Anticipating the Era of Drug-Eluting Stents

Components of a Drug-Eluting Stent Program Four key elements that must be considered when developing a drug-eluting stent include: The drug, The polymer, Release kinetics, and The stent delivery system. The Drug Restenosis is a complex biological process that involves inflammation, smooth muscle cell proliferation and migration, matrix secretion, and other contributing factors.^{1-4 The first drug extensively investigated as part of a drug-eluting stent system was a derivative of taxol called taxane, which was incorporated into a polymeric sleeved stent by the company Quannam. While the stent design and dosing were not optimal, a clinical study with this device demonstrated the potential of site-specific stent-based drug elution to markedly inhibit restenosis. Following these results, the drug paclitaxel (taxol) has been studied by both Boston Scientific and Cook Inc. as described below. Paclitaxel was isolated from the bark of the Pacific yew tree, Taxus brevifolia. It was originally developed as part of a large-scale effort, headed by the U.S. National Cancer Institute, to investigate potential chemotherapeutic agents from natural sources. 5 Paclitaxel has a unique mechanism of action that promotes the assembly of tubulin into stable microtubules which are not able to function properly. 5,6 Microtubules are necessary for the function and structure of normal active cells, and play an essential role in cellular division, cell migration, intracellular signaling, and extracellular secretory processes. 7 Since microtubular function is integral to multiple cellular activities, many of which are involved in the restenotic cascade, it was hypothesized that paclitaxel could reduce restenosis. As described above, preliminary data suggests that taxol is very effective in inhibiting restenosis. Animal studies have documented safety of this compound, which allows normal vessel healing while at the same time inhibiting neointimal proliferation, cellular migration, inflammation and secretion of the extracellular matrix. Sirolimus (rapamycin) has been approved by the FDA for use by Wyeth-Ayerst as an immunosuppressive agent for the prevention of acute renal allograft rejection, and is currently being investigated by Cordis as an anti-restenotic agent. The inhibitory effect of sirolimus on intimal hyperplasia is mediated through decreased smooth muscle cell proliferation and matrix production, along with diminished inflammation. After entering the cell, sirolimus interacts with FKBP (FK506 Binding Protein) to form a sirolimus:FKBP complex, which in turn inhibits TOR (Target of Sirolimus), a key regulatory kinase. The inhibition of TOR results in inactivation of P70 and up-regulation of P27. P27 is a tumor suppressor protein which inhibits uncontrolled cell proliferation under normal cell conditions. P70 and P27 protein are two opposing forces, the balance of which is crucial for normal cell proliferation. The inactivation of P70 results in the inhibition of the translation of several ribosomal proteins and cyclins, which then leads to the arrest of cell cycle between the late G1 phase and the S phase. P70 inactivation can also inhibit the transcription of certain proteins. Ultimately, the arrest of the cell cycle results in the inhibition of smooth muscle cell proliferation and matrix production. Other drugs being evaluated for their effects on restenosis include everolimus and ABT-578, both Rapamycin analogs. Numerous other anti-restenotic drugs are in the investigational pipeline for use in drug-eluting stents. The Polymer Once a drug with suitable anti-restenotic properties is identified, a method must be devised to coat the drug onto the stent. Incorporating the drug into a polymer, which is then coated onto the stent surface, is one elegant way to tightly regulate the release of the drug. An ideal polymer carrier must: Provide an inert substrate that maintains excellent vascular compatibility following depletion of the drug; Deliver consistent and predictable drug release; Withstand the stresses of stent manufacturing and delivery. Polymer carrier characteristics that must be evaluated and optimized include: Bio- and vascular compatibility: The polymer carrier alone should show similar tissue responses compared to bare metal stents. Programmability: Polymer carriers can be modified to precisely control drug dose, rate and duration of release. Elastomeric Properties: The polymer carrier must allow stent delivery and expansion without structural compromise. Durability: The polymer carrier must maintain its integrity throughout normal manufacturing and use. Two companies which have successfully used polymer carriers in the development of their drug-eluting stent programs are Boston Scientific and Cordis Corporation. Boston Scientific has combined paclitaxel with its polymer, and Cordis has applied a topcoat to its drug/polymer basecoat both with the purpose of controlling the release of the drug. Guidant also has developed a non-reactive proprietary polymer for use with everolimus. Abbott is investigating stents coated with phosphorylcholine, a naturally occurring biocompatible component of cell membranes, to absorb and deliver ABT-578 and other compounds. Finally, Cook does not use a polymer to coat the drug onto the stent. Rather, through a proprietary surface modification process, paclitaxel is directly applied onto the abluminal stent strut surface for elution in the vascular tree. Release Kinetics It is important not only to establish the proper dose of the drug, but also to control the rate of release of the drug from the stent. To determine appropriate dose, both the maximum safe dose and the minimum effective dose must be identified in animal studies (usually a porcine model). The maximum safe dose can be defined as the highest dose where vascular healing is present in spite of drug effect. The minimum effective dose can be defined as the dose showing excellent safety with the potential to demonstrate efficacy in human clinical trials. Proper dosing is dependent on both the amount of drug loaded on the stent and the rate which the drug is released over time by the polymer. One advantage of polymer carriers is to control drug release kinetics with precision. For example, Boston Scientific is focusing its current clinical research on two formulations of taxol which is loaded onto the stent at a dose concentration of 1 µg/mm2 of stent surface area. One formulation, termed slow rate release, has a lower peak level at 48 hours, compared to the moderate rate release formulation, which has an approximately nine-fold higher peak level at 48 hours, despite the same dose concentration on the stent. The Stent Delivery System The stent and balloon delivery system is an integral component of the drug-eluting stent. Deliverability and trackability to be able to effectively deliver the stent is of course essential, as is excellent scaffolding to ensure uniform drug delivery. A repeating unicellular design which minimizes gap formation on the outer curves of bends may also be an important design element. The stent should be well matched to the balloon to minimize trauma at the non-stented edges which could serve as a nidus for restenosis. The stent must also be visible to facilitate accurate placement, assuring complete lesion coverage and no gaps between adjacent stents. Industry and Clinical Trial Update Cordis Corporation, a Johnson & Johnson company. Cordis Corporation has been investigating the safety and efficacy of the slow release sirolimus (rapamycin) coated BX Velocity stent (trademarked the Cypher stent) in a series of clinical investigations. The six-month follow-up QCA and IVUS data from the RAVEL trial (RAndomized Study with the Sirolimus-Coated Bx VELocity Balloon-Expandable Stent in the Treatment of Patients with de novo Native Coronary Artery Lesions) trial, a 238-patient, double-blind, randomized trial, revealed a 0% restenosis rate, virtual elimination of late loss, and no edge effect. Following RAVEL, the U.S. pivotal SIRIUS trial was performed, in which 1,101 patients at 53 centers were studied to compare the performance of the Cypher sirolimus-eluting stent to the BX Velocity® control stent. Cordis Corporation’s nine-month follow-up data from the first 400 patients in its Sirolimus-Coated Velocity Stent in Treatment of Patients with de novo Coronary Artery Lesions study (SIRIUS) was presented at the Paris Course for Revascularization in May 2002. The in-stent restenosis rates were 2% for the Cypher stent and 31.1% for the control. When the edges were also considered, the overall restenosis rates were 9.2% for the Cypher stent and 32.3% for the control, reflecting the fact that some restenosis occurred at the proximal and distal edge in both the sirolimus and control populations, with no significant beneficial anti-restenotic drug effect seen at this location. One of the conclusions reached from this data was that neointimal hyperplasia was less effectively suppressed at the proximal and distal stent margins, consistent with the lipophilic nature of sirolimus, which ensures very focal activity at the site of implant only. The complete data from the 1,101 patient SIRIUS study will be presented at the 2002 TCT meeting in September in Washington, D.C. for the first time. Boston Scientific Corporation. Boston Scientific continues to make steady progress with its paclitaxel-eluting stent incorporating a polymer carrier. The company’s TAXUS I study is a 61-patient, randomized, double-blind, multi-center safety trial utilizing the slow rate release dose formulation. The trial included 31 patients in the experimental arm and 30 in the control arm, with de novo lesions up to 12 mm in length and approximately 3.0 mm in diameter. Study results indicate zero restenosis in the group treated with paclitaxel-eluting stents versus 10.1% in the control arm at six months. In addition, no patient developed either early or late stent thrombosis. On the basis of the favorable results from TAXUS I, the pivotal European trial TAXUS-II was undertaken. Final results of the TAXUS II clinical trial in which both slow and moderate rate release kinetics were studied are expected to be reported at TCT 2002. Intravascular ultrasound (IVUS) was used on all 537 patients in the study at placement and follow-up. The primary endpoint is mean % in-stent net volume obstruction at six months as measured by IVUS. The TAXUS III trial was a single-arm registry examining the feasibility of implanting up to two slow rate release paclitaxel-eluting stents for the treatment of in-stent restenosis. The trial enrolled 30 patients. Major adverse coronary events (MACE) by 10 months after implantation included six target lesion revascularizations (TLRs), one coronary artery bypass graft, and one peri-procedural, non-Q-wave myocardial infarction. There were no stent thromboses and no deaths. Five of the six TLRs were prompted by restenosis in an area of the lesion not covered by a drug eluting stent, or by abnormal IVUS findings with no angiographic restenosis. Quantitative coronary angiographic analysis of stented segments within the paclitaxel-eluting stent yields a restenosis rate of four percent (1 of 25) at six months. Volumetric IVUS demonstrated only 11% obstruction of the stent lumen with neointimal proliferation. The TAXUS IV trial is the U.S. pivotal study of the slow rate release paclitaxel-eluting stent. More than 1300 patients were enrolled in this randomized, multi-center study between March and May of this year. The study is currently in the follow-up phase with an endpoint of 9-month target vessel revascularization (TVR). The blinded 30-day results will be presented at TCT in September 2002, while the final 9-month analysis should be completed in 2003. The large TAXUS-V trial, U.S. pivotal study of the moderate rate release paclitaxel-eluting stent, is expected to begin in late 2002. The preliminary plans for this study call for investigating the safety and efficacy of this device in de novo lesions up to 40 mm in length, in-stent restenosis, as well as bifurcation lesions and left main stenoses. Cook Incorporated. Several studies have been performed to evaluate the safety and efficacy of a stent eluting taxol without the use of a polymer, through application of a proprietary direct binding methodology. ASPECT (Asian Paclitaxel-Eluting stent Clinical Trial) compared the safety and efficacy of high-dose and low-dose densities of 3.1 mcg/mm2 and 1.3 mcg/mm2 dose densities of paclitaxel-coated stents versus uncoated stents in patients with single de novo lesions in native coronary arteries. This prospective, multi-center, blinded study evaluated the use of coated and uncoated Supra G stents in 177 patients equally randomized to one of the three treatment arms. Six-month angiographic results demonstrated a significant reduction of binary restenosis 4% in the 3.1 mcg/mm2 dose arm vs. 27% in the control arm, respectively. Cook’s 192-patient ELUTES (European EvaLUation of pacliTaxel-Eluting Stent) trial evaluated four doses of paclitaxel and a control V-Flex stent system in de novo lesions up to 25 mm in length in native coronary arteries 2.5-4 mm in diameter. The randomized, prospective dose-ranging study included dosages of: 0.2 mcg/mm2, 0.7 mcg/mm2, 1.4 mcg/mm2, and 2.7 mcg/mm2. Patients were evaluated at six months using angiography, analyzed by an independent core angiographic laboratory to determine the effectiveness of each dose of paclitaxel. The results showed a dose response relationship with the lowest restenosis rate of 3.1% in the 2.7 mcg/mm2 dose arm vs. 20.6% in the control arm. Guidant. Guidant has completed a 1,043 patient trial entitled DELIVER which utilized the Penta stent coated with 3 mcg/mm2 taxol using Cook’s non polymer based system. Single de novo lesions Medtronic. Medtronic is continuing development work with the Resten-NG 3rd generation c-myc oligonucleotide anti-sense compound licensed from AVI Biopharma. In May, Medtronic signed a licensing agreement with Abbott Laboratories. The agreement gives Medtronic co-exclusive rights to Abbott’s drug ABT-578 (a rapamycin analogue) as well as the phosphorylcholine (PC) coating Abbott recently acquired with the purchase of Biocompatibles International. The Abbott trial, with the ABT-578 coated stent and entitled PREFER, is expected to begin in the fall of 2003. Perspectives and a Look to the Future Drug-eluting stents represent a breakthrough technology for the care of patients with coronary artery disease. Preliminary results suggest that these devices reduce ischemic target vessel revascularization rates to}

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