CDU Contributing Editor

While only two drug-eluting coronary stents are currently cleared for sale in the U.S., numerous others are peeking over the horizon, awaiting their turn in the sun. The existing products and those that are on the way reflect a variety of different approaches in terms of both the drugs and the polymer coatings chosen by the companies vying for a spot in the marketplace.

The two commercialized products are the sirolimus-eluting Cypher stent from the Cordis (Miami Lakes, Florida) subsidiary of Johnson & Johnson (New Brunswick, New Jersey) and Boston Scientific's (Natick, Massachusetts) paclitaxel-releasing Taxus stent. Both were extensively studied in clinical trials and received CE mark approvals in Europe prior to FDA approval. The stents are constructed from 316L stainless steel coated with a non-biodegradable (biostable) polymer loaded with a drug to prevent artery reclosure.

The Cypher stent's metal scaffold is coated with three layers of polymers. The primer layer is a coating of Parylene C onto which is sprayed a solution of two biodegradable polymers, polyethylene-co-vinyl acetate (PEVA) and poly n-butyl methacrylate (PBMA), containing the active agent, sirolimus. The top layer is a drug-free coating of a solution of PEVA and PBMA that serves to control drug release and prevent a burst effect. The polymer platform was developed for Cordis by SurModics (Eden Prairie, Minnesota).

The Cypher stent releases 50% of its sirolimus content during the first week after implantation and 85% of the drug over 30 days. All the sirolimus is eluted after 90 days. Sirolimus is licensed by Cordis from Wyeth (Madison, New Jersey), which sells it under the Rapamune brand name for use in preventing the rejection of kidney transplants.

The Cypher stent was recently approved for use on diabetic patients. The blood vessels of diabetics tend to scar more heavily than the general population, especially with bare metal stents, causing reclogging of the artery. The Cypher stent is sold in 80 countries and was recently approved for marketing in Japan. Japan is the world's second-largest interventional cardiology market, with approximately 166,000 angioplasties performed annually, 70% of which involve stent placement. The Cypher Select has a more flexible construction than the Cypher stent and is designed for enhanced deliverability. It is sold in Europe but not yet approved by the FDA for sale in the U.S.

The Taxus stent is coated with non-biodegradable poly (styrene-b-isobutylene-b-styrene), also known as Translute polymer. The stent provides a burst release of paclitaxel during the initial 48 hours followed by slow release over the next 10 days and no further release after 30 days. The Taxus stent quickly achieved a 70% market share because it is more flexible and therefore easier to use than the Cypher stent. However, a problem of a small balloon that is used to deploy the stent failing to deflate has recently led to Boston Scientific's recall of about 88,000 Taxus stents. The company is working on its next-generation product, the Liberte stent, which has been designed to further enhance deliverability and conformability, particularly in challenging organs. It will include a balloon with a five-way fold, built-in protection of the stent edge, improved flexibility (15% greater than the Taxus stent) for insertion in tortuous vessels, a smaller strut diameter, and will be available in three sizes for placement in small, medium and large vessels. The Liberte stent is currently available in international markets in a bare-metal version. Boston Scientific recently received an investigational device exemption from the FDA to begin clinical trials of the Liberte DES.

Paclitaxel, the active agent in the Taxus drug-eluting stent, is in the class of drugs called taxanes. It prevents the accumulation of anti-inflammatory cells at the site where angioplasty was performed and is licensed by Boston Scientific from Angiotech Pharmaceuticals (Vancouver, British Columbia) for this indication. Paclitaxel is a leading cancer drug for treating metastatic breast cancer, metastatic ovarian cancer and Kaposi's sarcoma. It is sold by Bristol-Myers Squibb (New York) as Taxol, and by Aventis (Strasbourg, France) as Taxotere.

While a large accumulation of cells around and inside the implanted stent can clog the interior channel and cause restenosis, some cell accumulation is desirable because it allows a thin layer of endothelial cells to accumulate on the inside of the stent and form a smooth cover, incorporating the device into the artery itself and reducing the tendency for clotting. This process, called endothelialization, is important in preventing the complication of thrombosis. Patients typically take an anticlotting drug for six months after stenting.

Competitive activities in DES

There is much competitive activity in the drug-eluting stent field with novel stent coatings that release a variety of drugs being developed as well as fully biodegradable stents. Besides J&J and Boston Sci, other leading cardiovascular products companies are targeting the DES market. Both Guidant (Indianapolis) and Medtronic (Minneapolis) are conducting clinical trials in Europe of their DES devices, which are claimed to be more flexible than currently available products. Cook (Bloomington, Indiana) is developing the Logic PTX stent coated with paclitaxel, but without any polymer to contain the drug. Cook markets in Europe the V-Flex stainless steel coronary stent that is treated by a proprietary process with paclitaxel. No polymer coating is used. Paclitaxel has long tissue retention and therefore remains in the vessel wall for an extended period. Cook recently reported that it would initiate the first U.S. trial for use of a DES to treat peripheral (non-coronary) vascular disease. It will use its Zilver PTX self-expanding vascular stent coated with paclitaxel for implantation in the femoropopliteal artery.

Medtronic's Endeavor is a thin-strut cobalt chrome stent onto which is coated phosphorylcholine loaded with a smooth muscle cell inhibitor, ABT-578, which has properties similar to those of sirolimus. Both the drug and delivery matrix are licensed from Abbott Laboratories (Abbott Park, Illinois). The originator of the phosphorylcholine coating was Biocompatibles (Farnham, UK), whose cardiovascular stent business was acquired by Abbott in a $243 million deal in May 2002. Approval of the Endeavor stent in Europe is projected by the end of this year and in the U.S. by the end of 2005. A 1,200-patient study in Europe of the Endeavor stent vs. Medtronic's Driver bare-metal stent was completed and a clinical trial on about 400 randomized patients that compares the Endeavor stent vs. the Cypher stent is under way in the U.S. The Endeavor stent shows rapid elution of ABT-578 with 70% to 80% of the drug released within 48 hours of implantation. A residual amount of the drug remains for about 30 days.

Abbott Laboratories is developing the TriMax stent, which is made from a stainless steel-tantalum composite. The stent is coated with phosphorylcholine and elutes ABT-578 over a 30-day period, similar to the Cypher and Taxus stents. It will enter a 100-patient clinical trial in Europe in the second half of this year and will be evaluated against the Taxus stent.

Guidant is clinically evaluating two DES devices. Its Champion stainless steel stent is coated with polylactic acid, a biodegradable polymer licensed from Biosensors International (Singapore) that biodegrades to carbon dioxide and water, and releases everolimus, which Guidant has licensed from Novartis (Basel, Switzerland). It is being developed by Guidant's subsidiary, Bioabsorbable Vascular Solutions, and has completed a one-year follow up of a 106-patient feasibility trial. The pharmacokinetics of drug release are similar to the Cypher stent except that the drug is completely eluted after 45 days. Guidant announced in late spring a six- to eight-month delay in the Champion stent program, causing speculation among analysts that the stent may not be launched in the U.S. until 2007.

Guidant also has completed patient enrollment for its Multi-Link Vision cobalt chromium stent that is coated with a non-biodegradable polymer that releases everolimus. At an earlier stage in development is a biodegradable and programmable amino acid polymer coating technology acquired by the company from Medivas (San Diego). Guidant also acquired technology from SyneCor (Research Triangle Park, North Carolina) for a fully bioabsorbable everolimus-eluting stent. The leading supplier of bare-metal coronary stents, Guidant had a 39% share of the global market in 2002. The company entered into a strategic alliance with Cordis earlier this year to jointly develop biodegradable stent technology.

Variety of approaches from smaller firms

A growing number of smaller and mostly private companies also are developing DES products (see Table 1) . A variety of stent designs and materials and a range of drugs, including combinations of drugs, are being explored. Also, stress studies are exploring ways of increasing stent-to-vessel contact while decreasing stress and bending points in the stent strut design and damage to polymer coatings upon stent expansion, or at bend points in the strut.

Conor Medsystems (Menlo Park, California) is developing a non-surface-coated stent with drug delivery capabilities. Its stent platform allows for the programmed delivery of multiple drugs with different elution profiles. The MedStent is contoured and has ductile hinges, which concentrates the stresses and strains of stent expansion in a small area. This allows for 90% of the stent struts to be underformed during stent expansion and makes it possible to create holes in these areas without sacrificing strength, scaffolding or flexibility. The Conor stent consists of a metal framework with laser-drilled holes that act as drug reservoirs, and a bioerodible polymer coating to control delivery. The drugs can be eluted either into the lumen or into the tissue and up to five different drugs can be eluted from one stent. The drug reservoirs provide up to 16 times the drug volume of conventional surface-coated stents and permit a drug concentration gradient to be set up in each depot. The MedStent is in clinical trials in Europe.

Sorin Biomedica Cardio's (Saluggia, Italy) Carbo- stent features deep drug reservoirs covering the external stent surface and a stent construction designed to optimize the individual mechanical response to stent expansion, flexture and torsion. After depositing a drug, the stent is covered with the company's Carbofilm coating, designed to increase hemo/biocompatibility, minimize the risk of thrombosis and significantly reduce tissue interaction and hyperplastic reaction.

The Conor and Sorin products will make it possible to deliver therapeutic agents from reservoirs for prolonged elution of drugs for treating various cardiovascular conditions such as angiogenesis, acute myocardial infarction, sequelae of acute ischemia, remodeling and vulnerable plaque.

Orbus Medical Technologies (Fort Lauderdale, Florida) is developing the R-stent with a dual-helix structure and a biological coating called Genous Bio-engineered Surface. Instead of delivering drugs to the vessel wall, its R-stent uses a coating with an antibody specific to the antigen cells that are in the blood, thereby capturing the patient's circulating endothelial progenitor cells in order to accelerate the natural healing process. The Genous endothelial progenitor cell capture technology is designed to limit restenosis by quickly covering the stent with a layer of biocompatible endothelial cells and is being evaluated in clinical trials. Orbus has said it believes that the rapid formation of a functional endothelium will prevent thrombus and minimize the risk of restenosis.

Implant Sciences (Wakefield, Massachusetts) and CardioTech (Woburn, Massachusetts) are collaborating in a joint venture under the Cornova name to develop a DES. The device will use Implant Sciences' thin film coating technology and CardioTech's microporous and biocompatible ChronoFlex polycarbonate/polyurethane that contains a commercially available drug for preventing restenosis. The product will use a stent with thinner struts than existing drug-eluting stents and will be treated with a radiopaque material for better visualization. The cost of the product is expected to be under $1,000. It is targeted for the European market, where stents are reimbursed at a lower rate than in the U.S.

Biotronik (Berlin) is developing the Lekton Magic Absorbable Metal Stent and has reported no restenosis in eight patients receiving the stent after one month in below-the-knee implants. An international coronary clinical study is being planned. Biotronik also is collaborating with Control Delivery Systems (Watertown, Massachusetts) for use of its Codrug technology in the development of a coronary stent that elutes a combination of drugs.

Biosensors International, which has U.S. operations in Newport Beach, California, is conducting a 120-patient clinical trial in Germany and Brazil of its S-Stent, which is coated with polylactic acid, a bioerodible polymer, that contains biolimus A-9, an analog of sirolimus with a stronger burst effect. It is being compared against a bare coronary stent. Biosensors has an agreement with X-Cell Medical (New York) that is developing anti-restenosis compounds. Biosensors licensed to Guidant its stent design and the use of polylactic acid.

Devax (Irvine, Caloifornia) is developing Axxess, a self-expanding Nitinol drug-coated stent and the first bifurcated stent designed to elute an anti-restenotic drug. It is comprised of one main vessel stent with a flared shape that conforms to the native bifurcation anatomy and a second cylindrical side branch stent. The flared stent allows open access to both side branches, which permits follow-on stent treatment. The stent is applicable to several areas within the vasculature, including the carotid and biliary arteries, although the company's initial focus is in the coronary arteries. Devax is working with Biosensors International to coat its bifurcation stent system with biolimus A-9 coupled with a bioerodible polymer. The Devax bifurcation system has CE-mark approval. Clinical trials of the Axxess Plus were begun in Europe this year.

Reva Medical (San Diego) is developing a thin-walled, stainless steel bare-metal stent that has a patented Slide & Lock geometry in which a series of stent elements slide and lock into position upon balloon expansion during stent placement. The company also is developing, in collaboration with the New Jersey Center for Biomaterials (Piscataway, New Jersey), a fully biodegradable and temporary DES with the Slide & Lock feature that is coated with a biodegradable polymer that is visible by radiography/fluoroscopy for accuracy in placement and continued monitoring after implantation. The polymer is from the family of tyrosine-derived polycarbonates.

Endovasc (Montgomery, Texas) has entered into a joint venture with Tissuegen (Arlington, Texas), named Endovasc-TissueGen Research Sponsors, to develop a biodegradable DES. Endovasc has co-licensed its patented, time-released prostaglandin E-1 drug and TissueGen is contributing technology relating to bidegradable, drug-releasing polymer fiber scaffolds.

Design and Performance Corp. (Richmond, British Columbia) is developing the Over and Under bovine pericardium-covered stent for use in the saphenous vein. It is a pre-mounted, low-pressure, balloon-expandable stent constructed from an electropolished stainless steel laser-cut tube and covered with a thin layer of bovine pericardium. The stent can be deployed using low balloon pressures, thereby reducing complications such as edge restenosis. Chemical modification of the bovine pericardium can be performed to allow for its use in drug delivery to the vessel wall. The saphenous vein is used as a graft in coronary artery bypass surgery. The plaque in the saphenous vein is much softer than in the coronary arteries. The pericardium is provided by Medical Ventures (Richmond, British Columbia).

Allvivo (Lake Forest, Ca;ifornia) is developing a stent with a biomimetic (triblock copolymer) coating that incorporates an anti-inflammatory drug which is tethered to the stent surface using polyethylene oxide. The company is conducting animal trials.

Advanced Bio Prosthetic Surfaces (San Antonio) is developing a microporous covered stent that relies on nanotechnology and microfabrication processes. Using its molecular thin-film deposition process, the company is developing a drug delivery stent system with struts and covers that are both hollow and microporous. The hollow struts act as reservoirs to contain therapeutic agents without the need for polymer carriers. The system is designed for circumferential uniformity of elution directly into the vessel wall with flexibility in the type of agent used and location of the reservoirs. The company's first product, eNitinol, is a self-expanding, covered nitinol stent designed for use in restenosed saphenous vein grafts. The all-metal, elastic film covering allows for expansion in tandem with the stent. Expandable properties are provided by a longitudinal slot pattern.

Memry (Bethel, Connecticut) seeks to use its shape memory alloy technology in a DES and is collaborating with Biomer Technology (Runcom, UK), a developer of polymers and biocompatible coatings.

Translumina (Munich, Germany) uses a passive diamond-like carbon nanolayer coating that is applied by plasma-assisted chemical vapor deposition for coronary and peripheral stents to increase biocompatibility. A polymer coating is not used. Its stent Magic Box coating machine is marketed for use in the cath-lab and enables the free choice of drugs and individual doses for preparing a DES.

Lombard Medical (Abingdon, UK) is developing a family of PEP (programmable elution profile) polymeric coatings for the controlled release from drug-eluting stents.

MIV Therapeutics (Vancouver, British Columbia) has developed, in collaboration with researchers at the University of British Columbia (also Vancouver), a process for applying an ultra-thin coating of hydroxyapatite (HAp) to metal stents and, ultimately, as a multi-layer porous coating for drug-eluting applications. The highly biocompatible HAp coating is intended to inhibit the inflammatory response elicited by bare stents. This research is being funded by a grant from the Natural Sciences and Engineering Research Council of Canada.

Shiga Medical Center (Shiga, Japan), in collaboration with Igaki Medical Planning Co. (Kyoto, Japan), is developing the Igaki-Tamai biodegradable drug-eluting stent, fabricated from polylactic acid and containing tranilast, an anti-allergy drug that inhibits the migration and proliferation of vascular smooth muscle cells.

TyRx Pharma (New Brunswick, New Jersey) has a collaboration with one of the leading stent marketers for evaluating its desaminotyrosine polyarylate as a biodegradable coating on a metal stent or as the material of construction for a fully biodegradable stent.

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