Drug-Eluting Stents Safety Issue Create Opportunities

By P. Driscoll
About MedMarkets [From the April 2007 edition of MedMarkets, by MedMarket Diligence.] Subscribe

The market for drug-eluting stents has yet to recover completely from controversies first voiced in 2006 related to device safety. As a result, while the leading manufacturers are working to regain lost market share, the door has been opened for new devices (such as biodegradable stents) to enter the market, devices that can address the safety issues while producing outcomes that still surpass those of bare metal stents. In 2006, reports began to hit the U.S. market that drug-eluting stents (DESs) might pose an increased risk of late stent thrombosis for some patients (see MedMarkets, [subscribers only] Drug-Eluting Stents Vie for Market Share With Innovation, Acquisitions, October 2006). Combined with manufacturing issues, both Johnson & Johnson/ Cordis and Boston Scientific (the only two competitors in the U.S. market) saw significant drops in sales by year-end. Earlier in 2006, physicians were using DES devices in roughly 90% of all stent implants. By the beginning of 2007, physicians were opting to use DESs in only 75% of cases, opting instead for bare metal stents. With some studies showing that usage of DESs result in positive outcomes when paired with an anti-restenotic drug such as Plavix, physicians have become reluctant to risk using a DES if the patient is not likely to use the medication due to cost or noncompliance. As a result, many are speculating that the market for DESs has reached a plateau. Optimistically, the DES share of the stent market might grow back to 85%, but given the anticipated entry of new competitors (Abbott Vascular, Medtronic Vascular, and others) into the market, it is vital for leading manufacturers to develop next-generation products as quickly as possible. In fact, beginning in late 2007, the introduction of new generation products and new technologies will spur the market to halt its current downturn and begin growing again, albeit at a modest rate (see chart above, Worldwide Market for Drug-Eluting Stents). Market competitors are shown in the chart below, Developers of Cardiovascular Drug-Eluting Stents.

FDA Responds to Market Pressure

In response to the previously mentioned study results questioning the safety of DESs, the FDAs Circulatory System Devices Panel met in December 2006 to review safety data. According to a statement posted in January, the FDA panel did confirm a slight increase in stent thrombosis for the Cypher and Taxus stents when compared to bare metal stents within one year after implantation. However, the panel also found that this increased risk of thrombosis did not result in an increased risk of death or myocardial infarction when compared to bare metal stents. In studies examined by the FDA panel, DESs were not associated with an increased rate of all-cause mortality when the devices were used as approved. All told, the FDA panel stated that larger, longerterm studies are necessary. In addition, the agency is to consider requiring up to five years of post-approval studies for DESs.

Medicare Responds to Cost

In 2002, Medicare approved payment coverage of DES. This is unique in that the Medicare approval came prior to the FDA approval, which usually is not the case. However, in light of the FDA panel recommendations, Medicare may reconsider its coverage of DES. At the least, the agency may limit coverage to FDA-approved indications. In 2005, Medicare paid roughly $14.7 billion for DES surgeries.

The COURAGE Trial Controversy

In late March at the annual meeting of the American College of Cardiology (ACC), researchers presented controversial results from the COURAGE study, stating, in patients with stable coronary artery disease, percutaneous coronary intervention (PCI) did not reduce the risk of death, myocardial infarction, or other major cardiovascular events when added to optimal medical therapy. The COURAGE study compared optimal medical therapy (i.e., lifestyle intervention and intensive pharmacological therapy using cholesterol-lowering statins, blood pressure drugs and aspirin) to a combination of optimal medical therapy and PCI (i.e., angioplasty and primarily bare metal stents but also some DES). Because the study covers more than four years, the majority of stents used were bare metal. Regardless, even though DESs are simply too

new to have played much of a role in the study, the DES market was directly impacted by it. Most clinicians agree that outcomes in stent patients are greatly improved when the patient maintains a regimen of an anti-clotting drug such as aspirin or Plavix for at least one year after stent implantation. The problem with the study is that patients with stable coronary disease are not typically recommended for stent therapy. In additional, the optimal medical therapy used in the study was more aggressive than what would be typically prescribed in everyday practice. Nonetheless, the manner in which the results were presented (and reported on by the media) did not put stents in the best light. The good news is that U.S. health insurers dont seem to be overly concerned with the COURAGE study results. Several big insurers (including Aetna and Blue Cross Blue Shield) recognize that the issues surrounding stent implantation go beyond the endpoints of the COURAGE study. The COURAGE study was sponsored by the U.S. Department of Veterans Affairs, the Canadian Institutes of Health Research and several pharmaceutical companies, including Merck, Pfizer and Sanofi-Aventis.

Durables Remain the Standard

In spite of the controversy, standard DESs (which elute an active drug and stay behind to keep the vessel propped open) are still used in the majority of stent implantations. Although Boston Scientific was the second company behind Cordis to market a DES, the former is the current market leader with its Taxus Express2 stent and the upcoming Taxus Libert next-generation device. Unfortunately, Boston Scientific was unable to launch the Taxus Libert as planned in late 2006 due to a warning letter it received from the FDA in regard to unrelated issues. As a result, the FDA will not grant marketing approval for the Taxus Libert until the issues are resolved. Meanwhile, the device is available internationally in all areas except the United States and Japan. In April 2007, Boston Scientific announced that it did receive Japanese marketing approval earlier than anticipated for the Taxus Express2 stent. The company will launch the device in the $500 million market Japanese market once it gains reimbursement approval as well. Another bit of good news Boston Scientific obtained this year was in January when the FDA extended the shelf-life for Taxus Express2 from 12 months to 18 months. The shelf-life is already set at 18 months internationally. Boston Scientific is also moving ahead with a new device, the Promus stent, which is scheduled to hit the U.S. market in 2008. Developed by Guidant under the Xience name, the everolimus-eluting stent was folded into the Abbott portfolio when Guidant was acquired. Abbott has granted Boston Scientific distribution rights in the United States, where Boston Scientific will market the stent under the Promus name. Abbott has retained international distribution rights for the Xience, which it launched in Europe in January 2007. Xience holds an advantage over other DESs in that it is thinner and more flexible than many others. With struts that are roughly one-half the size of Cordis Cypher stent, the Xience presents less risk of clotting than other stents might.

Meanwhile, Johnson & Johnson is attempting to regain market superiority with its Cordis Cypher stent. J&J and Boston Scientific are currently tussling in court in regard to DES patent infringement issues. Boston Scientific had previously prevailed in lower courts in disputes related to the stent itself and the polymer that binds the drug to the stent. However, in mid-April, a U.S. federal court ruled that J&J does not infringe on the patent. The end of this story is not yet in sight; Boston Scientific vows to consider all options available. In November 2006, the lead investigator of the ARTS II study, Patrick Serruys, MD, PhD (Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands), presented data related to Cordis sirolimus-eluting Cypher stent. The preliminary data showed that Cypher may provide a viable alternative to surgery in patients with lesions in two or more vessels. After three years, patients showed a MACE rate for Cypher that at 80.2% was statistically similar to CABG surgery (83.9%). When compared to bare metal stents, Cypher passed with flying colors as the MACE rate for bare metal was 65.3%. In regard to severe events (death, stroke or heart attack), 91.6% of Cypher patients did not experience a significant event, compared to 89.0% of CABG patients and 86.7% of bare-metal stent patients. ARTS II includes 607 patients from 45 European centers. While Cordis next-generation Cypher Elite stent is scheduled to begin U.S. clinical trials later this year, the company recently completed its $1.4 billion acquisition of DES developer Conor Medsystems. Conors first-generation paclitaxel-eluting CoStar received CE Mark in February 2006 and expects a U.S. launch in late 2007 or 2008. The second-generation CoStar II device is currently in clinical trials. The company is also developing the pimecrolimus-eluting Corio and the SymBio, the latter of which elutes both pimecrolimus and paclitaxel. Medtronic Vasculars Endeavor stent is following hard after the market leaders. Its Endeavor zotarolimus-eluting stent received CE Mark in July 2005 and anticipates a U.S. approval later this year. In safety trials, Endeavor showed an overall thrombosis rate of 0.3% with no stent thrombosis beyond 30 days. In October 2006, preliminary data were presented at the TCT 2006 annual meeting on the companys next-generation Endeavor Resolute stent. The first-in-man RESOLUTE trial showed the zotarolimus stent resulted in a MACE rate of 3.8% with no target lesion revascularization and no stent thrombosis. The trial followed 130 patients at 12 centers in Australia and New Zealand. The Endeavor Resolute incorporates the proprietary BioLinx polymer system, which is designed to accomplish extended release of drugs and is compatible with multiple drug platforms. In a head-to-head comparison, Endeavor and Endeavor Resolute showed equal rates of biocompatibility at 28, 90 and 180 days. MIV Therapeutics (MIVT) jumped fully into the DES fray in February 2007 when it completed its acquisition of India-based Biosync Scientific, developer of (among other products) stainless steel and cobalt chromium stents, both of which have already obtained CE Mark. MIVT intends to apply its proprietary coatings to Biosyncs bare metal stents to create a new polymer-free DESthe Smart stent. MIVTs stainless steel Smart stent will be capable of eluting midastaurin, sirolimus or zoledronic acid. In porcine studies, MIVTs polymer-free hydroxyapatite coating fared well when compared to Cordis Cypher stent, producing outcomes that were just as good or better than the latter. MIVT plans to begin first-in-man studies early this year. MIVT is also

developing a nanofilm coating with sufficient capacity to carry adequate amounts of anti-inflammatory drugs. Still pending is MIVTs planned acquisition of China-based Vascore Medical, announced in September 2006. Like Biosyncs stents, Vascores bare metal stents would also provide a suitable platform for MIVTs biocompatible coatings. In March 2007, shares of Xtent gained 5.7% when investors caught news of good prospects predicted for the companys Custom NX DES. Xtents DES can be customized for use in single, long and multiple lesions in a variety of lengths and diameters. The company intends to make its DES less expensive than other manufacturers stents by setting a single per-procedure price. The Custom NX uses Biosensors Internationals Biolimus A9 coating, which is still awaiting FDA approval. Custom NX is currently in European clinical trials with a launch there anticipated in 2008 and a launch in the United States in 2010. In December 2006, CorNova announced that its cobalt-chromium Valecor stent received the CE Mark. Valecor will be used in the development of a new DES, which will incorporate CardioTech Internationals custom-formulated ChronoFlex polymer. Valecors structure is characterized by its thin strut size. CardioMind is developing its Sparrow DES for small vessels. The Sparrow is coated with sirolimus in a biodegradable polymer matrix. The device is placed with a 0.014 guidewire platform. In porcine studies, the results of which were presented at CRT 2007 in March, safety was demonstrated with low intimal thickness, favorable lumen area, and minimal inflammation and foreign body response. In addition, a study of overlapping stents (minimum of 4 mm) showed no strut fractures at 28 or 90 days. Tissue compatibility and biocompatibility were also demonstrated. In the subsequent CARE I clinical trials, there were no MACE at 30 days for 19 patients. Six-month angiographic and IVUS results are expected in June 2007. In December 2006, the first patient was enrolled in Biotroniks first-in-man study, ProLimus I, which is examining the companys ProGenic DES. The ProGenic is based on the companys PRO-Kinetic cobalt chromium stent. ProGenic also utilizes the PROBIO silicon carbide passive stent coating, a bioresorbable poly-l-lactic acid (PLA) polymer drug carrier and pimecrolimus. The ProLimus I trial is a prospective, nonrandomized, multicenter study examining the safety and efficacy of the ProGenic. In April 2007, the first patients were enrolled in Relisys Medical Devices COREL clinical trial. This prospective, open-label randomized trial will enroll a total 150 patients to examine the efficacy of the companys Corel+C DES. The coating on this cobalt chromium stent elutes paclitaxel, which is incorporated into a macroporous nanostructured carbon-composite matrix developed by CINVENTION. Encouraging animal trials were completed in April 2007 in Washington, DC.

Biodegradable DES Take the Stage

In the DES industry, the term bioabsorbable has been used interchangeably. In some cases, it has referred to the coatings on the stent and, in other cases, to the stents and coatings in their entirety, which degrade until nothing remains. These biodegradable

stents prop open the vessel, deliver an anti-restenotic drug and then, with its job completed, dissolve and leave behind a healthy vessel. However, one of the primary debates in regard to biodegradables is whether they will remain viable long enough to effect the necessary therapeutic benefit. Within the biodegradable DES camp, there are polymers and metallics. Polymers have been utilized for their ability to dissolve promptly. However, studies conducted over the last few years show that in some cases, bits of polymers may be left behind undissolvedand any rough surface in the vessel provides ready ground for restenosis. (This can be a particular problem for polymer matrices covering durable stents.) There is also the question of whether polymers can provide optimum biological incompatibility. In experimental models, polymers have proven to incite a greater inflammatory reaction than inert materials. In addition, the biological response to a polymer is dependent on its formulation (including chemical structure and bulk load) and the time required for dissolution. Fortunately, polymer is not the only biodegradable material available to device developers. Some researchers have shown promising results related to development of degradable metal stents constructed of magnesium (Bernhard Heublein, et al., Hannover Medical School, Hannover, Germany) or iron (Matthais Peuster, et al., Georg-August University, Germany). To date, most research on metallic stents has involved magnesium (Biotronik is the leading developer in this area with its magnesium-based AMS stent), however, magnesiums durability and stiffness reportedly can be less than optimal, hence the interest in iron-based stents. In most cases, research and development of biodegradable materials is still at an early stage. Only a handful of companies are known to have a fully bioresorbable, biodegradable stent in development (see chart, Fully Biodegradable Cardiovascular Stents). None of these biodegradable stents have yet received FDA approval, but progress is being made. Abbott Vasculars everolimus-eluting BVS stent began first-in-man clinical trials in March 2006. Six-month results from the ABSORB trial (presented at the March 2007 ACC and CRT meetings by Principal Investigator Dr. Serruys) showed the BVS barely outperformed a bare metal stent in a panel of 26 patients. But more importantly, there were no reports of MACE or cases of acute or subacture stent thrombosis at 30 days. Dr. Serruys did note that higher-than-desired late

loss rates led to a redesigned, next-generation stent that will be used in the next round of studies, starting soon in Europe and New Zealand. Bioabsorbable Therapeutics, Inc. (BTI), is working with a stent dubbed IDEAL, in which salicylic acid is incorporated into a polymer backbone. In addition, sirolimus is initially eluted from the stent and total degradation occurs within six months of implant. The balloon-expandable stent has produced positive results in porcine studies comparing it to a bare metal stent and Cordis Cypher. BTI is also looking at additional applications for the device, such as treating nonobstructive vulnerable plaque, gene transfer for infarct repair, and angiogenesis. At CRT 2007, trial results were reported for REVA Medicals resorbable stent. Positive preclinical studies have paved the way for the first human clinical trial (RESORB) to begin in 2Q07 with a bare bioresorbable stent. A bioresorbable paclitaxel-coated version will be tested as well, beginning in 4Q07. REVAs bioresorbable stent is deployed into the artery with a unique slide-and-lock design. In summary, the sheer proliferation of information related to established or new DES over the past year point to a market that, while in flux, is here to stay. In spite of unexpected complications, the performance of many DES still surpasses other therapies availableprovided a proper patient population is identified. Within the next few years, the market can expect to see several new stents launched, giving clinicians more options than ever for patients who can benefit from stent placement.

Links: Abbott Vascular (Redwood, City, CA; http://www.abbottvascular.com) Avantec Vascular (Sunnyvale, CA; http://www.avantecvascular.com) B. Braun Melsungen (Melsungen, Germany; http://www.bbraun.com) Beijing Lepu Medical Device (Beijing, China; http://www.lepumedical.com) Bioabsorbable Therapeutics, Inc. (BTI; Menlo Park, CA; http://www.bioabsorbabletx.com) Biosensors International (Newport Beach, CA; Singapore; http://www.biosensorsintl.com) Biosync Scientific (Surat, India; http://www.biosyncscientific.com) Biotronik (Lake Oswego, OR; Berlin, Germany; http://www.biotronik.com) Blue Medical Devices (Helmond, The Netherlands; http://www.bluemedical.com) Boston Scientific (Natick, MA; http://bsci.com) CardioMind (Sunnyvale, CA; http://www.cardiomind.com) CardioTech International (Wilmington, MA; http://www.cardiotech-inc.com) CINVENTION (Weisbaden, Germany; http://www.cinvention.com) Conor Medsystems (Menlo Park, CA; http://www.conormed.com) Cordis (New Brunswick, NJ; http://www.cordis.com) CorNova (Burlington, MA; http://www.cornova.com) Devax (Irvine, CA; http://www.devax.net) DISA Vascular (Cape Town, South Africa; http://www.disavascular.com) Endovasc (Montgomery, TX; http://www.endovasc.com) Estracure (Montreal, Quebec, Canada; http://www.duravestinc.com/estracure) Johnson & Johnson (J&J; New Brunswick, NJ; http://jnj.com) JW Medical Systems (Division of Shandong Weigao Group Medical Polymer,

ShanDong, China; http://www.weigaogroup.com) Kaneka (Osaka, Japan; http://www.kaneka.co.jp) Medlogics Device Corporation (MDC; Santa Rosa, CA: http://www.medlogicsdc.com [under construction]) Medtronic Vascular (Minneapolis, MN; http://www.medtronic.com) Merck (Whitehouse Station, NJ; http://merck.com) MicroPort Medical (Shanghai, China; http://www.microport.com) MIV Therapeutics (MIVT; Vancouver, BC, Canada; http://www.mivtherapeutics.com) OrbusNeich (Wanchai, Hong Kong; http://www.orbusneich.com) Pfizer (New York, NY; http://pfizer.com) Relisys Medical Devices (Hyderabad, India; http://www.relisysmedical.com [under construction]) REVA Medical (San Diego, CA; http://www.teamreva.com) Sahajanand Medical Technologies (SMT; Surat, India; http://www.smtpl.com) Sanofi-Aventis (Paris, France; http://sanofi-aventis.com) Sorin Biomedica Cardio (Saluggia, Italy; http://www.sorincardio.com) Terumo (Shibuya-ku, Japan; http://www.terumo.co.jp) TissueGen (Dallas, TX; http://www.tissuegen.com) Translumina (Hechingen; Germany; http://www.translumina.de) Vascular Concepts (Barcelona, Spain; http://www.vascularconcepts.com) Vascore Medical (Suzhou, China; http://www.vascore.com) X-Cell Medical (Monmouth Junction, NJ; http://www.x-cellmedical.com) Xtent (Menlo Park, CA; http://xtentinc.com)Tags: medtech, stents, drug-eluting cardiology market data