The Smaller Contenders for the DES Market

These stents have a variety of unique designs and are composed of many different materials. The polymers (or their absence thereof) are as distinctive as the drugs they elute. The following twelve companies are an example of the innovation and originality of design that thinking outside the box can create. Allvivo (AVI) has taken a novel approach to the DES market. Rather than develop a stent and coating, they have elected to only develop the coating and leave stent manufacture to others. Jennifer Neff, PhD, Director of Technology, states, We initially were developing both stents and coatings but came to the realization we should remain true to our core competencies, which is the creation of stent coatings. Allvivo has developed a bio-mimetic coating incorporating an anti-inflammatory drug that is tethered to the stent surface using polyethylene oxide. This type of coating provides a clear alternative to cytotoxic or immunosuppressive drug-eluting stent coatings. The surface coating is inspired by the body’s natural healing mechanisms and the immune system’s ability to recognize self from non-self. The design incorporates specific elements of the immune system to minimize inflammation at a very early stage and prevent the subsequent processes that lead to restenosis. This provides a favorable surface for healing and regeneration of the endothelium. Allvivo’s immunologists and polymer scientists designed a coating consisting of two layers: EGAP (End Group Activated Polymer) is a tri-block co-polymer coating that forms a thick brush-like layer of polyethylene oxide. This layer acts as a protective shield to prevent protein absorption, platelet activation and thrombus formation, while allowing the specific attachment of active, desirable proteins. Factor H is a human plasma protein that plays an important role in our immune system. Factor H has natural anti-inflammatory and protective capabilities, and unlike other agents, it intervenes at an early point to prevent a cascade of inflammatory mediators that leads to tissue damage and restenosis. With AVI’s proprietary coating technology, Factor H is covalently linked to stents through the activated end groups of the EGAP coating. The combination of these two layers into a single coating offers major advantages over current DES.¹ Advanced Bio Prosthetic Surfaces is developing a micro-porous covered stent that relies on nanotechnology and micro-fabrication processes. Using its molecular thin film deposit process, the company is developing a drug delivery stent system with struts that are hollow, micro-porous and have a high tensile strength. The hollow struts act as reservoirs that contain therapeutic agents without the need for a polymer carrier. The agent(s) are delivered in a uniform fashion by direct contact with the vessel wall. Additionally, the hollow struts can be filled with therapeutic agents that are customized to the patient. The company’s first product, eNitinol, is a self-expanding, covered Nitinol stent designed for use in restenotic saphenous vein grafts. The all-metal, elastic film covering allows for expansion in tandem with the stent. An interesting side note is that the development of this stent is being done at the University of Texas Health Science Center in San Antonio, Texas, the same institution where the Palmaz-Schatz stent was developed.² Biosensors International is conducting a 120-patient clinical study in Germany and Brazil (STEALTH) on the safety and efficacy of its drug eluting stent the S-Stent. Trial enrollment has been completed, and the six-month results were presented at EuroPCR in May 2005. The S-Stent is coated with polylactic acid, a bioerodible polymer that contains Biolimus A9, and an analog of sirolimus with a stronger burst effect. The bioreabsorbable polymer degrades to water and carbon dioxide as the drug is released, mitigating side effects such as inflammation or polymer flaking. Biosensors International has an agreement with X-Cell Medical, which is developing anti-restenosis compounds. They have also licensed the stent design and use of polylactic acids to Guidant Corporation.³ Biotronik is developing the Absorbable Metal Stent (AMS) made with a magnesium alloy. This stent has proven to be animal blood- and tissue- compatible in long-term clinical results. The Behind The Knee (BTK) stent procedure has been performed with encouraging clinical results (12-month limb salvage of 94.7% and patency rate of 73.3%) and it has been followed by the INSIGHT study (the CE-mark approval study for BTK indications). Biotronik expects to enroll the last INSIGHT patient at the end of the first quarter in 2006. Biotronik is also collaborating with Conor Medsystems on the research and development of bioabsorbable drug-eluting stent technologies.⁴ Conor Medsystems has developed a non-surface-coated stent with drug-elution capabilities. The stent platform allows for programmed delivery of multiple drugs with independent rates of release. This will allow for the treatment of different disease conditions such as restenosis and potentially, the treatment of patients suffering from acute myocardial infarction. The CoStar stent uses a cobalt chromium alloy with hundreds of laser-drilled holes. These holes act as drug reservoirs when filled with a matrix of drugs and a bio-erodible polymer that provides for controlled drug delivery. As a result of the proprietary reservoir design, drugs can be eluted bi-directionally, either into the lumen or vessel wall, and have the capability of combining a large array of drugs with independent release kinetics. The drug reservoirs can provide a larger drug volume than that of a conventional surface-coated stent and permit individual drug concentration gradients to be set up in each depot. The CoStar stent is engineered with a design feature called a ductile hinge. The hinge permits the concentration of stent expansion stresses in a small area and allows the stent to expand uniformly, thereby assuring accurate delivery of the drug. Since the CoStar stent is not surface-coated, the extent of polymer surface contact with the vessel is approximately 15% as compared to conventional surface-coated DES designs. The Conor CoStar stent is currently being evaluated in clinical trials in Europe (EuroSTAR), India (COSTAR I), and the U.S. (COSTAR II).⁵ Design and Performance Corporation is developing the Over and Under bovine pericardium-covered stent for use in saphenous vein grafts. It is a premounted, low-pressure balloon-expandable stent constructed from an electro-polished stainless steel laser cut tube. It is covered with a thin layer of bovine pericardium, which is provided by Medical Ventures. The stent can be deployed using low-pressure balloon inflations, which can prevent complications such as edge dissection and restenosis. Chemical modification to the bovine pericardium can be performed to allow for its use in drug delivery to the walls of the saphenous vein grafts.⁶ Devax is developing Axxess Plus, 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-through stent treatment. The stent could be used to treat blockages in several areas within the vasculature, including the carotid and biliary arteries; however, the company’s main focus is on the coronary arteries. Devax licensed the drug Biolimus A9 and a polymer coating from Occam International, an affiliate of Biosensors International. Devax completed a clinical study of Axxess Plus in Europe in December 2004. The trial included 138 patients who were treated between July and December. A six-month angiographic follow-up was completed in June 2005; the results are yet to be published. Approximately 1 million percutaneous coronary interventions were performed in the United States in 2004. Of these, approximately 15“20% involved lesions at a bifurcation.⁷ Endovasc has entered into an agreement with Tissuegen to develop a biodegradable drug-eluting stent. Endovas has co-licensed its patented time-release prostaglandin E-1 drug and Tissuegen is contributing its technology related to drug-releasing polymer fiber scaffolds. Many cardiovascular experts believe this type of stent will be the stent of the future. As the drug elutes into the vessel, the stent dissolves, leaving nothing to set up restenosis or thrombus occlusions. Endovasc has also developed and patented a stent coating, PROStent, comprised of a polymer and Prostaglandin E-1 (PGE-1). This coating slowly releases the hormone PGE-1, which provides several potent activities that counteract the insult brought about by the surgical placement of a metal stent in a blocked artery vessel. At the onset, PGE-1 acts to block the inflammatory activity that occurs in response to the invasive procedure by down-regulating the immune response. The anti-thrombotic activity of PGE-1 prevents the formation of clots, which generally cause the initial blockage of the vessel. PGE-1 promotes the proliferation of endothelial cells needed to heal, repair and rebuild damage to the lining of the vessel caused by vascular disease and placement of a stent in the vessel. At the same time, PGE-1 blocks the proliferation and migration of vascular smooth muscle cells (SMC) to prevent the slow buildup of SMC in or around the ends of the stent. This process is referred to as restenosis, and can occur in the weeks to months that follow the procedure.⁸ OrbusNeich is developing the Genous Bioengineered R-stent with a dual-helix structure and a biological coating called Genous Bioengineered Surface. Instead of delivering drugs to the vessel wall, the Genous Bioengineered R-stent uses a coating with an antibody specific to the antigen cells that are in the blood, therefore capturing the patient’s circulating endothelial progenitor cell (EPC) in order to accelerate the natural healing process. EPC originates from bone marrow and circulates in the blood stream. The Genous EPC capture technology is designed to limit restenosis by quickly covering the stent with a layer of biocompatible endothelial cells and has been evaluated in clinical trials, such as the HEALING II study. The final results of this study were presented at the Transcatheter Cardiovascular Therapeutics symposium in October 2005. During the course of this trial, 63 patients were treated at 10 centers in Belgium, Germany, and The Netherlands. OrbusNeich reported the HEALING II patient population consisted of the following: 67% had hyperlipidemia, 52% had a family history of coronary artery disease, and 24% had previously experienced a myocardial infarction. The index lesions had an average reference diameter of 2.63 mm, a minimal lumen diameter of 0.98 mm, and an average lesion length of 9.83 mm. Fifty-seven percent of all lesions were Type B2/C. The clinically driven target lesion revascularization (TLR) rate at six months was 6.3%, with an overall major adverse cardiac events (MACE) rate of 7.9%. Additionally, no subacute or late thrombosis was reported. OrbusNeich has received CE mark approval and is allowed usage of the product under the auspices of an Internet-based registry called e-HEALING. e-HEALING is a multi-center, worldwide registry enrolling approximately 5000 patients from 100-120 centers in Latin America, Europe and Asia Pacific.⁹ REVA Medical has developed a reabsorbable stent that has a patented Slide and Lock geometry. Slide and Lock geometry allows stent elements to slide and lock into position upon balloon expansion during stent placement and possesses steel-like strength. REVA has secured the exclusive worldwide rights to a tyrosine-derived polycarbonate co-polymer developed at Rutgers University. This polymer possesses safety, strength, degradation, and material processing properties for use in the bloodstream. REVA has successfully incorporated the polycarbonate material with the Slide and Lock stent geometry to create a fully reabsorbable drug-eluting stent. It should be noted that one of the Big Three, Boston Scientific Corporation, has made an equity investment in and secured an exclusive option to purchase REVA Medical.¹⁰ Sorin Group‘s Janus Tacrolimus-eluting Carbostent features a stent construction designed to optimize the individual mechanical response to stent expansion and torsion, drug reservoirs covering the external stent surface, and a design that eliminates the need for a polymer coating. After drugs are deposited in the reservoirs, the surface of the stent is covered with a thromboresistant carbofilm TM coating (a permanent, hemo-biocompatible proprietary coating) that increases biocompatibility and minimizes the tissue interaction with the stent. The Janus Tacrolimus-eluting Carbostent stent will allow for the delivery of therapeutic agents that reduce restenosis and also treat such conditions as acute myocardial infarction or acute ischemia. This stent can also be used to promote angiogenesis.¹¹ Translumina has taken a unique approach to the DES market by creating the Drug-Eluting Stent System. The system is composed of two parts, the Yukon DES and the Stent Coating Machine (SCM). The premounted stent system, Yukon DES, utilizes Transluminal’s new surface finishing technology, which enables the individual application of a drug or drugs at different dose rates. The porous surface bonds the drug without having to use polymers. The Translumina Stent Coating Machine (SCM) is an innovative system developed to allow application of a free choice of drugs at individual doses on the Yukon DES platform. The drug-coating process takes place directly in the cath lab, allowing the interventionalist freedom to adjust treatment depending on the individual patient’s requirements. Recently, Translumina completed the Intracoronary Stenting and Angiographic Restenosis: Test Equivalence Between 2 Drug-Eluting Stents (ISAR-TEST) Study in Munich, Germany. The objective of the study was to assess whether the polymer-free rapamycin stent is not inferior to the polymer-based paclitaxel stent in terms of restenosis. The primary endpoint of the study was late lumen loss at follow-up angiography (in-stent analysis). At the nine-month follow-up, the polymer-based paclitaxel stent and the polymer-free rapamycin stent both showed similar incidences of in-stent late lumen loss. The conclusions were that the polymer-free rapamycin-eluting stent has an anti-restenotic effect that is not inferior to the polymer-based paclitaxel-eluting stent. This may represent the first successful non-polymer approach to drug-eluting stent technology in interventional cardiology.¹² In conclusion, there are many different drug-eluting stent designs and coatings on the horizon, as well as opinions as to the direction this market will take. However, one thing is clear. The two companies who are now at the top cannot rest on their laurels. There are many companies out there who are working diligently to surpass their achievements. Dennis Chadwick can be contacted at Dennis.Chadwick@carolinashealthcare.org. He has nothing to disclose.

1. Developing Biomimetic Surface Coatings for Cardiovascular Devices. http://www.allvivo.com/index.html (Accessed December 13, 2005).

2. Lorek, L.A. UTHSC technology paying off. University of Houston, San Antonio Express - News. January 4, 2005. http://www.uh.edu/ednews/2005/saex/200501/20050104uthsctech.html (Accessed December 13, 2005).

3. New DES Platforms: Optimizing Safe Treatments for Real-World Patients. http://www.biolimusa9.com/; also available at http://www.biosensorsintl.com/sub.htm (Accessed December 13, 2005).

4. Press Release: Revolutionary development in the treatment of atherosclerotic disease: first human implant of Absorbable Metal Stent (AMS). http://www.biotronik.com/ content/detail.php?id=2732 (Accessed December 13, 2005).

5. The stent designed for drug delivery. www.conormed.com/tech/stent.html (Accessed December 13, 2005).

6. Over & Under Stent. http://www.medicalventures.com/OVER%20UNDER%20STENT.htm (Accessed December 13, 2005).

7. 02 Technology. Proprietary HAp Coating Technology. Drug-Eluting Stents. http://www.mivtherapeutics.com/technology/drug_eluting_stents (Accessed December 13, 2005).

8. Endovasc-TissueGen Research Sponsors, LLC Biodegradable, Drug Eluting, Vascular Stents: http://www.endovasc.com/proddev/ endovasctissuegen_research_spon.htm (Accessed December 13, 2005).

9. OrbusNeich. Genous Bio-engineered stent. http://www.orbusmt.com/genous/ (Accessed December 13, 2005).

10. REVA Medical: Reabsorbable Stent. http:// www.teamreva.com/tech_resorbable.html (Accessed December 13, 2005).

11. Berg, Jeffrey. Two drug-eluting stents on U.S. market, others on the horizon. Cardiovascular Device Update September 2004;10(9).

12. Drug-Eluting Stent System - Yukon DES +SCM. http://www.translumina.de/dess_en. html (Accessed December 13, 2005).