Medical Device Daily
First there were bare metal stents with a high risk of restenosis, repeat hospitalizations and angioplasty procedures. Drug-eluting stents (DES) followed, which overcame the re-blockage conundrum, but there was a new risk: late-stent thrombosis. OrbusNeich (Hong Kong) is building significant momentum in the development of its new approach to coronary stenting which relies on endothelial progenitor cell (EPC) capture technology that entirely changes the healing mechanism of stents.
OrbusNeich has initiated enrollment in a randomized clinical trial of the Combo Bio-engineered Sirolimus Eluting Stent (Combo Stent), which combines EPC for rapid endothelial coverage with an abluminal sirolimus drug elution for the control of neointimal proliferation. In the trial Combo Stent is going up against Boston Scientific's (Natick, Massachusetts) Taxus Libert paclitaxel-eluting stent.
"The advantages [of EPC] are twofold: It protects the body from attacking the metal with platelets that can lead to blood clotting and protects against thrombus," Steve Rowland, PhD, VP of R&D at OrbusNeich, told Medical Device Daily.
Genous is the name of OrbusNeich's EPC capture technology. It is believed to promote healing because the stent surface is coated with antibodies that attract EPCs circulating in the blood to form an endothelial layer – within 48 hours in animals – that provides protection against thrombosis and modulates restenosis. Additionally, the Combo Stent uses the SynBiosys biodegradable polymer matrix from SurModics (Eden Prairie, Minnesota), which degrades over time, allowing the stent to become bare metal, eliminating the late-stent thrombosis risks presented with current drug-eluting varieties.
"A weakness of DES technology is that current devices use biostable polymers," Rowland said. "Once gone there is inflammation. We use a biodegradable polymer system to deliver drug that is gone in 90 days, so there is no chance of a delayed or chronic reaction."
The Genous technology was first used in OrbusNeich's Genous Bio-engineered R stent, already commercially available in more than 60 countries (not including the U.S.) since 2005. The company reports a growing body of evidence from multiple clinical studies that the Genous stent is effective for patients who are non-responsive to or cannot tolerate long-term dual antiplatelet therapy.
"EPCs are bone marrow-derived cells, naturally occurring," Rowland said. "Their role is to restore damaged or diseased endothelium; they're genetically predisposed to perform that role. We recruit these cells with immobilized antibodies. By doing so, we are changing the healing kinetics."
That means patients can take anti-platelet therapy for a much shorter time period, possibly one month, compared with the current gold standard of one year. Some people, however, can't tolerate the therapy at all, and that's the niche patient population for the Genous Bio-engineered R stent.
The Combo Stent is designed build on the best of the Genous Bio-engineered R stent technology combined with low-dose sirolimus drug elution.
The new trial, called REMEDEE (Randomized Evaluation of an abluMinal sirolimus coatED bio-Engineered stEnt) will enroll 180 patients at up to 20 sites in Asia, Australia, Europe and South America. Investigators are seeking to demonstrate the safety and effectiveness of the Combo Stent compared to the Taxus Libert in the treatment of single de novo native coronary lesions ranging in diameter from greater than or equal to 2.5 mm and less than or equal to 3.5 mm and less than or equal to 20 mm in length.
Patients to be included will have symptomatic, ischemic heart disease due to a stenotic lesion located in a native coronary artery.
The primary endpoint: In-stent late lumen loss of the Combo Stent compared to DES at nine months post-procedure. Secondary endpoints include all-cause and cardiac mortality, myocardial infarction, Major Adverse Cardiac Event (MACE) and stent thrombosis rates at 30 days, nine months and one through five years, as well as clinically driven target lesion revascularization, target vessel revascularization and target lesion failure rates.
Just how much tissue growth has the company seen in earlier studies of Genous compared with DESs?
"In our preclinical work with Combo, we actually have data showing lower neointimal growth than commercially available DESs and we demonstrated similar endothelial coverage and functionality compared to our current, CE marked Genous Bio-engineered Stent," Rowland said. "Histological and optical coherence tomography (OCT) data out to 28 days show that the Combo Stent had lower neointimal hyperplasia and stenosis, as well as lower inflammation and fewer giant cells on the stent struts than Cypher and Xience V."
He said the Taxus was chosen as a comparator because, "It's a widely used device with 50,000+ in trials. We think it's a reasonable and valid measuring stick."
The first patient enrolled in REMEDEE is a 48 year-old man with a lesion located in the proximal left anterior descending artery. The Combo Stent was successfully inserted at John Hunter Hospital (Newcastle, Australia) by Greg Bellamy, MD, and Sukumaran Thambar, MD.
One of the principal investigators for REMEDEE is Ian Meredith, MBBS, PhD, professor of cardiology, Director of MonashHeart and executive director of the Monash Cardiovascular Research Centre (Melbourne, Australia).
"The pre-clinical work has shown the effectiveness of combining the endothelial progenitor cell capture technology to promote endothelialization coupled with the low dose, abluminal sirolimus elution to regulate hyperplasia," Meredith said. "The Combo Stent could be the best of both world's approach for patients at the highest risk of restenosis."
Once REMEDEE is completed, and assuming positive results, a CE mark submission process will start in Europe. In the U.S., however, additional studies will be needed before seeking FDA review.
David Kujawa, director Strategic Marketing for OrbusNeich, explained the reason for the broad geographic distribution of study sites: "All signals seem to indicate that the world is moving toward an integrated trial strategy where one large trial conducted across multiple geographies could one day be done to satisfy product approvals in all major markets," he said. "REMEDEE's broad distribution of study sites is reflective of this trend as well as reflective of the fact that we currently sell our products and have relationships with doctors in over 60 countries worldwide. Furthermore, this covers more territory for regulatory approvals and because the sites are so dispersed in multiple time zones it allows 24 hour patient enrollment for faster recruitment."
A few months ago, OrbusNeich reported that interim data from a prospective registry showed safety in a broad population of patients that underwent primary percutaneous coronary intervention and implantation of the company's Genous Bio-engineered R stent for ST-elevation myocardial infarction (STEMI).
In the study of 652 consecutive STEMI patients, the rate of MACE was 6.7% and the rate of subacute thrombosis was 1.1% at 30 days follow up (MDD, Sept. 25, 2009).
At the same time, the company reported results of a much larger study of almost 5,000 patients, called e-HEALING, in which the Genous Bio-engineered R stent was shown to be safe and effective in real world use, including in the treatment of patients with diabetes mellitus.
It evaluated 4,987 of the 4,996 enrolled patients and found a target vessel failure (TVF) rate of 8.1% at 12 months with a follow-up rate of 92%, a target lesion revascularization (TLR) rate of 4.4%, a major adverse cardiac events (MACE) rate of 7.7%, a subacute thrombosis (SAT) rate of 0.5% and a late stent thrombosis (LST) of 0.3%. Those data were presented at the Transcatheter Cardiovascular Therapeutics symposium, TCT 2009, in San Francisco.
And while the HEALING study highlighted the effectiveness in patients with diabetes, the Combo Stent is aimed at all patients.
"Our hope is that the Combo Stent could benefit the broadest patient population possible," Kujawa said. "If our biggest challenge is keeping up with market demand, we would not be disappointed."
Lynn Yoffee, 770-361-4789;