Next-generation drug-eluting stents tackle shortcomings of Cypher, Taxus February 7, 2006 Shelley Wood

Transcription

1 Page 1 / 7 Sujet : Date : De : A : CC : Next-generation drug-eluting stents tackle shortcomings of Cypher, Taxus 06/05/ :35:41 Paris, Madrid Evelyne Germe JPBEREGI jpberegi@chru-lille.fr Next-generation drug-eluting stents tackle shortcomings of Cypher, Taxus February 7, 2006 Shelley Wood New York, NY - With several new drug-eluting stents (DES) already available in Europe and in pivotal clinical trials in the US, interventional cardiologists are starting to hope that the innovative newcomers will resolve many of their concerns or complaints about the Cypher (Cordis/Johnson & Johnson) and Taxus (Boston Scientific) devices. Dr Mitchell Krucoff (Source: Duke University Medical Center) "With any breakthrough technology that changes the landscape of medical therapeutics, the reality is, the first version is always the worst version," Dr Mitchell Krucoff (Duke Clinical Research Institute, Durham, NC) told heartwire. "In the case of firstgeneration DES, these are essentially bare-metal stents that have been spray-painted with plastic." While next-generation versions of both the Cypher and Taxus, known as the Cypher Select and Taxus Liberté, are already CE approved and poised for US approval, both have focused primarily on easier deliverability, a major buzzword of the early DES era. Elsewhere, companies have tried to emulate or improve on the success of the Cypher by developing new macrolide immunosuppressive ("limus") drugs, such as biolimus A9 (Biosensors), everolimus (Guidant), tacrolimus (Sorin, Abbott), and zotarolimus (Abbott, Medtronic) for stent-based delivery. Likewise, innovation in stent composition and design continues, with many second-generation drug-eluting stents available outside North America doing away with stainless steel for the base stent, replacing it with alloys that maintain radiopacity and strength but permit thinner, more flexible struts. Indeed, Cordis/J&J has its own cobalt-chromium stent, the Cypher Neo, still several years away from US approval. Cypher Select (Source: Cordis/J&J) Perhaps the biggest and most contentious flurry of activity centers on the actual mechanics of drug-delivery and the need for a polymer coating. Polymers have been hailed by some as essential to controlled drug elution and maligned by others as a ticking time bomb: the potential cause of increased late thrombosis and other adverse tissue responses. The polymer has also been blamed for stent-delivery glitches; in particular, the increased friction, or "stickiness," between the delivery balloon and the stent itself. Although the original Taxus and Cypher stents both have polymer coatings, other DES developed at the same time, such Cook Inc's drugeluting stent program, did not make it through clinical testing, having failed to demonstrate superiority over bare-metal stents a fault blamed largely on the inability to regulate elution of the drug. Puzzling over polymers Liberté (Source: Boston Scientific) Trea And He Though pathophy cl associatio h inform

2 Page 2 / 7 New stents, however, are revisiting the concept of polymer-free Dr Marie-Claude Morice stents or at least trying to develop polymers that will disappear over time. As Dr Marie-Claude Morice (Institut Cardiovasculaire Paris Sud, Massy, France) emphasized to heartwire, operators have enough years of experience with bare-metal stents to feel confident that a metal stent can remain in the coronary system without causing late adverse effects. The same cannot be said for the polymer. "It's a very important issue," Morice said. "The polymer coatings currently used reflect the early phase of DES development. The long-term outcome of bare stents is well known, whereas that of polymer coatings is not." Dr Adnan Kastrati (Deutsches Herzzentrum, Munich, Germany) agrees: "Why would you have something on the stent that you don't need? There are not enough data to show that polymers are risky over the long term, but there are still some concerns," Kastrati said. tr Miro Sym P Ackerm Hocin Mower a Miche Sympo Wednesd He Scientific here for m unrestr gr Those concerns stem from a number of sources, experts say. For one, says Krucoff, even a polymer that is not loaded with drug can cause localized reactions in the artery. "In the preclinical work with the Cypher stent in pigs, for instance, it was very dramatic that once the sirolimus had eluted, there was an intense subsequent inflammatory response at the cellular level that generated profound late in-stent restenosis," Krucoff explained. Dr Adnan Kastrati "Now, it's very clear we're not seeing that in humans, but on the other hand, this does give us an animal model that alerts us to the fact that, once the drug has eluted, if the polymers persist, these are not inert substances." Scanning electron microscope studies also indicate that polymer integrity can become damaged during stent delivery, cracking or peeling away from the stent struts, but the extent of the problem and its clinical impact are unknown. "We can never really be sure what the true denominator is that we're dealing with," Krucoff told heartwire. "For instance, if you're concerned that in high-pressure balloon delivery you could potentially fragment or cause the polymer to flake well, how many thousand times does that have to happen for any one time you have late stent thrombosis?" Krucoff points out that the potential problems associated with polymer integrity may depend on type of drug, dose, and properties of the polymer itself. For example, he says, studies of the Taxus stent indicate that only 20% of the paclitaxel embedded in the polymer actually elutes during the healing process, but that amount, as shown in the pivotal trials, is clearly enough to substantially reduce the risk of restenosis. "But what about the rare occasion when something else happens?" Krucoff asked. "The coronary artery constricts, or you overlap the stents and create more fragmented polymer when the stents are dilated with a high-pressure balloon where they've overlapped, and you create unusual contortion, and more drug is eluted from the polymer what happens then? No polymer is inert, and whether or not it is still eluting drug, or if it is just how the tissue responds to the polymer all of those things get back to our concerns."

3 Page 3 / 7 Getting away from the polymer Kastrati's group recently became the first to show that it may be possible to get away without using a polymer coating, at least for relatively simple lesions. As reported by heartwire, Kastrati et al's ISAR-TEST trial used an in-house system for applying sirolimus to The Translumina a "rough" bare-metal stent. The ISAR-TEST results, first presented stent-coating system at the 2005 TCT meeting, were recently published as a rapidaccess publication online in Circulation [1], proving that a nonpolymer approach to drug-eluting stents can work in a field where other nonpolymerized stents have repeatedly met with failure. The economic benefits of a coat-it-yourself stent were one of the rationales behind ISAR-TEST, but Kastrati insists that the most important factor was the drive to create a stent that does not have a permanent polymer coating. "The most important factor is that we don't want to have polymers permanently on the stent, so we can be sure that, after six months, we have a bare-metal stent like those for which for many years we had no concerns about long-term efficacy," Kastrati said. The long-term outcome of bare stents is well known, whereas that of polymer coatings is not. For her part, Morice told heartwire that coating stents in-house is "a good temporary solution," comparable to the manual crimping of bare-metal stents in years past, and may play a role until the cost of DES declines. In the long run, however, "I do not think that 'coat-it-yourself' stents will have a major role," she says. "They will never compete with industrially engineered stents." Morice has, herself, been involved in research examining polymer-free stents, most recently the JUPITER trial, testing the Janus Carbostent, a nonpolymerized stent coated with tacrolimus. The Janus is available in Europe, but not the US. As previously reported by heartwire, the JUPITER trial disappointed investigators by failing to show a difference between the tacrolimus-coated Janus stent, with its unique reservoir design, and the bare-metal Tecnic carbostent. When Morice first presented the results at the TCT 2005 meeting, she told heartwire she still believes the Janus stent has potential, an opinion she now says has not changed. "The bare-stent version is associated with an excellent outcome in terms of late loss and restenosis, and the reservoir concept is a good idea," Morice said in a recent interview. "However, the drug effect is minimal or nonexistent, although tacrolimus is probably a very good antirestenotic drug. The drug dosage is perhaps insufficient or the release profile should be improved." Second-generation stents Other companies are working to get around the problem of polymer tackiness and tissue reactions by using them only on the abluminal surface of the stent. The idea is to direct drug at the vessel wall, and not the bloodstream; indeed, even Biosensor's nonpolymerized paclitaxel-coated Axxion stent is coated with drug on its outer (abluminal) side only. Likewise, the Janus stent's reservoir design releases drug only

4 Page 4 / 7 on the outer aspect of the stent. Drug reservoir on the Janus stent (Source: Sorin) In fact, the Janus, like another much-talked-about up-and-comer, the CoStar stent (Conor Medsystem), was perhaps one of the first stents designed specifically for drug elution. Both stents employ reservoirs where drug can be loaded, rather than plastered over the entire outer and inner surface area of the stent, as was done with the first-generation stents Cypher and Taxus. The Janus is designed for abluminal elution, while the Costar has different wells on both the luminal and abluminal sides of the vessel, such that antiplatelet drug could potentially be released in one direction and antiproliferative drugs in another. While the Janus uses no polymer at all, the CoStar uses poly (lactic-co-glycolic acid) (PLGA), a proprietary bioresorbable polymer, but only within the small wells embedded in the stent where the drug is loaded, leaving the actual surface of the stent CoStar (Source: polymer-free. As Krucoff, who is the principal investigator for the Conor) US trial of the CoStar stent (COSTAR II), explained to heartwire, using the CoStar "feels like you've gone back to bare-metal stent delivery," doing away with "stent stickiness," a charge that has been leveled at the Cypher and Taxus and believed to be linked to problems deflating or removing the balloon during stent deployment. "The most immediately noticeable difference is that, with all the polymer down in these wells, the surface of the stents themselves is polished cobalt chromium, so there's no sticky, tacky plastic on the surface," Krucoff said. "These stents just fly into the coronary arteries, compared with polymer-coated stents." Innovation in next-generation DES Manufacturer Name Drug Stent material Polymer Status Abbott ZoMaxx Zotarolimus Tantalum/stainless steel Durable Biosensors Axxion Paclitaxel Stainless steel None CE Biosensors Boston Scientific BioMatrix Biolimus- A9 Taxus Liberté Stainless steel Bioabsorbable Paclitaxel Stainless steel Durable CE Conor CoStar Paclitaxel Cobalt chromium Bioabsorbable Cordis/J&J Cordis/J&J Cypher Select Cypher Neo Sirolimus Stainless steel Durable CE Sirolimus Cobalt chromium Durable Guidant Champion Everolimus Stainless steel Bioabsorbable Guidant Xience V Everolimus Cobalt chromium Durable CE

5 Page 5 / 7 Medtronic Endeavor Zotarolimus Cobalt chromium Durable CE Sorin Janus Tacrolimus Stainless steel None CE SMT Infinnium Paclitaxel Stainless steel Bioabsorbable CE Terumo Nobori Biolimus- A9 Stainless steel Bioabsorbable To download table as slides, click on slide logo below Now you need it, now you don't While not everyone agrees on the absolute need for a polymer, most concede that the best-of-both-worlds strategy would be to have a polymer that disappears after it has done its job. BioMatrix (Source: Biosensors) Sahajanand Medical Technologies' (SMT) Infinnium stent elutes paclitaxel via a proprietary biodegradable polymer, while Conor Medsystem's has its own PLGA bioabsorbable polymer that it is testing on its CoStar stent. Other front-runners in the field are Guidant, Biosensors, and Terumo, whose Champion, BioMatrix, and Nobori stent programs, respectively, all use Biosensor's proprietary bioresorbable polymer. Last year, however, Guidant announced that it would first be moving forward with its Xience (previously known as the Vision) DES program, which uses a durable polymer, instead of its Champion stent program, as a result of "link fractures" seen in the Champion's stent platform during testing. Still, as Krucoff pointed out to heartwire, second-generation stent manufacturers focusing on bioresorbable polymers are for the most Reva (Source: Reva part basing their technologies on elements that are already well Medical) established in the coronary stent world: antiproliferative drugs delivered via metal stents. Beyond these are the devices he believes are best described as "third-generation" devices, namely fully bioresorbable stents, made completely out of dissolving polymers or magnesium. Companies like Reva, Endovasc/TissueGen, and Igaki-Tamai have all presented or published data in recent years on stents made completely out of biodegradable polymers that elute drug as they dissolve. Taking another tactic, Biotronik is working away on a drugeluting magnesium-based alloy that degrades over the course of approximately two months and, in 2004, signed an agreement with Conor to develop a fully absorbable magnesium-based DES. This is "an entirely new domain," Krucoff says. Maybe it's enough to "There are some totally novel questions that will have a bare-metal stent have to be answered to make these fully with a good drug on it. bioresorbable stents usable and government approved in the US," he says. "What is the difference between the rate in which you deliver drug and the rate at which the stent ultimately loses its physical properties that are a part

6 Page 6 / 7 of the scaffolding? And is that different if that is a metal scaffolding vs a plastic scaffolding? The answers to all of these questions really have to be worked out. The second-generation stents, like the Conor stent, can come forward very quickly because the components they are using are all very well known. Third-generation, fully bioabsorbable stents, will enter a new domain in such fundamental ways that they're certainly going to have to do a lot more work." Kastrati, likewise, called the whole field of bioabsorbable platforms "an interesting idea" but pointed out that it is one that has been around from the dawn of bare-metal stents, when people were first concerned about leaving bare metal in coronary arteries. Those fears, he points out, have largely disappeared. If the polymer problems can be solved and the stent design doesn't pose late hazards, having the stent disappear altogether might not be necessary. "If we can get a good drug," says Kastrati, "maybe it's enough to have a bare-metal stent with a good drug on it." Other nitpicks, other solutions Asked what sort of innovations they hoped to see in the next few years, experts pointed to alterations related to safety and Axxess-Plus (Source: deliverability, many of which are already well into clinical testing. Devax) Leading the way are dedicated bifurcated DES, such as the conical-shaped Axxess-Plus stent (Devax Inc), or systems and techniques that would facilitate the placement of main and side-branch DESs. Elsewhere, companies are working on dedicated left main stents, while still others are looking at ways to combine different drugs on a single stent with the aim of inhibiting smooth-muscle-cell proliferation, reducing thrombogenicity, and boosting reendothelialization. At least one company, Xtent Inc, is focusing on the problem of how to avoid the need for overlapping stents by having the capacity to deliver longer stents, at customizable lengths, and multiple stents within a single catheterization. The Cypher stent was recently awarded FDA permission to change its labeling to Xtent (Source: Xtent explicitly permit overlapping stents, but operators have raised Inc) concerns about the effects of overlapping for the Taxus and, more recently, the Cypher stents. Investigators for the TAXUS V trialnoted an increase in non-qwave MIs in patients with overlapping stents, potentially due to a double dose in the areas of overlap, while a recent study of the Cypher stent found focal restenosis in overlapped segments [2]. Xtent has developed a system that permits an operator to first deliver a stent, detach the length desired, expand it, then move on to stent separate lesions in the same vessel or in a different vessel, without needing to retract and reintroduce the catheter. Currently, the system can deliver up to 60 mm of stent. The Xtent system also uses a bioabsorbable polymer and Biolimus-A9, licensed from Biosensors. -SW

7 Page 7 / 7 Sources 1. Mehilli J, Kastrati A, Wessely R, et al. Randomized trial of a nonpolymerbased rapamycin-eluting stent versus a polymer-based paclitaxel-eluting stent for the reduction of late lumen loss. Circulation 2006; 113: Minutello RM, Bhagan S, Feldman D, et al. Angiographic pattern of restenosis following implantation of overlapping sirolimus-eluting (Cypher) stents. Am J Cardiol 2006; 97: Related links Indian paclitaxel-eluting stent gets CE approval but can't encroach on Taxus turf [HeartWire > Guidewire; Dec 22, 2005] Coat-it-yourself rapamycin-eluting DES comparable to Taxus, ISAR-TEST study shows [HeartWire > Guidewire; Oct 17, 2005] Business Week article examines promise and potential pitfalls ahead for Conor drug-eluting stent [HeartWire > MediaPulse; Oct 21, 2005] First-in-man coronary use of absorbable metal stent "promising" [HeartWire > Guidewire; Mar 06, 2005] Virmani still warns the sun will set for drug-eluting stents: Nature needs to heal, she says [HeartWire > News; May 27, 2004] The stuff of dreams: First-in-man data for new stents, new drugs, new antirestenosis options [HeartWire > News; May 26, 2004] Polymer problems or doctor error? Deployment glitches with Taxus stent spur disquiet and reassurances [HeartWire > News; Apr 29, 2004] Evelyne