X-Cell Medical: Putting Safety First

Most medical device start-ups seeking to tap into the enormous drug-eluting stent market have focused on novel stent or stent platform design, on the theory that drug efficacy is a given. But X-Cell Medical is betting that they've come up with a better drug. And they're making their case by stressing the importance of safety.

Most drug-eluting stent start-ups are designing second-generation products to feature a better stent platform. X-Cell believes it has a better drug.

By David Cassak

The ability to bring an active therapeutic profile to an otherwise inert medical device is an important part of what has made drug-eluting stents (DES) so revolutionary an advance for the device industry. And that revolution can be described both in clinical terms—in the radical reduction in restenosis rates—and in commercial terms. Indeed, the device industry has never seen a product that has created anything like a $6 billion market in so short a time.

The key to the DES revolution, of course, is the device's drug component—the active therapeutic agent that is actually responsible for reducing restenosis. It's curious, therefore, that, particularly among the small device start-ups who've risen recently to challenge for their share of the DES market, all of the focus on second- and third-generation stents is on novel stents and stent design.

Indeed, most DES companies, big and small, in order to reduce development risk and time to market, have opted to adopt drugs that have already been approved rather than find novel compounds. Thus, they've focused on a handful of analogs to the drugs currently being used on the wildly successful drug-eluting stent marketed by Johnson & Johnson (Cypher) and Boston Scientific Corp. (Taxus), sirolimus and paclitaxel, respectively. The rationale: these agents have already proven so effective in combating restenosis, efficacy will be a given and any advances in the future will be virtually indistinguishable. As a result, the only meaningful differential between DES companies will come through novel device technology.

But if the drug component is what separates a drug-eluting stent from a bare metal stent, it's unwise to dismiss so quickly its importance—so, at least, argues Princeton, NJ-based X-Cell Medical Inc. Indeed, X-Cell's senior managers, all of whom have extensive backgrounds in the pharmaceutical and biotech industries, turn the arguments of most DES start-ups on their heads, insisting that it is the device technology that is a given and that meaningful differentiation can come only from the drug component of the stent. And X-Cell takes its argument one step further: future therapeutic differentiation will focus not on enhanced efficacy—how much better can DES get?—but on a critical, but under-appreciated issue: DES safety.

A Second-Generation Compound

Founded in late 2002, X-Cell is one of the latest companies to come out of Accelerated Technologies Inc. (ATI), the cardiovascular device accelerator backed by some of the most prestigious names in cardiovascular medicine. (See "Is This the Model for Device Development?" IN VIVO February 2005 (Also see "ATI: Is This the Model for Device Development?" - In Vivo, 1 Feb, 2005.).) Several years ago, as the first drug-eluting stents were coming to market, ATI's founding physicians were convinced that the DES opportunity could support many more than two companies, notes Oded Ben-Joseph, MD, PhD, X-Cell's CEO. "The other thing that was clear was that, like any other drug, neither paclitaxel nor sirolimus would be 100% effective in all patients," he adds.

X-Cell's plan was to discover not just a second- or third-generation stent, says Ben-Joseph, but second- and third-generation compounds. A former tenure-track professor at the University of Michigan, with a PhD in bio- and neurochemistry from Cambridge University in England, Ben-Joseph left academia in the early 1990s to launch a medical device start-up in Israel focusing on laser treatments for various skin conditions and allergic rhinitis. "I've always been lured by industry," says Ben-Joseph, who also has an MBA. "I always found it more interesting, more intellectually stimulating than academia."

Ben-Joseph's early career also spanned both devices and biotech. After selling his laser start-up, he joined an Israeli venture capital firm, Medica Venture Partners, where he ran a biotech company called Ester Neurosciences Ltd. , which was developing drugs based on cholinergic mechanisms in the brain to treat neurodegenerative disease. It was at Medica that Ben-Joseph met Yuval Binur, Jeffrey Barnes, and Jonathan Fleming, who are backers of ATI. After several years in Israel, Ben-Joseph wanted to return to the US. The offer to join ATI's newest (at the time) venture was irresistible—as was the ability to work on a technology that combined drugs and devices.

Wide Variations in Efficacy

Indeed, unlike many device start-ups trying to develop next-generation drug-eluting stents, who argue that it will be device technology such as stent delivery systems that will create meaningful differentiation in DES, X-Cell is banking firmly on the innovativeness of its drug. "What we bring to the table is the biotechnology," says Ben-Joseph. "We feel strongly that a large portion of the value [in a drug-eluting stent] lies in the drug used, and not in the stent or the polymer."

In fact, to device executives who argue that it is the stent technology that will differentiate, if only because the clinical efficacy of the drug being eluted is a given, X-Cell counters that it is the device technology that is a given. "Stents have basically become commodities by now," argues Ben-Joseph. In contrast, say X-Cell officials, drugs, by their very nature, allow for wider variations in efficacy among different patient populations than device-oriented companies admit.

X-Cell officials, nearly all of whom have biotech and/or pharmaceutical company backgrounds, are well aware, notes Ben-Joseph, that there are multiple pathways or targets for any therapeutic intervention. It is, therefore, "mind-blowing to us that there are only two families of drugs right now" being used in DES—paclitaxel and the "olimus" family that embraces sirolimus, everolimus, zotarolimus (Abbott Laboratories Inc. 's ABT578), Biolimus A9, Ariad Pharmaceuticals Inc. 's AP23572, tacrolimus, and pimecrolimus—he says.

That means that all of the other DES companies are using essentially the same molecules to compete with J&J and Boston Scientific, Ben-Joseph goes on. From a biotech perspective, "all they can hope for is to develop me-too or me-three products," he says. Worse, from a business perspective, they're ensuring little differentiation in arguably the most important aspect of the stent: therapeutic efficacy. "That's hard for me to understand," says Ben-Joseph.

Indeed, X-Cell officials point out, two companies are, in fact, building their drug-eluting stents around the same compound: Abbott and Medtronic Inc. , both of whom will use Abbott's ABT578 (zotarolimus) on their respective stent platforms. And industry reports note that, should its proposed acquisition of Guidant Corp. succeed, [See Deal] Boston Scientific will have shared rights to Guidant's everolimus program with Abbott (along with some IP and clinical trials assets), even with the spin off to Abbott of Guidant's vascular business. [See Deal] For device-oriented start-ups, such a strategy validates the importance of device technology; for X-Cell, the strategy ensures that whichever company gets to market second will have a product that is, at best, no better than the market leaders.

X-Cell officials also point to the potential litigation risk: if all new drug-eluting stents are, pharmacologically, variants of stents already on the market, they risk infringing patents. And then there are the safety issues raised recently, including that of sub-acute thrombosis by sirolimus and paclitaxel. All of these risks are mitigated, if not eliminated, Ben-Joseph notes, if a company designs its drug-eluting stent around a novel compound rather than a novel stent design. "It's amazing [that anyone would run that risk]," notes Ben-Joseph, "because there are so many other pathways."

A Background in Biotech

X-Cell officials are just as likely to list as competitors drug and biotech companies such as Avantec Vascular Corp. , (a unit of Goodman Co. Ltd. ), Kaneka Corp. , and Ariad Pharmaceuticals, the last a Cambridge-based company working on new analogs of rapamycin, as cardiovascular device giants like Johnson & Johnson's Cordis Corp. , Boston Scientific, and Medtronic. And the technology they are betting on to differentiate their drug-eluting stent is a compound called estradiol.

X-Cell's biopharma orientation is reinforced by a senior executive team that, for the most part, has backgrounds in pharmaceuticals, not medical devices. Thus, in addition to Ben-Joseph who, as noted, ran both device and biotech companies in Israel, William R. Baumbach, PhD, X-Cell's executive director, drug research and development, did drug discovery and assay development for more than a dozen years at various divisions of Wyeth Research, as well as for a small drug discovery company called Morphochem AG. Hari Shankar, PhD, is X-Cell's executive director, drug delivery and formulation, and was, before joining X-Cell, involved with formulation and biomaterials in cardiovascular devices at J&J, starting at J&J's original cardiovascular device business, Johnson & Johnson Interventional, before joining Cordis Corp. (In the early 1990s, Shankar was the project leader on J&J's first drug/device combination product, its heparin-coated stent, before moving on to work on the project that led to Cypher.) Finally, Steve Peltier, RAC, X-Cell's executive director, clinical & regulatory affairs has worked in both biopharma and medical devices for companies such as Pfizer Inc., Wyeth, Bristol-Myers Squibb, and Johnson & Johnson, as well as a biotech company, Ortech International Inc.

Bill Baumbach's responsibility is "to make judgments about which drugs can be viably formulated for efficacious local delivery from a device," he explains. For Baumbach, the key to estradiol and a better drug-eluting stent is safety. Like many device-oriented DES executives, he argues that the efficacy of any DES compound has to be a given. Thus, he notes, "Estradiol's efficacy has essentially been shown in a variety of studies over the years, both in animals and even in humans, the latter in a clinical trial called EASTER. "The drug itself has been shown to be extremely potent at a nanomolar and sub-nanomolar level." It's also very stable, particularly when compared to paclitaxel and sirolimus, which translates into long-shelf life, something that has been an issue with the drug-eluting stents currently on the market.

But for X-Cell, estradiol's real value lies in the fact that it doesn't have the aggressive cytotoxic effects of the compounds used on the drug-eluting stents currently on the market. The drug works on two mechanisms. It promotes vessel dilatation and endothelialization in a short-acting effect. Its impact at the level of nuclear receptors is longer-acting, promoting or enhancing endothelial cells while inhibiting smooth muscle cells. Explains Baumbach, "Estradiol has been shown to block smooth muscle cell migration and proliferation in a mild way—not so much by killing cells, but by gently reducing their rate of growth."

Baumbach notes that only estradiol can beneficially impact both endothelial and smooth muscle cells. The goal in preventing restenosis safely, he says, is to halt or slow down smooth muscle cell proliferation while at the same time enhancing the proliferation of endothelial cells to repair the damaged endothelium. Estradiol can thus make distinctions between the different cells, and it also blocks the inflammatory response from vascular injuries, something neither paclitaxel nor sirolimus can do. "They're not selective drugs," he says. "They stop both smooth muscle cells and endothelial cells from proliferating, and that's not a good thing."

Better Because It's Safer

If estradiol is a novel compound in the realm of drug-eluting stents, it's not an untested drug. In use for more than 60 years, it is a key component in hormone replacement therapy (HRT) and contraceptive pills. "That's another good thing about it," says Oded Ben-Joseph. "It's FDA-approved and has been around for a long time." And while it's a generic in the field of HRT—it's the basis of Wyeth's franchise drug, conjugated estrogen (Premarin)—X-Cell has exclusive, patented rights in the area of drug-eluting stents. "In that regard, it's not a generic," says Ben-Joseph.

Data on the three-year follow-up of the EASTER trial was just reported last October, and X-Cell officials have begun to do their own clinical trials of the drug. A small, sub-optimized study, with 30 patients in Brazil, assessing the impact of estradiol on restenosis rates, EASTER was promising, showing a late-loss index of 0.54, within range of other drug-eluting stents, notes Steve Peltier. "We find that very encouraging, particularly since drug release was complete in the first few hours, a situation far from optimal," he says. With X-Cell's optimized ETHOS (EsTradiol-eluting stent in Humans for restenosis) trial, he goes on, "we anticipate a better late-loss."

X-Cell officials have in-licensed their stent platform from OrbusNeich --the company used Abbott's BiodivYsio stent for the EASTER trial—and will be using that stent in their ETHOS trial, which will feature three arms: a control group, as well as a slow-release and a moderate-release formulation of estradiol. One issue: are release kinetics, generally speaking, a critical issue in the efficacy of drug-eluting stents? "It's a good question," notes Hari Shankar. "That's why we're doing these studies." It's also why ETHOS will look at slow- and moderate-release of the drug, following EASTER's fast-release. "We're trying essentially to bracket the spectrum [of release kinetics]," he says. (A second ETHOS trial, ETHOS II, designed to test yet another, more sophisticated release profile is scheduled to begin enrolling patients in the first quarter of 2006.)

Launched in early August, the ETHOS I trial has already reached its enrollment goal of 95 patients and is being conducted at three centers, one in Brazil, in the lab of Alex Abizaid, MD, and the other two in Germany, including the Siegburg Heart Centre, which is run by Eberhard Grube, MD and the Heart Center in Trier, which is run by Karl Hauptmann, MD. "The six-month data is obviously the criteria on which we'll judge the efficacy of the product," says Peltier. "And we'll look not only at restenosis under IVUS, but all of the secondary angiographic parameters." Indeed, one clear goal: to prove that X-Cell's DES can deliver a better late-loss index that is, says Peltier, "competitive in today's drug-eluting stent marketplace."

Even more important, however, is the safety profile, measured by MACE (major adverse cardiac events)--the first data released for patients with a three-month follow-up shows no reported incidents of MACE, notes Peltier. Such results are important for X-Cell, not just to prove clinical efficacy, but for differentiation in the marketplace. With so many next-generation drug-eluting stents doing non-inferiority studies, X-Cell officials are hoping to make the case that their stent is actually better because it has a better drug. And, Peltier points out, "there are two ways you can claim superiority: on efficacy and on safety. An enhanced safety profile is much better, from a marketing angle, than even having a few points more on the efficacy side."

A Breath of Fresh Air

Oded Ben-Joseph calls X-Cell's biotech orientation, "a breath of fresh air" in a world of second-generation stent companies that are almost exclusively device-oriented. Not that X-Cell ignores the device components of its drug-eluting stent: notes Ben-Joseph, "We're a true interdisciplinary team. We do have a profound understanding of the device side."

But it is the skills and capabilities inherent in their pharmaceutical biotech orientation that distinguish X-Cell, say company officials. Thus, notwithstanding X-Cell's commitment to estradiol, Baumbach notes that one of X-Cell's strengths lies in its ability to do highly sophisticated drug discovery. "We're very busy with estradiol right now," he says. "But we have the capability, if we want to use it, to screen hundreds of compounds a week, looking for a new approach to restenosis."

Such a capability is not only beyond the reach of most device companies, but extremely onerous in its own right—Cordis screened nearly 800 compounds before narrowing their choice to three in developing Cypher. That's why most device-oriented stent companies have turned to drugs in the paclitaxel and sirolimus families to find the compounds for their stents. But at X-Cell, estradiol was just one of several approaches to restenosis X-Cell explored—it also worked for a while on XC441, a platelet-derived growth factor receptor inhibitor, as well as on XC771 and SC551, both novel inhibitors of cell signaling pathways—estradiol might be just the first of several compounds the company uses on its stent platform.

Skills like drug discovery aside, there are also important cultural differences between drug and device companies. Steve Peltier notes that "the mentality of a device company is short-term, with multiple product iterations." The mentality of biotech companies is much different, he says: "The R&D time is much longer before you get your product to market, and the changes made are not incremental or quick because you have to look at toxicity as well as efficacy, and once you put it in a human, each person reacts differently."

That's why, notwithstanding all of the talk about stent design and delivery systems, large device companies themselves recognize the importance of the drug component of their drug-eluting stent. Cordis is a case in point. In bare metal stents, Cordis got to market first and quickly took 90% of the market, only to lose much of that when second-generation stents from Guidant Corp. and AVE (now Medtronic Vascular ) came to market.

But in drug-eluting stents, the reverse happened. Most analysts thought that Cordis, still smarting from taking its lumps in bare metal stents, would in fact trail Boston Scientific in getting to market. But, in fact, because of J&J's in-house pharma expertise, it got there first—and just as tellingly, bare metal stent rivals, Guidant and Medtronic, have stumbled or lagged significantly in getting their own drug-eluting stents to market. When asked why, former Cordis group VP, Robert Croce, noted, in an interview in IN VIVO, that it was all because of the drug. "On the pharma side, it's a lot trickier, a whole different world, and we had in-house expertise," he said. "It was actually one of the great projects at J&J, and everyone still talks about how well the collaboration worked within the corporation. We had help from everywhere to make this work. And it's hard for me to imagine if you didn't have that pharmaceutical expertise down the street from you, that you could do it quickly." (See "Building Billion-Dollar Businesses: An Interview with Robert Croce" IN VIVO, December 2005 (Also see "Building Billion-Dollar Businesses: An Interview with Robert Croce" - In Vivo, 1 Dec, 2005.).)

Even Guidant and Boston Scientific officials have noted the tremendous re-orientation, in terms of both costs and culture, that adding a pharmacological expertise has entailed. (See for example, "Guidant's Guiding Spirit: An Interview with Beverly Lorell, MD" IN VIVO, May 2004 (Also see "Guidant's Guiding Spirit: An Interview with Beverly Lorell, MD " - In Vivo, 1 May, 2004.).)

A Shot in the Dark

Perhaps that's why Bill Baumbach calls the early efforts by device giants to find the drug they used on their stents "a real shot in the dark, given the complexities of formulation and preclinical testing." Even for a company skilled in drug discovery, finding the right compound is a combination of "philosophy, data, and a lot of luck," he says. Just as critical: making certain the compound you want to use is available. "The licensing issue, to some extent, has to come first because you don't really want to put a lot of effort into something that you ultimately can't get," says Baumbach.

X-Cell's biopharma perspective underscores another important difference between its approach to drug-eluting stents and that of other, device-oriented companies. For the most part, the device companies that have developed drug-eluting stents have utilized a single compound with the hopes or expectations that it will be effective in all—or at least a very large number of—patients. But pharmaceutical companies know that most compounds work for only a small segment of any broad patient population. Indeed, the reason why there can be six or seven drugs in any one therapeutic category is that even the best drug won't work for every patient. Thus, a physician may start a patient on one statin, lovastatin (Mevacor), for example, and then switch patients to others, such as atorvastatin (Lipitor) or simvastatin (Zocor), depending on how the patient responds.

Bill Baumbach notes that X-Cell isn't actively screening for a DES compound beyond estradiol, but he says the company's biotech orientation "brings out the differences between a pharma approach [to drug-eluting stents] and a device approach," and implies what company officials hope will be an edge for X-Cell's estradiol-based stent. Even physicians today, he concedes, tend to choose drug-eluting stents on the basis of the ease-of-use and/or comfort with a particular stent's design or delivery system—you can't, after all, simply switch one stent for another if the patient experiences restenosis, the way you switch a patient from one statin to another.

But the notion that there is an important variability in the way individual patients respond to any given compound should, X-Cell officials hope, convince interventionalists to focus more on the safety than on the efficacy of the drug-component of the stent they choose for their patients—if only because, ultimately, since any given patient's response to a DES is unpredictable, the benefit of keeping patients safe from something like sub-acute thrombosis will outweigh any marginal differences in preventing restenosis, particularly when all DES are delivering similar restenosis reduction rates. "What will happen eventually is that physicians will start to understand which of these drugs is safer than another," says Baumbach.

Safety First

Baumbach concedes that sub-acute thrombosis occurs only in about 1% of all DES cases. "But a huge percentage of those who experience sub-acute thrombosis die, and every physician feels very strongly about this," he says. It's not that efficacy isn't important, adds Oded Ben-Joseph, but "safety is what we need to prove; that's the edge that we'll have in the market." It may be that only half of one percent of all stent patients die from sub-acute thrombosis, he notes, "but given the number of stents implanted every year, that's a large number of patients."

And indeed, safety issues seem to be increasingly coming to the fore at major clinical meetings like TCT and PCR. With each new study clearly showing the efficacy of drug-eluting stents, interventionalists no longer need to be convinced that the products work; now they want to look at other issues, which include things like expanded indications, efficacy in patient population sub-groups, and, of course, safety. (And some leading interventionalists, most notably Renu Virmani, MD, have been highlighting long-term safety issues since the release of RAVEL data.)

Thus, at last year's PCR meeting, whole sessions focused on the likely risk posed by sub-acute thrombosis in drug-eluting stents. (See "At PCR, How Big is Small?" IN VIVO June 2005 (Also see "At PCR, How Big is Small?" - In Vivo, 1 Jun, 2005.).) But if safety is a real issue, why have so few companies addressed it? X-Cell officials argue that their own pharma and biotech backgrounds may have made them more sensitive to safety issues than a long-time device executive might be.

Then there's a timing issue. Any disadvantage that X-Cell may face in trailing Cordis and Boston Scientific into the market is, says Hari Shankar, offset by the benefits of hindsight. Shankar argues that in their focus on finding a compound that works against restenosis—and the follow-on efforts to prove that it does—the large DES companies didn't pay enough attention to what he calls "the balance between safety and efficacy." "When they started on their pursuit of this Holy Grail, they probably didn't give much thought to it at the time, at least not a lot of active thought," says Shankar.

Nor is sub-acute thrombosis the only safety issue. Bill Baumbach notes that many DES patients now face extended anti-platelet therapy, which can have problems for some patients. "For people on long-term Plavix, it not only gets expensive, but it can be dangerous," he says. X-Cell hasn't yet begun to study the implications for antiplatelet therapy with estradiol, but Baumbach says it is on the company's agenda.

Finally, related to the issue of release kinetics is the issue of toxicity. Because it's a naturally-occurring hormone and not a cytotoxin, estradiol is simply safer than paclitaxel or sirolimus. Steve Peltier says that such considerations should go far with physicians today "who want to expose their patients to the least amount of drug possible and still get efficacy." X-Cell's clinical studies will look at dose level and response because, as he says, "we all know that toxicity is a function of dose response." And notes Hari Shankar, similar issues are raised in the reduction or elimination of the use of polymers.

Partnering Up

Of course, a focus on safety presents its own challenges for X-Cell, particularly in its clinical trials work. Given the small incidence of problems such as sub-acute thrombosis and the fact that it often occurs late, to definitively prove estradiol's enhanced safety profile, X-Cell's trials would have to be very large and its patients followed for years. Still, at least in the preliminary stages of X-Cell's development, Oded Ben-Joseph says that the ATI physicians who have been promoting X-Cell are excited about the importance of safety and, therefore, about the prospects of the company. "Safety is a major issue for them," he notes. "Marty Leon, in particular, has been talking about that for years. They like the fact that the only two drugs currently being used on stents are cytotoxic, and estradiol is a much gentler drug." (See sidebar, "Safety and the Next Generation of Drug-Eluting Stents.".)

X-Cell officials argue that one major difference between X-Cell and other second-generation DES companies lies in the company's expertise in screening compounds and conducting clinical trials, which comes from their biotech and pharma backgrounds. "Because we have a biotech-like drug discovery capability, we can develop a third or fourth generation drug," says Oded Ben-Joseph. But, perhaps because of that expertise, commercialization of X-Cell's stent, which requires device skill sets, "is a whole different issue," Ben-Joseph adds. In fact, he says, "we don't expect to commercialize the product ourselves; we'll have to partner with someone else."

X-Cell expects to have CE mark by late 2006 and is beginning to look for potential partners now. Here, too, X-Cell officials argue that they present a clear choice from other second-generation stent companies precisely because X-Cell's value lies in its drug, not in some novel stent design or stent delivery platform. (Even in Europe, says Ben-Joseph, "The market is moving toward the drug-side. I think that within the next couple of years, the European market is going to be remarkably similar to the American market.")

Thus, the ideal candidate for a partnership, says Ben-Joseph, is a company, either already on the market or just about to get there, that frankly has concerns about its drug, particularly as the DES market grows more mature. "It could be a small company or a large company," he says, "but it's one that needs to bring something different to the market to secure an edge because they're not going to capture a large share of the market with an inferior drug."

Or maybe it's a company looking for a different drug. With so many next-generation drug-eluting stents piggybacking on either paclitaxel or sirolimus, a company wishing to differentiate itself could do so with estradiol, simply because it's a different compound. That's why X-Cell believes that its estradiol stent will likely serve not as a replacement for a partner's existing DES program, but as an addition, an adjunct or even a combination product, used with the partner's own main compound. (Ben-Joseph notes that estradiol is compatible with a wide range of polymers and can therefore integrate with another company's stent and stent delivery program fairly readily.)

Ben-Joseph argues that convincing physicians of the importance of safety and therefore of the value of estradiol shouldn't be hard. "There's a lot of concern about safety right now and interventionalists are always hungry for new products," he says. Rather, the tougher sell may be convincing potential partners that X-Cell has something different. "What will be more challenging for us will be convincing industry," he goes on.

Ben-Joseph doesn't rule out the possibility that X-Cell could take its estradiol-eluting stent to market by itself. But it's clearly not where the company's inclinations lie. Rather, Ben-Joseph says that X-Cell will seek to broaden or expand its opportunity "not necessarily by pushing a drug-eluting stent to market by ourselves, but by developing the technology around our core." Two possibilities: using an estradiol-eluting stent to treat vulnerable plaque and acute myocardial infarctions (AMI). "We feel that without changing clinical practice, we can impact interventional medicine in both areas, delivering a drug that will do more than just block restenosis," says Bill Baumbach.

(In previously published clinical literature, estradiol was shown in preclinical models of AMI to reduce both infarct size and cardiomyocyte apoptosis and was shown to be cardioprotective against infarction. In vulnerable plaque, the drug has demonstrated that it down-regulates MMP-1, thus reducing the cap thinning that takes place, and that it reduces IL-18, which is associated with an unstable plaque phenotype.)

Other opportunities notwithstanding, however, X-Cell's challenge is to prove that, in a drug-eluting stent marketplace that is both maturing and growing more crowded at the same time—unlike most device markets, in which the ranks of competitors thin out as the market matures—its estradiol-eluting stent is different, and in a meaningful way. Oded Ben-Joseph argues that achieving an anti-restenotic effect, through a combination of smooth muscle cell proliferation and novel endothelial growth promotion, should not only establish X-Cell's safety claims, but, more importantly, confer a clinical competitive advantage on the company, one of the few new DES companies to attempt to bring what Ben-Joseph calls, "a highly differentiated and attractive new drug class to the DES market."

If X-Cell succeeds, it will be not just because it is able to demonstrate superior safety, but more importantly, because enhanced safety proves to be a valid differentiating factor in the booming DES marketplace. "It's amazing to us how undifferentiated this market is," says Ben-Joseph. "From where we stand, virtually everyone coming into this market is selling basically the same product. It's a race to the end, and right now, all of the horses are similar."

Safety and The Next Generation of Drug-Eluting Stents

For interventional cardiologists, the phenomenal efficacy of drug-eluting stents in reducing restenosis has always been the primary appeal of the new technology. But as first-generation stents give way to second-generation stents, says Marty Leon, MD, safety, not efficacy will move center stage in clinicians' selection decisions around the new stents.

Leon, who serves as Medical Director for X-Cell through his affiliation with Accelerated Technologies Inc., is enthusiastic about estradiol and says that the drug is clearly differentiated from the compounds, paclitaxel and sirolimus, currently on the market. Because it's a hormone and not a cell cycle inhibitor, he notes, "It does more things and different things." It's not, like sirolimus, a powerful antiproliferative agent, Leon goes on, "though it does have antiproliferative effects and anti-inflammatory effects. And it's our feeling that it will have enough in the way of antiproliferative effects to importantly impact restenosis."

Most importantly, Leon says, estradiol is pro-healing in a way that those other compounds aren't and thus underscores a new way of thinking about the clinical efficacy of drug-eluting stents. "We've seen with Taxus and Endeavor that you don't have to have a late-loss index of 0.1 or 0.2 to have very low restenosis rates," he says. That makes estradiol potentially special. "We think it has virtues in that it may be safer than the other compounds from the standpoint of what it does to the biology of the vessel wall," he says.

Sub-acute and late thrombosis as well as incomplete apposition and late-incomplete apposition—all are concerns because they're apparently showing up more with drug-eluting stents than they did with bare metal stents. Studies show that sub-acute thrombosis, for example, occurs in less than 1% of all DES cases. Still, says Leon, it's meaningful and is beginning to change the way interventionalists think about which stent to use. "The major issue for second-generation drug-eluting stents is not to improve the efficacy, to move the restenosis rate from 5% to 3%, but frankly to make them safer," he says. In addition, Leon calls the dual anti-platelet therapy—clopidogrel (Plavix) and aspirin--currently required for DES patients "extremely problematic."

As a result, Leon goes on, anything that can be done to improve the safety profile of a stent becomes valuable. Even a slight improvement in SAT (sub-acute thrombosis) rates, from 1% to 0.5% means that one in 200 patients isn't going to have a major problem later. "That's meaningful," Leon says about such a shift. "No one's going to care if the restenosis rate drifts from 4% to 5% or 5% to 7%. But if one in 200 patients avoids out-of-hospital sub-acute thrombosis, which results in a Q-wave MI 75% of the time and in death 25% of the time—that is a more than adequate trade-off."

That's why "safety has to be a predominant concern for next generation stents," he says. Moreover, continuing study of DES patients is beginning to show that there are selected patient sub-groups at risk for safety issues such as SAT. "We're just beginning to understand what those populations are," he says. For X-Cell, he goes on, "if we can demonstrate in the ETHOS I trial that we have a low enough restenosis rate and the late-loss is in range of what we think is acceptable, then I think the safety issues will become important in specific patients."

Of course, proving estradiol's superior safety is easier said than done. Leon concedes that there's a lot of work yet to do. Moreover, safety can be more difficult to prove than efficacy, if only because it requires larger patient pools to be tracked over longer periods of time. X-Cell's early clinical studies are encouraging, but too small to be anything like definitive. "You have to do not hundreds but thousands of patients to talk about safety," Leon notes. Indeed, Medtronic's Endeavor trial raised serious questions, not so much about what is an acceptable late loss index, but about what kinds of data are necessary to prove clinical endpoints. "These are daunting studies to do," Leon says. "If you want to show a reduction in stent thrombosis from 1% to 0.5% with an 80% power in a randomized trial, you need to study 10,000 patients." (See "Will Late Loss Debate Stifle Device Start-Up Innovation?" IN VIVO, November 2005 (Also see "Will Late Loss Debate Stifle Device Start-Up Innovation?" - In Vivo, 1 Nov, 2005.).)

In that regard ETHOS is really just a first step. If X-Cell can demonstrate that the trial was well-conducted and that the data from the first 95 patients indicates strong safety results and competitive efficacy, "then we'll launch into next-phase studies to really explore some of the issues relative to safety."

But, he goes on, "it's not realistic" to expect a company the size of X-Cell to do a 10,000 patient randomized clinical trial. Can, however, the company skirt the issue? Can it make the case to clinicians that it doesn't have the critical mass it needs in its studies, but given that we understand how estradiol works, we can assume or extrapolate that it is safer? Leon isn't sure and suggests other possible pathways for X-Cell. One is to go out and raise the money to do such studies, most likely through an IPO rather than additional private financing. Another possible path: to leverage relationships with other companies to get the resources required for more extensive studies.

In addition, Leon notes, X-Cell has "already begun to explore experimentally" some possibilities around combination therapies as they relate to estradiol. "One of the things you'll see in DES over the next several years is combination therapies," he points out. "We're seeing Conor Medsystems moving in that direction with pimecrolimus and paclitaxel, Abbott with dexamethyzone and zotarolimus and Cordis, possibly, with sirolimus and heparin. And you could imagine that estradiol might be a nice second drug in a combination therapy that would have specific effects."

Such combinations would affect not just restenosis, but other therapies, such as vulnerable plaque. With vulnerable plaque, says Leon, "safety is a critical concern: you don't want to take moderate stenoses and treat them prophylactically with agents that potentially could be deleterious and cause major safety concerns." X-Cell has also looked at what Leon calls "some very interesting effects that estradiol has on patients with acute myocardial infarctions."

Clinical issues aside, there are other questions that X-Cell's focus on safety raises. For example, if safety is such a big issue, why aren't the big stent players, who have so many resources, making a major push in this area? And can X-Cell find a differentiated niche, or have they simply highlighted the issue so that the big players can jump in? Marty Leon says that he's encouraged every big company he works with to address the safety issue, "and they're already engaged in their own efforts to improve the safety profile for their drug-eluting stent," he notes. "I think they're all very conscious of the clinical need to move in that direction. I don't think it's just going to be highlighted by X-Cell."

Still, Leon believes that in some respects, a small company like X-Cell may be better positioned to tackle the issue of safety than big companies are. He notes that ATI executives thought long and hard about tackling an area like drug-eluting stents and was convinced to do so, in part, by the strong biotech and pharma backgrounds of X-Cell's senior managers. "We have a superb experimental pharmacologist working there and one of the key people who helped to develop all of the coatings for Cordis in the 1990s," he says. "We have the expertise resident within X-Cell to deal with some of the key issues, and I think we've made very good use of some of our out-sourced collaborators for drug carrier systems, for stent designs, and for experimental models to study the effects of estradiol."

Also a factor, however, is a kind of nimbleness that X-Cell can bring, specifically as a small start-up. Big companies, Leon says, can become "paralyzed to a state of indecision and inactivity and sometimes a smaller organization can address concerns in a focused way and make progress that goes beyond what the big companies can do." Indeed, he notes, for all of X-Cell's challenges, X-Cell's been able to accomplish a lot in the short time it's been around. Says Leon, "Given the company's band-width, what's striking is that we've gotten through a very serious first-in-man study, with a potentially commercializable product in such a small company."