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See the December 2015 report, “Global Market Opportunities in Peripheral Arterial and Venous Stents, Forecast 2020”. A $500 advance discount is available until publication.
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The worldwide market for drug-eluting, as well as bare, bioresorbable and other stents, is now the subject of the May 2009 report by MedMarket Diligence, Report #C245.
Below is an excerpt from MedMarket Diligence’s coverage of the drug-eluting stents market in mid-2008. The previous scarcity of long term data left some uncertainty about DES’ clinical and market potential, compared to bare stents or even coronary artery bypass grafting, but the completion of multiple clinical trials has gone a long way toward ensuring at least several years of solid growth and the proliferation of competitors in the DES market.
After clinical trial results were released in 2006 showing that bare metal stents had outperformed drug-eluting stents (DESs), the market for DESs took what turned out to be fairly minor hit, with some physicians backing away from the newer technology and choosing to implant bare metal stents instead. Subsequent to those results, a number of studies revealed that DES offer better outcomes with morbidity that is competitive with bare metal stents (see the clinical trials list here).
Four-year data presented in September 2007 at the European Society of Cardiology meeting showed that in a 35,000-patient Swedish registry, patients receiving DESs are not at a higher risk of dying or suffering a heart attack as compared to patients receiving bare metal stents. While DESs do present a small increased risk of late-stent thrombosis after the first year, this is offset by better outcomes in the early months after implantation.
Nonetheless, it remains that stent sales have decreased across the board over the last two years and many physicians still need to be convinced of the devices’ performance and safety. In addition, opportunity is still great for those who would develop new DES technology that can further decrease the rate of restenosis.
The fourth quarter of 2007 proved to be the worst yet for the DES market. While some studies showed that DESs comprised nearly 90% of all stents implanted in 2006, that figure fell to roughly 60% by the end of 2007. These declines—fueled by restenosis concerns as well as studies showing that in some patients, stenting should be delayed in favor of drug therapy—led to layoffs at Boston Scientific and Johnson & Johnson. Now that the market has leveled off, the percentage of DES stents implanted seems to be holding at roughly 60%.
Meanwhile, the FDA proposed in March 2008 more stringent guidelines for DES clinical trials. Under the new guidelines companies must submit clinical trial data on patients at one and two years post-op, as compared to the previously required nine-month period. In addition, companies should continue to monitor patients for five years post-op. While this does not affect stents currently in the market (namely Cypher by Johnson & Johnson/ Cordis, Taxus Liberte by Boston Scientific, and Endeavor by Medtronic), it does result in a significant delay for companies bringing their first DES to market.
Johnson & Johnson
Johnson & Johnson was the first company to bring a DES to market through its Cordis subsidiary. However, Cordis saw a 15% operational sales decline in the first quarter of 2008 as compared to the prior year, primarily due to increased competition as well as contraction of the DES market worldwide.
In December 2007, Johnson & Johnson unveiled a new ad campaign designed to reassure consumers as to the safety of its Cypher stent as well as combat the competition in the market for DES. The company also set up a web site (http://www.cypherusa.com) to provide marketing and general product information to patients and physicians. The direct-to-consumer marketing approach has been criticized by many as an effort by the company to minimize physician input as to which procedures would be appropriate for which patients.
In May 2007, Johnson & Johnson announced it would discontinue marketing its CoStar stent outside the United States, would no longer seek U.S. FDA approval of the device, and had ceased ongoing clinical trials for the stent. The CoStar stent was developed by Conor Medsystems, a company Johnson & Johnson had purchased a few months earlier. The decision was made after the CoStar failed to meet its primary goal in the COSTAR II study. In the COSTAR II study, the stent was compared to Boston Scientific’s Taxus Express2 (also a paclitaxel-coated stent). While the CoStar did not present safety issues, neither did it prove superiority to the Taxus stent. Researchers said the CoStar stent presented ineffective dosing of paclitaxel, resulting in more frequent repeat revascularization procedures. The company is now working to develop a new version of the CoStar that uses sirolimus, the drug used on the Cypher stent. In a market where physicians have been reverting back to implanting bare metal stents due to performance issues of DESs, product manufacturers are looking for devices that will not only match the performance of but will outperform currently available DESs.
In other disappointing news, Conor’s GENESIS study involving a pimecrolimus-eluting Corio stent was terminated in late March 2008. The study involved three devices: the company’s Corio stent; its dual-drug (pimecrolimus and paclitaxel) SymBio stent; and its paclitaxel CoStar stent. After six months follow-up, in-stent late loss was greatest with the Corio stent, mid-range with the SymBio stent and least with the CoStar stent.
A new randomized clinical trial dubbed the RES-ELUTION study began in March 2008 to compare a Conor coronary stent that elutes sirolimus to Boston Scientific’s Taxus Liberte paclitaxel-eluting coronary stent. The primary endpoint of the study is angiographic in-stent late lumen loss at six months. Secondary endpoints include target lesion failure, target vessel failure, major adverse cardiac events (MACE), stent thrombosis, target lesion revascularization, target vessel revascularization, and angiographic in-stent and in-segment binary restenosis at six months. The multicenter study will be conducted at 40 sites outside the United States and resulting data will be used to support a CE Mark filing.
Among the sets of clinical data released over the past several months, Boston Scientific announced positive data from the ARRIVE registries and the TAXUS studies. In addition, Boston Scientific announced in February 2008 the start of the PROENCY registry, which will assess different Olimus-eluting stents, including its Promus/Xience V (everolimus), Medtronic’s Endeavor (zotarolimus) and Johnson & Johnson’s Cypher (sirolimus) stents. The registry will enroll up to 2,500 patients with simple and complex lesions at multiple sites in several European countries. Half of the patients will receive the Promus stent and half will receive either the Cypher or the Endeavor stent to attain a 2:1:1 ratio. The primary endpoint will be the rates of MACE (cardiac death, all myocardial infarction and target vessel revascularization) at 12 months.
Also in February 2008, a U.S. District Court in Texas reached a verdict finding that Boston Scientific’s Taxus Express and Taxus Liberte DESs infringe on a patent held by Dr. Bruce Saffran. While the jury awarded damages of $431 million, Boston Scientific plans to contest the verdict.
In May 2008, a World Intellectual Property Organization arbitration panel decided in favor of Boston Scientific, refuting a claim by Medinol alleging the Liberte and Taxus Liberte stents infringed various U.S. and European patents held by Medinol. Under the terms of the settlement agreement, Medinol holds the right to appeal to another WIPO panel.
In February 2008, Medtronic received FDA approval for its Endeavor zotarolimus-eluting coronary stent, becoming the third company to receive marketing approval for a DES in the United States.
In May 2008, Medtronic saw the first implants of its next-generation Endeavor Resolute stent as part of the RESOLUTE III trial comparing Medtronic’s stent to Abbott’s Xience V. The pivotal RESOLUTE III trial will be conducted in more than 100 countries outside the United States. The Endeavor Resolute stent received CE Mark approval in October 2007 and is still limited to investigational use in the United States.
The Endeavor Resolute incorporates the company’s biocompatible polymer dubbed BioLinx, designed to offer the same biocompatibility as the Endeavor’s phosphorylcholine (PC) while lengthening the amount of time the drug is exposed in the vessel. BioLinx blends hydrophilic and hydrophobic elements and is the first polymer created specifically for a DES.
Results from clinical studies performed with Abbott Vascular’s Xience stent have been encouraging and the company expects to receive FDA approval for the device in 2008. Xience received CE Mark approval in 2006.
Over the last few months, data from the SPIRIT II and III trials have been released by the company. In May 2008, the first long-term data from the pivotal SPIRIT III trial was presented at the EuroPCR 2008 meeting showing the Xience V everolimus-eluting coronary stent performed well against Boston Scientific’s Taxus stent. At two years follow-up, the Abbott stent showed a 45% reduction in the risk of MACE (7.3% for Xience V versus 12.8% for Taxus) and a 32% reduction in the risk of target vessel failure (10.7% for Xience V versus 15.4% for Taxus). The prospective, randomized SPIRIT III trial involves 1,002 patients at several sites in the United States.
Abbott Vascular is also working on a drug-eluting, fully bioabsorbable vascular stent (BVS). The device is currently the focus of the ABSORB clinical trial, for which positive one-year results were published in The Lancet (371: 899–907, March 15, 2008), The results showed 100% procedural success in 30 patients and 94% device success (29 of 31 implantation attempts). At one year, the MACE rate was 3.3% and no late stent thromboses were recorded. The prospective, nonrandomized ABSORB trial is designed to accommodate up to 60 patients in Belgium, Denmark, France, New Zealand, Poland and The Netherlands.
In April 2008, Biosensors International launched its BioMatrix drug-eluting stent outside the United States. The device combines a biodegradable polymer with the company’s proprietary drug Biolimus A9. The BioMatrix stent received CE Mark approval in January 2008.
Simultaneously with the product launch, Biosensors began enrollment in a five-year patient registry designed to track the safety and efficacy of the BioMatrix stent in up to 5,000 patients.
In March 2008, Biosensors opened enrollment in the BEACON II registry, which is designed to enroll 1,000 patients in 15 centers across Asia, Australia and New Zealand. Results from the original BEACON study were presented in October at the TCT 2007 meeting. In that study, the BioMatrix showed a 2.1% target vessel revascularization rate and an 86.5% MACE rate.
Biosensors International is also striving to make its presence known in the DES market through corporate liaisons. For instance, in Europe, Terumo markets the company’s BioMatrix under the Nobori label.
In another agreement, Biosensors acquired the remaining 50% equity of JW Medical Systems in May 2008. JW Medical Systems was established in 2003 as a 50:50 equity joint venture between Biosensors and Shandong Weigao Group in China. JW Medical Systems, which will now likely be absorbed into Biosensors, has been developing the Excel sirolimus-eluting stent. The CREATE registry study is ongoing in China and incorporates the Excel biodegradable polymer DES. Results presented in October at the TCT 2007 meeting showed the stent had achieved both primary and secondary endpoints with a MACE rate of 0.63% and 1.4%, respectively, in 30-day and 6-month follow-ups. Excel has been available commercially in China since December 2005.
Xtent is developing its Custom NX DES, which incorporates Biolimus A9 licensed from Biosensors International. In December 2007, Xtent submitted its application for CE Mark registration, based on the CUSTOM I, II, and III trials. In March 2008, the company was informed that it would receive a response to its CE Mark application in the second quarter of 2008. Xtent had previously filed an IDE application with the FDA in September 2007 to gain the right to begin U.S. trials.
French company Stentys is developing a bifurcated coronary DES, which was first implanted into a human patient in September 2007. The successful procedure involved a 56-year-old male patient in Siegburg, Germany. The Stentys device is unique in that the stent-opening for the side branch can be created anywhere in the stent after implantation, thus ensuring that the procedure’s success is not dependent on accurate positioning.
In March 2008, Stentys announced that it had completed an $18 million Series B round of venture financing, led by the U.K.-based Scottish Equity Partners. The financing will be used to complete clinical trials and obtain CE Mark status.
MIV Therapeutics (MIVT) saw the first human implantation of its hydroxyapatite-coated VESTAsync DES and the launch of the MIVT Pilot Trial in May 2007. The trial will evaluate the safety and efficacy of MIVT’s polymer-free nanoscale microporous hydroxyapatite DES for the treatment of single de novo lesions in native coronary arteries. Dr. Alexandre Abizaid performed the procedure at the Institute Dante Pazzanese of Cardiology in Sao Paulo, Brazil. The MIVT stent is based on the company’s GenX coronary stent system and incorporates a coating that is only 700 nanometers thin.
In October 2007, Dr. Abizaid performed a live four-month follow-up case at the TCT 2007 conference. The physician also implanted a VESTAsync stent into another patient as part of the same live presentation. Follow-up data on the first 13 patients in the trial showed average late-lumen loss of 0.27 mm in-stent and 0.18 mm in-lesion with 0% restenosis. IVUS analysis showed volumetric obstruction of 2.8% and all patients were thrombosis-free.
Data presented in November 2007 at American Heart Association meeting showed that in animal studies, MIVT’s VESTAsync hydroxyapatite coronary stent coating with low-dose sirolimus resulted in less fibrinoid than seen with Johnson & Johnson’s Cypher stent. The data also showed a statistically significant difference between an increase in sirolimus and an increase in fibrinoid material, a strong indicator of delayed healing. Even though the MIVT stent presented a four-fold lower dosage of sirolimus as compared to the Cypher stent, less fibrinoid was seen overall.
Nine-month VESTAsync data presented at the American College of Cardiology meeting in March 2008 was consistent with the data presented at the October 2007 TCT meeting, with no significant difference between the four- and nine-month results. In addition, no late-acquired incomplete stent apposition, stent thrombosis or MACE were reported. The company is now gearing up for a larger clinical trial accommodating approximately 100 patients.
Other DES Developments
In May 2007, Brookwood Pharmaceuticals and Targeted Technology Ventures collaborated to create a joint venture—Aeon Bioscience—to develop a new DES that would be more resistant to restenosis. Aeon Bioscience is working to develop a new polymer coating with better biocompatibility than seen with the current market leaders. In October 2007, Brookwood Pharmaceuticals was acquired by SurModics, a development that is not expected to hinder Aeon Bioscience in its product development efforts.
In October 2007, ARIAD Pharmaceuticals signed a licensing agreement with ICON Medical to develop and commercialize DES devices that incorporate ARIAD’s mTOR inhibitor, deforolimus. Under the agreement, ARIAD receives an equity stake in ICON, up to $27 million in payments based on achievement of certain clinical, regulatory and commercial milestones for two products and royalties on worldwide sales of all ICON medical devices delivering deforolimus. ICON will build the DES around its proprietary metal alloy, Nuloy.
In December 2007, Devax completed patient enrollment in its DIVERGE clinical trial evaluating its Axxess bifurcated DES. To date, 302 patients are enrolled in the prospective, multicenter trial. The Devax Axxess Biolimus A9–eluting DES is a self-expanding nitinol stent designed for treating coronary and vascular bifurcation lesions.
In June 2007, Biotronik completed enrollment in its ProLimus I study, a prospective, nonrandomized trial incorporating 61 patients at five centers in Belgium and Germany and using the company’s pimecrolimus-eluting ProGenic stent.
CardioMind began its first-in-man trial in March 2008 with its Sparrow DES, a device that is 70% smaller in diameter than other DES on the market. The CARE II clinical trial began at St. Vincent’s Hospital in Melbourne, Australia, and will eventually enroll 220 patients. The Sparrow stent incorporates the SynBiosys biodegradable polymer stent from SurModics, which will allow the stent to gradually return to a bare metal state.
Endovasc and TissueGen mutually agreed in May 2007 to dissolve their joint venture exploring development of biodegradable stents for cardiovascular, ureteral and prostate applications. All intellectual property has returned to the respective owners.
Medlogics is developing its Synergy Biomatrix non-polymeric coating, which can be applied to stainless steel, nickel titanium and cobalt chromium alloys. The Synergy Biomatrix surface is less than 2 microns thick, as compared to polymeric coatings that are typically between 7.5 and 10 microns. The coating is also biodegradable and returns the stent to bare metal after releasing the drug. Current development programs are focusing on the Cobra-P (paclitaxel) and Cobra-Q (undisclosed drug) DESs. Medlogics has received a CE Mark for its bare Cobra stent and is launching the device in Europe in 2008. In February 2008, Medlogics signed an agreement granting the company licensing rights to CV Therapeutics’ biopolymer stent coating.
Below is a sampling of active drug-eluting stent companies:
Abbott Vascular (Redwood, City, CA; http://www.abbottvascular.com)
Aeon Bioscience (Birmingham, AL; http://aeonbio.com [under construction])
Avantec Vascular (Sunnyvale, CA; http://www.avantecvascular.com [under construction])
B. Braun Melsungen (Melsungen, Germany; http://www.bbraun.com)
Lepu Medical (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)
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://www.bostonscientific.com)
CardioMind (Sunnyvale, CA; http://www.cardiomind.com)
Conor Medsystems (Menlo Park, CA; http://www.conormed.com)
Cook Medical (Bloomington, IN; http://www.cookmedical.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)
ICON Medical (Cleveland, OH; http://www.iconmedicalcorp.com [under construction])
Johnson & Johnson (J&J; New Brunswick, NJ; http://jnj.com)
JW Medical Systems (See Biosensors International)
Kaneka (Osaka, Japan; http://www.kaneka.co.jp)
Medinol (Jerusalem, Isreal; http://www.medinol.com)
Medlogics Device Corporation (MDC; Santa Rosa, CA: http://www.medlogicsdc.com [under construction])
Medtronic Vascular (Minneapolis, MN; http://www.medtronic.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)
Relisys Medical Devices (Hyderabad, India; http://www.relisysmedical.com [under construction])
Sahajanand Medical Technologies (SMT; Surat, India; http://www.smtpl.com)
Sorin (Saluggia, Italy; http://www.sorin.com)
Stentys (Clichy, France; http://www.stentys.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)
X-Cell Medical (Monmouth Junction, NJ; http://www.x-cellmedical.com)
Xtent (Menlo Park, CA; http://xtentinc.com)
The worldwide market for drug-eluting, as well as bare, bioresorbable and other stents, is now the subject of the May 2009 report by MedMarket Diligence, Report #C245.