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Manny Villafana's Lucky Number 7

Could his seventh start-up, Kips Bay Medical, dramatically improve the results of coronary bypass surgery?

Manny Villafana's Lucky Number 7

Manny Villafaña pulls open a small drawer, pokes through what looks like a nest of slinky little worms, and gently picks out a prime specimen of his latest medical device: the eSVS Mesh.

The silvery mesh tube lies across his fingers; it’s about eight inches long, almost silky to the touch. It’s made of Nitinol, an alloy of nickel and titanium that has shape memory, meaning it always returns to its original shape after being deformed. That allows it to act like “support hose” of sorts, fitting snugly around the vein grafts used in coronary artery bypass graft (CABG) surgery and helping them last longer. Without support, nearly half of vein grafts fail after a few years. Sometimes, they have to be replaced with a repeat surgery.

Villafaña is widely known for his pioneering development and commercialization of medical devices. In 1972, he formed Cardiac Pacemakers, Inc., (now part of Boston Scientific) and developed the first pacemaker powered by a lithium battery. It can last for decades, compared with the 12-to-24-month life of mercury-zinc batteries that were standard at the time. In 1976, he started St. Jude Medical, which designed the first bileaflet mechanical heart valve, an improvement over the era’s single-occluder valves because it greatly reduced the occurrence of blood clots.

His new eSVS Mesh seems elementary by comparison. It has no moving parts, no batteries or electronics or robotics, no drugs to dispense.

Still, “this technology has a greater potential than anything I’ve done before,” Villafaña says. Numbers to back up the assertion are quick off his tongue: Each year, patients throughout the world receive 50,000 to 75,000 defibrillators, 250,000 tissue and mechanical heart valves, 500,000 to 600,000 pacemakers, and 750,000 stents. But about 800,000 coronary bypass procedures are done annually, requiring on average 2.3 vein grafts each.

“That’s a 1.8 million market potential for us!” he says.

“Us” is privately held Kips Bay Medical, the Plymouth-based company that Villafaña formed in 2007 to develop the eSVS Mesh for regulatory approval and commercialization. “We don’t have any competition,” he says. “If I were to develop a new pacemaker or new heart valve, I would be going against really tough terrain, with 10 to 30 competitors. But the mesh is absolutely brand new, and every surgeon I’ve talked to wants to see it and get involved with it.”

 

Veins “Blow Up Like a Sausage”

To the extent that heart surgeons are intrigued by the eSVS Mesh, it’s easy to understand why. For 50 years, they’ve been giving heart disease patients a new lease on life with coronary artery bypass graft surgery—but with mixed results.

The procedure goes basically like this: Surgeons take segments of healthy blood vessels from other parts of the body, and use them to create detours around blocked coronary arteries, enabling blood and oxygen to flow freely again to the heart muscle. On average, patients require two to three bypasses per CABG surgery. Surgeons typically use the hardy internal thoracic artery from the chest wall to fashion one of those bypasses, and then harvest large saphenous veins from the legs for the others.

The thoracic artery graft generally works very well—and in 95 percent of cases, it’s still working well 10 or 15 years later. The outlook for the saphenous vein grafts is not so rosy: Almost 50 percent clog up and fail within a few years.

In effect, saphenous veins just can’t handle the pressure of their new job in the heart. They’re made to withstand the relatively low-pressure blood flow in the legs—measured in millimeters of mercury, about a 4 or 5. Arteries, on the other hand, are made to withstand 140 or 150 millimeters of mercury pressure; they are much smaller in diameter than veins, with thicker, stronger walls. (It is possible to use other arteries instead of using saphenous veins for coronary bypass surgery. But arteries are trickier to extract, and their small diameter makes them a challenge to work with, so saphenous veins have become the default choice, despite their drawbacks.)

“The saphenous vein is big,” says Villafaña. “So when you connect it with a coronary artery, it’s like trying to connect a fire hose to a garden hose—it’s a total mismatch. But more importantly, the saphenous vein does not have the muscular structure of an artery, so when you put it under the high pressure of the heart, bingo! It blows up like a sausage!”

It seems contradictory, then, that vein grafts eventually fail because they become narrower and blocked. But what happens is this: As high-pressure blood flows through the weak-walled vein, the lining of the vein ruptures, interrupting the smooth flow of blood. In response, the body tries to smooth out the vein walls by causing the cells of the vein’s inner lining to reproduce. The walls get thicker and thicker, and eventually blood can’t pass through.

Villafaña is betting that the eSVS Mesh can give the saphenous vein graft what it needs to hold its own: the physiological attributes of an artery. He and his 10 Kips Bay employees manufacture the mesh in Massachusetts and the Twin Cities, and travel the globe to present it to surgeons and conduct human clinical trials.

“The contention is, if you do something to make the vein behave more like an artery, then maybe it will last more like an artery,” says Dr. William Cohn, director of minimally invasive surgical technology for the Texas Heart Institute in Houston and a member of the Kips Bay Medical advisory board. (Board members are offered a nominal number of stock options in the company as their only compensation, according to Villafaña. Cohn was not certain whether he had accepted the options. Other board members quoted in this story did.) The mesh “squeezes the vein down so the diameter is smaller, the wall essentially becomes thicker, and those two things conspire to bring the wall tension into the normal range, so you won’t click that biological switch that causes the intimal cells to reproduce and start multiplying.

“It sounds great in theory, but does it really work?” Cohn continues. “In baboons, it doesn’t work ‘sort of’—it works wildly well. If it works as good in people as it does in baboons, then this may be the most significant thing Manny’s done in his life.”

 

Another Swing at CABG

Kips Bay Medical and the eSVS Mesh aren’t Villafaña’s first attempt to solve the problems of coronary artery bypass graft surgery. After he cofounded GV Medical in 1982 to make a laser angioplasty device (GV Medical was eventually bought by Spectrascience, Inc.), then launched Helix BioCore in 1987 and reorganized it as ATS Medical to make an improved bileaflet heart valve, Villafaña in 1999 formed CABG Medical.

CABG Medical developed an artificial graft for use in coronary bypass surgeries. The device had the potential to replace not only the troublesome saphenous veins, but also a patient’s harvested arteries, making bypass surgery less invasive with fewer incisions.

“It worked fine in animals, but when we put it in a patient, it didn’t work,” Villafaña says. “We finally determined, but not with 100 percent certainty, that when the patient stood up, the weight of the graft moved the connectors [that attached the artificial blood vessel to the real one]. And if you moved the connectors, even just a little bit, the flow went up against the tube wall and it would clog up.”

He adds, “With animals, the graft remained on the same plane. If humans crawled, it might have worked.”

CABG Medical had gone public in 2004. When it failed in 2006, “we ended up giving money back to the shareholders,” Villafaña says. “We raised $38 million, gave back $30 million. These people still appreciate what we did. We got up to bat, swung the bat, and missed the ball. They didn’t shoot me,” he continues. “They said, ‘All right, take another swing.’ That’s what we’re doing now. With this one, we’re being even more cautious.”

That doesn’t mean that all of his past investors are back on board. In fact, Kips Bay Medical is funded by Villafaña himself and a single private investor who he describes as “extremely shy,” a personal friend who has backed his previous projects and insists on remaining anonymous.

“As we go forward, we’ll get more investors,” Villafaña says. “Let me put it this way: We would normally be a publicly held company by now. In all my companies, we were public before or right after we did the first human implant. Here we are sitting with patients who are out six months already, and we’re not public—not because we don’t want to be public, but the IPO market is gone. But I’m sure we’ll get there.”

 

“That’s What the Doctors Like to See!”

Kips Bay Medical got something of a head start in reaching its first human clinical trials, because just as the company is not Villafaña’s first effort to improve on cardiac bypass procedures, Villafaña has not been alone in working on the problem. He acquired the eSVS Mesh from Medtronic in 2007.

At the time, Medtronic was streamlining its cardiac surgery business. “The project we picked up—among others—was being either farmed out or disbanded,” says Michael Winegar, chief operating officer and vice president of regulatory affairs for Kips Bay Medical. Medtronic’s Chuck Grothaus says the mesh technology was promising, but because it wasn’t a high priority for the company, Medtronic believed it could be more successfully developed by someone else.

Terms of the deal remain confidential, Winegar says, but Kips Bay Medical owns “all of the rights—the IP [intellectual property] and the technology—to the product.” Medtronic retains rights to a royalty stream if the mesh eventually comes to market.

Villafaña says that Medtronic (where he began his medical device career in international sales in the 1960s) in turn acquired the intellectual property for the eSVS Mesh from its inventor, Dr. Peter Zilla at the University of Cape Town in South Africa. Medtronic had put several years of research and development into the mesh, Villafaña adds, and had racked up impressive data from animal trials using dogs and baboons. But he did his own animal studies.

“I wanted my own data so I could answer truthfully when doctors asked me what I thought of it,” he says.

In early 2008, Kips Bay Medical began “bilateral” studies in sheep, meaning that each animal had both a standard vein graft that could be monitored as a control and a second vein graft with the eSVS Mesh attached. Sheep have such thin-walled veins that their saphenous grafts often fail at 30 to 60 days, Villafaña says. In the Kips Bay study, the nonmesh grafts were completely clogged at 90 days; the mesh grafts were still wide open.

He’s eager to show videos, stored on his computer, of the vein grafts in animals. The nonmesh graft at 90 days shows up as a weak, gray line; blood can’t pass through. The mesh graft shows up black, as the blood courses through it unimpeded. “That’s what the doctors like to see!” Villafaña says with a grin.

 

Human Trials

Last August, Kips Bay Medical started human clinical trials overseas, “where the regulatory path is a little easier,” Villafaña says.

As of mid-April, the company and its clinical trial partners had implanted eSVS Mesh grafts in 71 patients at medical centers in Germany, Singapore, South Africa, Switzerland, Spain, and Australia. Villafaña says the results are so compelling that he’s cut his goal from 120 human implants to 80, and then will present his results to both European regulators and the Food and Drug Administration in the United States. He hopes to start human clinical trials in this country this year, and to commercialize the product abroad already in 2010.

He acknowledges it will probably take longer to get to market in the U.S. “The FDA may accept all of our international data and say we don’t have to do clinical trials in the U.S.,” Villafaña says. How likely is that? He laughs: “Oh, on a scale of 1 to 10, about zero! I don’t think it will happen, but by law, it could happen. It has happened in other cases. But what the reaction of the FDA will be—there’s no book written on that one. You plan for your most difficult course, and if everything gets easier, you’re lucky.”

Just as in the sheep studies, human patients receive one vein graft with mesh and one without, so that each person functions as his or her own control group. “We’ve taken pictures. It’s working,” Villafaña says, “and we’re very confident as we go forward.”

Dr. Uwe Klima, professor of surgery at the National University of Singapore, was the first to implant the eSVS Mesh in a human being. “The world’s first implantation is always exciting,” he says. “And it was exciting to have like a big family in the operating theater—roughly 35 to 40 people watching the procedure.”

Villafaña was there. He always attends the first implant at every surgical center and seems to relish the interaction with clinicians. He and his team arrive the day before the procedure to watch the surgeon practice the technique of gluing the mesh onto the vein graft to keep the device from slipping around on the vein. In Germany, Villafaña recounts, “the surgeon was holding the vein up in the air, waiting for the glue to dry, which takes a few minutes. She said, ‘What do we do now?’ I said, ‘Well, it’s my birthday. Why don’t we sing Happy Birthday to me?’ The whole group sang. The following day, when the operating room is filled with people and surgeons, we get to the point where the glue has to dry, and the whole operating room sang it again!”

Klima, who is also a member of the Kips Bay Medical advisory board, says the eSVS Mesh is “a very simple concept, but many times in life, the simple things work best. And maybe that’s going to happen in coronary artery bypass grafting, too. If you think a little more simply than before, you might hit the home run.”

 

Measuring Opportunities

Dr. Lyle Joyce, a cardiothoracic surgeon who recently moved from the University of Minnesota Physicians group in the Twin Cities to the Mayo Clinic in Rochester, has no relationship to Kips Bay Medical, but has watched the company’s work with interest. Joyce says there are companies working on technologies that eventually could produce biological grafts for coronary bypass surgery—using stem cells to grow a new artery. But the eSVS Mesh “is unique,” he says. “To my knowledge, there is nobody who is working on that particular concept.”

It’s a concept whose effectiveness puzzles him, he confesses. If the deterioration of saphenous veins had “just been a pressure phenomenon, I would personally have thought that putting a Nitinol stent around it isn’t going to make any difference,” Joyce says. “It seems like an external support would not necessarily be the same as having the internal biological makeup of an artery versus a vein.” But as Villafaña has presented specimens and studies to surgeons at various meetings, Joyce says, “I must admit, I’m very surprised and quite impressed.”

Even so, it’s debatable whether the market opportunity will be as big as Villafaña projects. For one thing, the emergence of stents that can be inserted into arteries to prop them open in a minimally invasive procedure presents an attractive and less costly alternative to coronary artery bypass graft surgery—though not as attractive as was once thought. Recent studies indicate that even the current generation of drug-coated stents, which are meant to prevent blood from clotting around the devices, can actually increase the risk of clotting, making bypass surgery the better option for some patients.

Then there’s the rise of statins, drugs with brand names including Lipitor, Crestor, and Zocor that are designed to reduce blockage in arteries. They could also take a bite out of the CABG market.

Dr. Bob Emery notes a cost factor, as well. Emery, who is medical director of cardiovascular surgery at St. Joseph’s Hospital in St. Paul, has worked with Villafaña on the St. Jude heart valve, the ATS Medical heart valve, the CABG Medical artificial graft, and now on the medical advisory board for Kips Bay Medical. As companies and governments look for health-care cost reductions, Emery notes, the mesh could be seen as a “costly adjunct to a bypass procedure.” He estimates that the additional cost of CABG surgery in the United States could be more than a billion dollars a year. “It ain’t peanuts,” he adds.

“Certainly Manny’s a cheerleader, and he can sell ice to an Eskimo,” but there’s a lot of work left to be done before the concept is fully proven, Emery says. “I think the data are very, very good and I think it will happen. I’m twisting Manny’s arm to be the first to implant it in a human in the United States—right here in Minnesota.”

Villafaña, meanwhile, is looking ahead at other possible applications of the eSVS Mesh. One is bypassing blood clots in the leg, for which Kips Bay Medical is now conducting animal trials. “That market is about half the size of the heart market—still an enormously big market,” Villafaña says. A third application is using the mesh to shore up shunts for dialysis. “They use a patient’s vein to connect to the dialysis machine, but the vein becomes weakened,” he explains. “We think you can take our mesh and put it around that vein so it can withstand the pressure of the dialysis.”

That would be another sizable market, Villafaña adds. “I can tell you this: We have enough work here for 10,000 years.”

About the Kips Bay Name

Manny Villafaña first put the name Kips Bay on a venture fund that he and a friend worked briefly at forming in 2007. “It wasn’t our cup of tea,” Villafaña says. “We went back to our knitting”—developing medical devices.

He revived the name for personal reasons when he started his latest device company. “I grew up in the South Bronx, and it was a very rough area,” he says. “The Boys Club took me under their wing, gave me opportunities, kept me out of trouble. If it wasn’t for Kips Bay Boys Club, I know I would have ended up in jail or dead. So I decided to name the company in honor of the men and women who took care of me, and the work they continue to do with children.”

 

On Retirement: “Let Me Tell You a Story”

People ask him when he’s going to retire, Manny Villafaña says, and the very notion seems to amuse him. (He preferred not to give his age for this story.) “One guy came to me and said, ‘Why are you working? Why don’t you play golf or something?’ So I said, ‘Let me tell you a story.

“‘One day I was in Spain, talking to surgeons about heart transplants. I said, “I’ve never seen one.” This was Friday. The surgeon said, “Okay, we’ll call you this weekend.” I said, “How do you know you are going to do one this weekend?” He took me to the window and we looked down at the street, which was full of motorcycles. “You see down there? On the weekend there are even more motorcyclists, and you’ll notice that none of them wear helmets. We’ll do one.”’”

Villafaña got a 2 a.m. call to come down to the hospital. When he entered the operating room, the patient’s chest was already open. “The door flings open, and a guy comes in, holding a mask to his face and carrying an Igloo cooler. He opens the cooler, and puts the new heart on a table. They start cutting the patient’s heart out and put it on the table, too. It’s still beating—every so often, it beats. They put the other heart in the patient, and as they are sewing up the chest, the new heart starts to beat—I can hear the ‘beep’ of the monitor. And the moment the new heart starts to beat . . . the old heart stops. It was like life had left the old heart and entered the new. I said to the guy, ‘When golf is as exciting as that, maybe I’ll take it up.’”

—P. K.

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