Medical Device Daily Associate

On the eve of the American College of Cardiology (Bethesda, Maryland) conference that starts this weekend in Atlanta, several companies involved in the still-hot drug-eluting stent (DES) market have reported news on their respective trials old and new.

One of the relative newcomers to the sector, X-Cell Medical (Princeton, New Jersey), developer of a stent system that uses a different class of drug than its competitors, reported that initiating enrollment in its multinational clinical trial to study the safety and effectiveness of the ETHOS (EsTradiol eluting stents in Humans for restenOSis) II coronary stent system.

The Ethos II DES is coated with a second-generation formulation of 17(beta)-estradiol, a drug that already is approved for use in hormone replacement therapy and other indications.

The ETHOS II trial is complementary to the company's ongoing ETHOS I trial, with full six-month follow-up data to be reported sometime in the second half of 2006.

President and CEO Oded Ben-Joseph, PhD, said X-Cell is confident that its drug ultimately will be a better choice for DES devices than drugs such as sirolimus, a rapamycin derivative used in Cordis ' (Miami Lakes, Florida) Cypher stent, and paclitaxel, used on Boston Scientific 's (Natick, Massachusetts) Taxus stent.

“The reason that we are such great believers [in] and so excited [about] ETHOS II is that we created a dosing and release kinetics profile which are tailor made to measure for estradiol specifically,“ Ben-Joseph told Medical Device Daily.

He noted that estradiol is very different from rapa-mycin and paclitaxel, which he said are utilized by a process of diffusion. In contrast, he said estradiol has a “receptive mediated effect.“

Estrogens are known to inhibit smooth muscle cell proliferation and to accelerate endothelial regeneration, suggesting that estrogen-coated stents may reduce restenosis in human coronary arteries. This was previously demonstrated in the 30-patient EASTER registry trial, using a non-optimized drug delivery system.

The ETHOS I trial was designed to further refine the drug dosage and evaluated two different release kinetics a slow-release version (two to four weeks) and a moderate-release version (a few days).

ETHOS II is designed to closely mirror ETHOS I. It will utilize the same three centers with the same trial directors – Heart Center Siegburg (Siegburg, Germany), under the direction of Eberhard Grube, MD; Krankenhaus de Barmh. Br der (Trier, Germany), under the direction of Karl-Eugen Hauptmann, MD; and the Institute Dante Pazzanese (Sao Paulo, Brazil), under the direction of Alexandre Abizaid, MD, PhD.

In the new open-label study, patients will receive a new formulation of estradiol with reduced polymer load. The study will include 35 patients with diagnosed stable and unstable angina or documented silent ischemia, with angiographic and intravascular ultrasound (IVUS) follow-up at six months to measure the percentage of in-stent volume obstruction.

“This particular profile that we have put together is much more sophisticated [than in ETHOS I] in the sense that it addresses the dose and the timing,“ said Ben-Joseph.

Bill Baumbach, PhD, executive director of drug research and development at X-Cell, said that concurrent with ETHOS I, the company did a series of in vitro and in vivo elution studies.

“Over the last six months,“ Baumbach told MDD, “we've been building up a lot of data in regard to how the drug elutes and developed more and more sophisticated versions of the polymer and dose and things like that. We basically optimized all these things concurrently and that resulted in the Ethos II product.“

The data from ETHOS II will be compared with the 95-patient ETHOS I trial, which also includes a bare-metal stent, for the elimination of restenosis in patients eligible for balloon angioplasty with symptomatic ischemic heart disease due to discrete de novo and/or restenotic coronary artery lesions.

Ultimately, the company believes, the results of this comparison will enable X-Cell to proceed toward a U.S. pivotal trial with a fully optimized product, though Baumbach noted that if the company needed to do yet another ETHOS study, it would not hesitate to do “if we feel, based on ongoing studies . . . that there's yet a better profile.“

“We have reason to believe that the Ethos system will be safer than both the products that are on the market,“ said Ben-Joseph, adding that as far as efficacy is concerned, “we think it will at least be in the range of whatever it is the other companies are doing.“

The company is pioneering new territory with its compound and it believes this will ultimately separate it from the herd. “All the other compounds that are being developed today are either analogs of rapamycin or paclitaxel directly,“ he said. “This is a new class of drug within this market.“

The company said it expects to complete enrollment of ETHOS II by the end of the month.

In other DES-related news:

• Boston Scientific said it has submitted the final module of the company's premarket approval (PMA) application for its Taxus Liberté paclitaxel-eluting coronary stent system to the FDA, although a warning letter from that agency threatens to hold up final approval.

The companywide warning letter, which was reported in January (Medical Device Daily, Jan. 30, 2006), cited Boston Scientific's management for not properly tracking complaints over certain products, including Taxus.

The company met with the FDA last month to discuss how to remedy the problems.

The Liberté is the company's next-generation DES system. The third and final PMA module contains nine-month data from the ATLAS clinical trial, a global, multicenter, pivotal study designed to support U.S. approval of the system.

ATLAS enrolled 872 patients at 72 sites in the U.S., Canada, Australia, New Zealand, Singapore and Hong Kong. The primary endpoint for the study is target vessel revascularization at nine months. Enrollment began in August 2004.

The company said it would announce nine-month data from ATLAS at the EuroPCR conference in Paris in May.

• Guidant (Indianapolis) reported enrollment of the first patient in a first-in-man clinical trial designed to evaluate the safety of a fully bioabsorbable everolimus-eluting stent platform for the treatment of coronary artery disease.

The trial, called ABSORB, will enroll up to 60 patients in Belgium, Denmark, France, New Zealand, Poland and the Netherlands.

“As the world's first clinical trial evaluating a fully bio-absorbable drug-eluting coronary stent, this initial implant marks a significant milestone for Guidant. This study will lay the foundation for our continued work toward offering a valuable alternative to current drug eluting stent implants that reside permanently in the treated coronary artery,“ said John Capek, PhD, president of Guidant's Vascular Intervention business.

The ABSORB trial will study the safety of bioabsorbable drug eluting stents developed by Bioabsorbable Vascular Solutions (Santa Clara, California), a subsidiary of Guidant Vascular Intervention.

These stents are designed to be fully absorbed by vascular tissue following the restoration of blood flow and drug elution in patients with coronary artery disease. Guidant has completed extensive preclinical studies on its bioabsorbable stent, gathering data on safety, drug dosing, and the mechanical properties of the stent.

ABSORB is a non-randomized study with an initial assessment of safety (MACE and stent thrombosis rate) at six months and a follow-up period of five years.

The first implant was performed by a team headed by John Ormiston, MD, and Mark Webster, MD, at Auckland City Hospital , (Auckland, New Zealand).

Ormiston and Patrick Serruys, MD, of the Thoraxcenter at Erasmus University Hospital (Rotterdam, the Netherlands), will serve as the study's co-principal investigators.