CDU Executive Editor

The news for drug-eluting stents (DES) in 2006 wasn’t good.

For this writer, the first indication of troubles to come were heard in early May 2006, at the EuroPCR conference in Paris. At an opening press conference Jean Marco, MD, of Clinique Pasteur (Toulouse, France), threw down a gauntlet, challenging the evidence which led to the assumption that DES devices are clearly better than their bare-metal stent (BMS) precursors.

The basis for his challenge was his claim — not well substantiated by him at the time but issued with considerable passion — that DES provided no improvement over BMS in terms of extending the lives of those implanted with the drug-eluting type of device.

That observation undercut the oft-repeated primary endpoint for this technology — essentially the only endpoint that had been used to support the benefit of and approval for DES: a significant reduction in restenosis as compared to BMS, hence reducing the need for repeat opening of clogged arteries. And throughout 2006, Marco’s charges were then subsequently underlined and expanded upon by a variety of other studies comparing DES and BMS over longer periods of study and with different endpoints.

And the news did not get any better. Some of the conclusions these studies produced were:

• that while DES may reduce restenosis significantly in the first few months, post-procedure — after periods as short as nine to 12 months — the rates of restenosis for DES and BMS devices are essentially the same;

• that the use of DES devices is associated with an increased risk of thrombosis;

• that the increased incidence of thrombosis is associated with increased mortality.

The broad publicity given to these reports resulted in a significant reduction in the use of DES, from as high as 90%-95% in some regions and hospitals, to as low as 75% or less in others.

While several observers have predicted a rebound in DES use for this year, that may be, at best, hopeful thinking. Casting a shadow on this view are reports that data from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) are set to be published in a peer-reviewed journal. That data —first made public in Sweden and then presented at the FDA’s public meeting concerning DES in December — indicated significantly higher rates of myocardial infarction and death among patients implanted with DES than for those implanted with BMS. That publication could further suppress the use of the first-generation DES devices and continue to impact the profit lines of the two U.S. manufacturers of DES devices, Boston Scientific (Natick, Massachusetts) and Cordis (Miami Lakes, Florida), a business of Johnson & Johnson (J&J; New Brunswick, New Jersey).

But whatever the future holds, it is clear that the problems being experienced by the first generation of DES products – Boston Scientific’s Taxus and Cordis ‘ Cypher — offer a large opportunity for the next generation of DES and other innovative stent systems being readied for submission to the FDA

Following are notes on some of the leading players preparing to grasp this opportunity.

Endeavor, Xience lead the race

Two DES products are clearly in the lead to be the winners of the next FDA approvals — the Endeavor from Medtronic (Minneapolis) and the Xience from Abbott Laboratories (Abbott Park, Illinois). While Abbott is expected to make its filing with the agency as early as next month, Medtronic completed its filings in November and so appears to have the pole position with several lengths advantage.

The company made its filing via four modules, beginning in late 2005, and it has made much of the depth of its data — that data covering 4,000 subjects followed for two to three years, which Medtronic hopes will meet what may become a closer examination by the FDA and its cardiovascular advisory panel. That closer examination is the probable fall-out from concerns with the first-generation devices.

The Endeavor won the CE mark in July of 2005 and a filing for approval in Japan is expected sometime around mid-year. If FDA approval is granted, it could come as early as September.

Michael Weinstein, device analyst with JPMorgan (New York/San Francisco), projects that Endeavor could immediately capture up to 20% of the DES market in the U.S. in its first quarter “out of the gate.”

The Endeavor DES is a stent that elutes the drug zotarolimus. The basic stent is made of a cobalt alloy with a modular architecture designed to enhance deliverability, the company says. It also features the use of a biocompatible polymer called BioLinx, designed to match the duration of drug delivery with the longer healing duration often experienced by patients with complex medical conditions.

The company has described BioLinx as having “an outer surface that is hydrophilic (or water-loving), offering better biocompatibility with the body, while the interior of the polymer is hydrophobic (or water-fearing) which helps to precisely control the drug release.”

Shortly before last year’s Transcatheter Cardiovascular Technology (TCT) meeting in Washington, the company trumpeted the launch of a large-scale trial comparing the Endeavor to Cordis’ Cypher, with a major focus on safety. That trial, called PROTECT (for Patient Related OuTcomes with Endeavor versus Cypher stenting Trial) will be, Medtronic said, the largest randomized trial ever conducted to assess key safety measures of two DES devices. The primary endpoint for the trial will be stent thrombosis, the focus of recent safety concerns, with secondary endpoints that include death and non-fatal myocardial infarction and other customary clinical efficacy end points. The study will enroll 8,000 patients that it described as “real-world” — clearly to differentiate it from a patient pool often very carefully selected in clinical trial settings — at 200 clinical centers in Europe and other international markets, and follow patients for an additional two years.

At the TCT meeting, a researcher reported four-month angiographic and clinical results from the RESOLUTE trial indicating that zotarolimus is a potent drug preventing restenosis, “even in challenging patient populations.” Clinical results for 30 days in 130 patients showed a major adverse cardiac event rate of 3.8%, with no target lesion revascularization (TLR) and no stent thrombosis.

The JP Morgan “MedTech Monitor,” however, reports “issues with Endeavor: modestly inferior efficacy and in the U.S. no rapid exchange delivery.”

Xience: possibly outrunning Endeavor?

Given those “issues,” industry analysts are predicting that this Medtronic product could be rather quickly passed over in the market by the Xience DES from Abbott, with Xience to become the leading product in the DES market for 2008.

Submission of a premarket application (PMA) for the Xience DES is expected early this year — possibly by next month. A best-case scenario is PMA approval of the Xience before the end of the year and commercialization in 2008, with analysts predicting rapid adoption.

Xience moved to the top of Abbott’s to-do list when in late 2006 it said it was scrapping its ZoMaxx DES program, based on analysis indicating the superiority of the Xience V. Xience V was acquired by Abbott from Guidant (Indianapolis) as a Federal Trade Commission-mandated divestiture, in conjunction with the multi-billion-dollar acquisition of Guidant by Boston Scientific early last year.

The Xience V is coated with and elutes the drug everolimus and is based on the Multi-Link Vision stent featuring cobalt-chromium construction. Among its key features is its absorbability. It is made of polylactic acid, which is absorbed and slowly metabolized by the coronary artery. The stent releases everolimus into the artery and then is slowly absorbed over time. The goal is to leave a healed natural vessel behind.

Abbott/Boston Scientific — Boston Scientific retaining a private-label version of the Xience called Promus — reported the international launch and initial implantation of the Promus/Xience V stent in Europe in January of this year, with Boston Scientific touting the achievement of being the first to offer two distinct DES platforms, the other being the Taxus. The Promus received CE-mark approval last October, and it is currently available in most major European and Asia-Pacific markets.

Xience V comes with some strong credentials. Positive results for the stent were reported from the SPIRIT II clinical trial at the World Congress of Cardiology in Barcelona, demonstrating a 58% reduction in TLR vs. Taxus, as well as a 58% reduction in major adverse events.

And in October, the stent got an additional boost at the ‘06 TCT conference, with reports concerning effectiveness in endothelialization and reduced inflammatory response.

Analysts and investors have expectations for further strong data to be presented for the Xience this March at the meeting of the American College of Cardiology (Washington) in New Orleans.

J&J to complement via CoStar

Fearing that the Cypher DES from its Cordis unit could be left in the marketing dust as these second-generation products come on line, J&J clearly has attempted to complement the Cypher via the purchase of Conor Medsystems (Menlo Park, California) for $1.4 billion in cash. With the purchase, J&J will acquire Conor’s CoStar stent system, a paclitaxel-eluting cobalt chromium stent with a bioabsorbable polymer. (The deal was closed earlier this month following approval by Conor shareholders.)

The acquisition is expected to speed up J&J’s commercialization of a second-generation DES. Previous expectations were that the company would not be able to bring a new DES product to market until 2009 or 2010, and the best-case scenario is now potential FDA-approval of the CoStar in late 2007 or early 2008, thus contending with Endeavor and Xience.

The architecture of the CoStar emphasizes a very controlled type of drug delivery. It incorporates hundreds of small reservoirs into which drug/polymer combinations can be loaded versus the conventional strategy of coating a drug on a mesh stent. The reservoirs on the Conor are designed to allow enhanced control of drug release. In addition, the device employs bioresorbable polymers absorbed by the body after the drug is released, leaving no residual polymer. Conor says that in conjunction with complete drug discharge, this may solve the problem of delayed stent thrombosis.

Conor launched the CoStar in a group of countries internationally in 2005, and in 2006 it received European Union regulatory approval for extending the shelf life of the CoStar from six months to 12 months.

In March of 2006 Conor exercised an option worked out with Novartis Pharma (Basel, Switzerland) to obtain a worldwide, non-exclusive license to the compound pimecrolimus (Elidel) for use with the CoStar. Conor said it selected pimecrolimus from among three Novartis pharmaceutical agents — the other two being imatinib mesylate and midostaurin — for the potential development of a product combining a Novartis compound with the CoStar. Conor is responsible for product development, including clinical trials, manufacturing and regulatory filings.

Based on that deal, Conor is developing a dual-drug DES called the SymBio. The SymBio, currently in a clinical trial called GENESIS, is a pimecrolimus/paclitaxel-eluting coronary stent system. Enrollment in that clinical trial, conducted in the Middle East and Europe, is expected to be completed early this year.

Sorin has next-generation stent in Europe

The Sorin Group (Milan, Italy) in February of 2006 reported the availability in Europe of its Janus Flex, a second-generation DES product, one year after the launch of its first-generation Janus Carbostent. The Janus Flex is a Carbostent combining a new delivery system with the company’s Janus platform, the company saying the new platform is designed to offer improved deliverability and conformance in especially challenging anatomies via what the company calls “superior flexibility.” Sorin said also that in pre-launch testing in Europe, the Janus Flex showed superior deliverability versus other DES systems.

The stent elutes the drug tacrolimus, with the stent’s architecture described as a “polymer-free platform with drug reservoir design allowing the drug to be delivered precisely to the vessel wall.” Sorin characterizes tacrolimus as a cytostatic drug, also known as FK506, produced by Astellas, and employing Carbofilm coating which “virtually eliminates the risk of thrombosis because of high biocompatibility.”

The company in May 2006 at EuroPCR reported six-month clinical results from its e-Janus international “real-world” registry. A multi-center prospective registry, the e-Janus data indicated that in the overall population completing six-month follow-up, 28.4% of the patients were diabetic, 50.4% had multi-vessel disease and 23% presented with an AMI. In the 238 AMI subset, there was a 6.3% MACE rate, a 4.6% rate of TLR and no late stent thrombosis.

“Real practice results are increasing their importance, and we are glad to see that amongst the real-world AMI patients — who are the most burdensome — Janus shows to be very safe and effective,” said Stefano Di Lullo, president of Sorin Group’s Vascular Therapy business.

At the time of that report, the company said that 2,500 patients were enrolled in the registry from 80 centers worldwide, excluding the U.S. and Japan. The company has not disclosed any plans to seek FDA approval.

Xtent ‘extends’ DES concept

Doing more and doing it more reliably is the emphasis of Xtent (Menlo Park, California), developer of what it calls next-generation “customized” DES technology. The company is focused on “multi-vessel” stenting and “long lesion” DES devices as an alternative to using multiple stents. Key to this system is the use of a single stent train capable of deploying the DES into multiple placements or into long lesions without the need of using several stents several stents in overlapping fashion.

Its CUSTOM II trial demonstrated the ability to do this — “in the history of coronary stenting” in the first human implant. The company reported the treatment of another patient with “the longest coronary stent of any kind ever delivered with a single catheter.” These first procedures were performed by Professor Eberhard Grube, MD, chief of cardiology, Siegburg Heart Center (Siegburg, Germany), and principal investigator for Xtent’s CUSTOM II clinical trial. In the first of the two patients, Grube treated two separate lesions in different arteries during a single insertion of the Xtent system, customizing the length of each stent in situ to match the length of each lesion. A stent 28 mm in length was placed in a marginal branch artery. Then, without removing the device, it was repositioned to deploy a second 32 mm stent in the left anterior descending artery.

In the second patient, Grube delivered a single 52 mm stent, the longest ever placed in the coronary arteries from a single catheter, said Xtent.

Xtent said the procedures were key steps to achieving European and U.S. regulatory approvals “over the next two to three years.” It also noted that its approach was developed as a way to challenge both the first-generation Taxus and Cypher devices and the others due to come online. “We had to look out into the horizon,” Greg Casciaro, president/CEO of Xtent, told Cardiovascular Device Update.

What the company saw there is the “more complex patient,” he said, requiring “more than one stent” and the need for a simplified strategy that would conflate multiple procedures into a single placement procedure.

“Both cases were excellent examples of how one device can easily replace two or three standard drug- eluting stents,” said Grube.

Assuming eventual commercialization, this stent strategy means faster procedural time and a cost falling between that of one DES placement and two DES placements, Casciaro said, hence a significant reduction for placements of more than two stents. The strategy, he added, positions Xtent for addressing the more than 50% of procedures requiring multiple placements — and growing.

And he suggested that as DES procedures continue to penetrate the traditional bypass procedural market used to treat more difficult disease, this “complex patient” market could grow to 80% of stent procedures, offering another possibility for expansion of the one-catheter approach.

The drug used in the Xtent system is Biolimus A9, together with a bioerodable (or absorbable) polymer, licensed from Biosensors International (Singapore/Newport Beach, California), together with a coating from a Biosensors subsidiary, Occam International (Eindhoven, the Netherlands).

With Biolimus, Casciaro said that Xtent is “smack-dab in the game with a drug of clinical efficacy that may be as a good as or better than what is currently available on the market today.”

He said that much of the company’s data concerning the efficacy of this drug use is being validated, or will be further validated, in its studies, but also backed in studies by Devax (Irvine, California) and Terumo (Tokyo), using the same drug.

Deliverability ‘fluid, efficient’

Casciaro emphasized the deliverability feature of the Xtent system — calling it “easy, fluid, efficient” —for the more difficult stenting issues is its main differentiator.

By comparison, he noted that in most DES stenting, the clinician makes a best “guesstimate” of what size DES to use. And he cited study figures indicating that up to 40% of current DES placements may involve placements of the wrong sizes.” Thus, he said, “The ability to customize to lesion length is something no one else can accomplish.”

The company is pursuing CE-mark approval and has predicted launch of a trial under an FDA investigational device exemption, currently being discussed with the FDA. It has set its earliest goal for U.S. commercialization for 2009.

The companys’ first trial, CUSTOM I, and data from that trial is scheduled to be presented at this year’s meeting of the American College of Cardiology and then at EuroPCR, Casciaro said.

Growing out of the Foundry (Redwood City, California) medical device incubator, Xstent is funded by venture capital firms including Advanced Technology Ventures, Latterell Venture Partners, Morgenthaler Ventures and Split Rock Partners.

The company in August of 2006 filed for an initial public offering to raise up to $103.5 million but in January amended its filing to an offer of up to 4.7 million shares at a price range of $16 to $18 a share, which would raise close to $79.9 million at the $17 mid-point.

The company, which plans to list its stock on the NASDAQ Global Market under the symbol XTNT, said it will use proceeds for clinical trials, R&D, infrastructure development, working capital and corporate expenses.

Other compounds for stenting

In addition to developing the second generation of DES devices, various companies are adding a variety of drug-related and non-drug materials to stents as a strategy for avoiding restenosis and the other problems being associated with DES.

Spun off of research activities of the UBCeram-Metals and Materials Engineering department of the University of British Columbia (Vancouver), MIVT Therapeutics (Vancouver) has developed multi-layer biocompatible and bioactive calcium phosphate functionally graded coatings on stents in two versions: a thin coating of crystalline hydroxyapatite (HAp) — a natural material found in human bones and teeth —used to screen the surface of a bare metal stent from surrounding tissue in order to reduce inflammatory response; and a thicker, porous, film of HA to create an adhesive layer suitable for application of drugs and drug elution. MIVT is promoting the material’s biocompatibility as a way of reducing inflammatory response in stent use.

In late 2006, MIVT reported results of an animal study of two of its DES technologies comparing stents coated with its polymer-free DES to the Cypher stent from Cordis. The company said that the study demonstrated that both of MIVT’s polymer-free, Sirolimus-eluting coatings are at least as good as the Cypher and it demonstrated its coatings’ potential and efficacy when compared to Cypher.

The four-week porcine study, performed by the Department of Cardiology, Thoraxcenter, of the Erasmus University Medical Center (Rotterdam, the Netherlands), indicated that three variations of MIVT’s polymer-free drug-eluting coatings were at least as effective as — and in some cases, better than — the Cypher.

MIVT recently said that it intends to begin the first human implants of a HAp Nano Film Coated stent early in 2007. Dr. Mark Landy, president/CEO of MIVT, told CDU that when the company is able to go to the FDA for approvals, it will offer “a number of generations of products.

MIVT in December unveiled its purchase of Biosync Scientific (Gujarat, India), a developer of interventional cardiology products, including stents. Landy said that Biosync has a “strong presence in India,” calling it the “largest in the cardiology market” in that country as well as having “footprints in China and India.”

MIVT said that Biosync provides it a “highly competitive” BMS platform that compares favorably with the best BMS devices available today. Both Biosync’s stainless steel and thin-strut cobalt chromium stents are CE-marked and available in other countries where the CE mark is recognized.

MIVT said it will use the Biosync stent platform as the underlying BMS technology for its proprietary biocompatible polymer-free DES devices and that the acquisition is its latest step in its plan to become a leader in the $8 billion-plus interventional cardiology market.

This past September, MIVT entered into a formal agreement to acquire Vascore Medical (Suzhou, China), a manufacturer and distributor of advanced interventional cardiology devices.

Still another: carbon-composite coating

Cinvention (Wiesbaden, Germany) reported extension of a license and supply agreement with Relisys Medical (Hyderabad, India) for the manufacture, marketing and sale of a non-eluting coronary stent with a bioactive nano-structured carbon-composite coating, Cinvention saying that coating has “pro-healing” properties. Relisys’ new stent is made of cobalt-chromium, its “nano-structured matrix” having a surface designed for improved endothelialization, according to the company.

Dr. Krishna Reddy, chairman of Relisys, said that this version of a coronary stent has the potential to overcome concerns with current DES. He said that the animal study results at Cardiovascular Research Institute (Washington), published in April, indicated that the bioactive nano-porous carbon coating — minus any polymer — might address endothelialization, thrombosis and continuing inflammation, the issues of concern with polymer-based DES.

The coating was developed by Cinvention, formerly Blue Membranes, which specializes in materials and surface engineering for biomedical applications. The Cinvention coating eliminates the use of polymers and provides a bioactive surface with less thrombogeneity and pro-endothelialization properties - thus reducing tissue inflammation and reaction, but enhancing engraftment.

N.G. Badari Narayan, managing director of Relisys, said additional animal studies to validate the coating are ongoing. Narayan reported that Relisys will focus on receiving the CE mark for its non-eluting stent this year and is targeting eventual FDA approval. The next step will be a multi-center clinical trial with 15 international centers to evaluate both non-eluting as well as the DES devices of Relisys.

Dr. Soh il Asgari, CEO and chief technology officer of Cinvention, said, “We have embedded a bioactive surface that attracts endothelial cells and promotes endothelial cell attachment and growth on these nano-structured carbons.

“Compared to other systems we also do not need to use questionable drugs, that are less selective, and also do not use any biologics that have to be attached on the surface previously. The coatings were derived from our cell cultivation knowledge and our products in the field of bio-manufacturing using mammalian cells.”

Cinvention says that its portfolio of nano-composite systems includes: drug delivery coatings; multi-functional device coatings; advanced carrier systems for bio-processing; tissue engineered biomaterials; and carbon/ceramic and mixed matrix membranes.

Relisys manufactures DES, angiographic/angioplasty catheters; occlusive devices and cardiac surgery disposables.