CDU

News out of the coated-stent sector over the past few weeks has been the stuff of daytime soap operas, with so many twists that if you miss an episode you might be completely lost. Will Johnson & Johnson be the first to market? Can Guidant and Cook retain their co-exclusive agreement using Angiotech's paclitaxel coating in the face of a lawsuit from competitor Boston Scientific? And can Abbott Laboratories rescue Biocompatibles International's batimastat-coated stent?

Most importantly, will those companies whose products were the subjects of positive clinical trial updates at last month's American College of Cardiology (ACC; Bethesda, Maryland) scientific sessions be able to ride the wave of positive news to market leadership in a sector full of folks jostling for position?

As the saying goes, stay tuned.

One installment in the ongoing saga involved privately held Cook's (Bloomington, Indiana) news early last month that it was abandoning its PATENCY Trial, which used the paclitaxel-eluting Logic PTX stent. The company apparently lost interest in the domestic trial, which received conditional FDA approval in January, succumbing instead to the charms of its burgeoning collaboration with Guidant (Indianapolis, Indiana) using the Achieve drug-eluting coronary stent. The DELIVER trial, which uses a paclitaxel-eluting Achieve stent, is ongoing. The two companies signed a distribution agreement last August in which Guidant would be the exclusive worldwide distributor of the new stent that Cook would develop and manufacture.

In another move, Cook said it would, upon approval of its CE mark submission, introduce its V Flex Plus PTX drug-eluting coronary stent in Europe using what it said is a newly developed balloon catheter technology. The company said it expects European approval for that device in 2Q02.

"Given the unusually rapid enrollment of more than 1,000 patients in the clinical trial of our Achieve stent and our strong expectations for the widespread acceptance of both the Achieve and V-Flex Plus PTX stents once they receive regulatory approval, we made a business decision to dedicate our resources and manufacturing capacity to ensure the successful launch of these two new drug-eluting coronary stents," said Cook Chairwoman Phyllis McCullough in a company statement.

It may simply have been that the size and cost of another coated-stent trial was more than the company thought it could bear at this time. The PATENCY trial was scheduled to have more than 1,100 patients and would have been spread out to more than 50 sites across the country. However, the cancellation of the company's only other independent domestic stent program does pose some interesting questions. For instance, what happens if the lawsuit with Boston Scientific (Natick, Massachusetts) over the use of Angiotech Pharmaceuticals' (Vancouver, British Columbia) paclitaxel compound in the Cook/ Guidant collaboration favors the plaintiff? Boston Sci contends that the licensing agreement for paclitaxel does not extend to Cook's partner. If Boston Sci wins the case, Cook could see its stent development program in disarray, and its roll of the dice could result in a further loss of time in the hotly contested sector. Companies such as Johnson & Johnson's (New Brunswick, New Jersey) Cordis (Miami Lakes, Florida) unit with its rapamycin-coated stent could gain even more ground on the competition. That company could see a launch of its device as soon as the middle of this month in Europe and early 2003 in the U.S.

"It's a strategic business decision," said Cook spokesperson David McCarty. "I think it speaks to the fact that Cook thinks its position [in regards to the paclitaxel litigation] is highly defensible," he told Cardiovascular Device Update's sister publication, Medical Device Daily.

Since Cook is a smaller company than most of its rivals, it felt that burning extra resources on what McCarty said was virtually a "duplicate" trial was unnecessary. "Given the time frame and the minimal share of market we probably can achieve on our own, it made the most sense to us."

While Guidant had to be pleased with Cook's increased focus on the Achieve stent, it really did not have any other options at that point in time. It reported the discontinuation of its own ACTION trial in Europe for the actinomycin-D stent coating early last month as well, citing "unacceptably high target lesion revascularization rates." Medical technology analyst Kevin Kotler, who at the time was with ABN Amro (New York) before that company's abrupt late-March decision to close down its equity trading business, said in a research report that the Cook news meant that there would be one less player in the U.S. drug-coated stent market. He said his firm had only assigned the company low market share – in the 2% range – and that he still expected Guidant to launch its drug-coated stent in the U.S. by early 2004.

Interestingly, as the news related to the litigation between Cook and Boston Scientific, Kotler said the move could be viewed as a positive since it will no longer have a conflicting internal paclitaxel trial. "This would reinforce the Guidant partnership as not only about distribution but also about research and development, which is common in the medical device industry," Kotler noted. He said that even if the judge rules against Cook, which might push Guidant to buy that company to access the paclitaxel license, then the price may be more reasonable "given that Cook no longer has its own U.S. trial on which to fall back." He also noted that it was possible that Guidant and Boston Scientific might reach some agreement involving patent sharing, royalties or some other similar avenue.

Speculating on the new dynamics of the relationship between Cook and Guidant was Larry Haimovitch, president of Haimovitch Medical Technology Consultants (Mill Valley, California), who covers the cardiovascular sector for CDU, said, "Cook might just be saying 'Hey, these guys at Guidant really have their act together ... why should we pursue our own program when we're [already] with a great program?'" He added, "This is important for Guidant. They need this deal to work."

While Boston Scientific, the other primary competitor in the coated-stent sector, may stand to benefit from a favorable ruling in the paclitaxel litigation, since it is the only other company in this country licensed to use the drug in stent coatings, it too has suffered delays, particularly in the regulatory arena. In mid-January, the FDA told the company that it would not clear the company's protocol for TAXUS IV, the U.S. arm of its paclitaxel-coated stent program, further delaying development. FDA approval finally was received late in the month.

Another would-be coated-stent player also reported disappointing results of a trial in early March. Biocompatibles International (Farnham, UK) and British Biotech (Oxford, UK) said they had suspended their collaborative BRILLIANT II Trial for CE mark approval of a batimastat-coated stent. The companies said that six-month clinical follow-up from the 150 patient BRILLIANT I Trial, in which enrollment was completed in November 2001, has indicated that the batimastat-coated BiodivYsoi stent did not show the benefit that was evident in the preclinical studies. The company's U.S. BATMAN II Trial of the stent, already being questioned by the FDA, also will likely suffer an implosion due to the negative European results.

That may or may not have led to the announcement a little later in the month that Abbott Laboratories (Abbott Park, Illinois) had entered into an agreement to acquire Biocompatibles' cardiovascular stent business in a cash deal valued at about $235 million (see Business Developments, page 14).

The academic spotlight shone on the coated-stent sector just past mid-March with the release of clinical trial results during the ACC meeting in Atlanta's sprawling Georgia World Congress Center. During a spirited opening-day news conference on drug-coated stents, new data from the RAVEL and "First In Man" studies using Cordis' sirolimus-eluting Cypher stent were disclosed for the first time.

Jean Fajadet, MD, of Clinique Pasteur (Toulouse, France) revealed the 12-month data from the RAVEL Trial using a Cypher stent. "More than 12 months after the initiation of this study, we are continuing to document exceptional findings: 0% restenosis, 0% percutaneous TLR [target lesion revascularization], no thromboses and no cardiac deaths," he said. The landmark RAVEL trial, involving 238 patients at 19 centers across Europe and Latin America, was the first large-scale stent study to document sustained zero restenosis at six months post-treatment. The study population includes patients with single de novo lesions measuring 18 mm in length and 2.5 mm to 3.5 mm in diameter. "The reduction in neointimal hyperplasia [the process leading to restenosis] has resulted in an event-free survival rate of 94% at 12 months in the sirolimus-treated cohort," Fajadet said. "This finding is far superior to the 71% event-free survival rate for patients in the control arm."

Twenty-four-month follow-up data for the 30 patients enrolled in the original First-in-Man Feasibility Studies in patients with de novo lesions also was presented. A South American pilot study also using a Cypher stent with rapamycin continued to demonstrate the promising 12-month results. Of these patients, 29 agreed to have repeat angiography at 24-month follow-up. The average sustained in-stent late loss was essentially zero. One patient had evidence of progression of a lesion immediately adjacent and proximal to the stent, resulting in 51% diameter stenosis. Two other patients had evidence of disease progression in unstented vessels. All three patients were treated with additional Cypher sirolimus-eluting stents. One additional patient was referred for bypass due to progression of disease in a different area of the treated vessel.

Patients showed "remarkable results, particularly in regard to sustained lumen cross-sectional area," said principal investigator Eduardo Sousa, MD, professor of interventional cardiology at Dante Pazzanese Institute (Sao Paulo, Brazil). He noted 24-month findings of virtually no late lumen loss and zero in-stent restenosis. "It is clear that we are not seeing any evidence of late 'catch-up' restenosis in the treated vessels of these patients, but we recognize that the underlying atherosclerotic disease may progress in other vessels or other areas of the same vessel," he added. He said there were no stent thromboses and no deaths. "This is a very well-characterized and carefully studied group of patients," Sousa said. "With the one-year data from the randomized controlled RAVEL trial and the two-year data from the first-in-man feasibility study, I am confident in the sustainability of the results we have seen thus far."

Also presented were eight-month clinical follow-up data for the 41 patients enrolled in the first-in-man study to evaluate the feasibility of using the Cypher sirolimus-eluting stent to treat in-stent restenosis (ISR). "In November 2001, we reported outstanding four-month follow-up data showing extremely low in-stent late lumen loss [0.08 mm minimum lumen diameter]; zero restenosis; and no TLR, stent thromboses, or deaths for the 25 ISR patients treated at Dante Pazzanese," Sousa noted. He added that investigators now have eight-month clinical follow-up data for these patients "indicating no change in their status."

In a separate ISR pilot study of the stent at Erasmus University (Rotterdam, the Netherlands), Patrick Serruys, MD, reported a high percentage of good results in a 16-patient population described as "extremely challenging patients in whom we pushed the envelope." Serruys said he and his associates purposely chose a population that included several previous brachytherapy failures, as well as patients presenting with total occlusions and one heart transplant patient. "Considering the advanced degree of coronary artery disease in these patients, which created a study population at high-risk for late problems, the Cypher stent yielded excellent results, with an in-stent late loss of 0.25 mm," Serruys said.

"This is staggering data," said Tim Fischell, MD, director of the Heart Institute at Borgess Medical Center (Kalamazoo, Michigan). Along with his father and brother, Fischell helped develop one of the stents used in many of the initial trials, the BX Velocity. He said the data disclosed at the ACC gathering was "fantastic." He told his hometown newspaper, the Kalamazoo Gazette: "The skeptics said that the early results were misleading, that the drug just delayed restenosis. That's not the case at all."

At another trial presentation later in the conference, results of the Boston Scientific TAXUS III study of a paclitaxel-coated Nir stent were presented by Eberhard Grube, MD, of the Siegburg Heart Center (Siegburg, Germany). The study showed a 17% major adverse cardiac event (MACE) rate of adverse events such as blood clots and vessel reclosings after six months, but no patients died or needed bypass surgery. "These results offer further promise that paclitaxel-eluting stents can be used safely and effectively in the treatment of in-stent restenosis," he said.

Press conference moderator Spencer King, MD, of Emory University (Atlanta, Georgia), cautioned against early overexuberance over drug-coated stents, since, at this point, most of the available data thus far is from small trials. Final proof will come from the larger studies coming out within the next year or so, he said. He added that there isn't much data on in-stent restenosis thus far, and what little there is, in relation to drug-coated stents, he called "very preliminary and not very convincing."