leading a revolution in mitral valve therapy. Yet, the company is doing so by taking a very conventional path.So far, Evalve is hitting all of the traditional benchmarks that are required for achieving its interventional conversion from surgery. The company has strong IP, a large market opportunity, an estimated two-year lead over its only competitor, and an experienced, stable management team. The next big challenge is the pivotal trial data, and the early results have been promising, showing safety, mid-term durability, reversal of left ventricular remodeling, reduced procedure times, and long-term durability. Chairman Allan Will is the first to admit that this has taken longer than anyone initially expected, but that is a pattern that is becoming increasingly common among device start-ups. Particularly in a complex clinical and technology area like heart valves, revolutions do not happen overnight.