Now that BIG and Terumo has got the CE mark, the question on everyone?s mind must be ? How good is the product ? Does it have what it takes to beat the competition out there ? Will it translate into tremendous revenue and correspondingly profitability for BIG ?

For some of the answers, lets turn to the recent TCT2007 symposium held on Oct 2007 for the family of companies that that uses the Biolimus/PLA polymer, with notable and renowned speakers like Gregg Stone (dpy chairman of Cardiovascular Research Foundation, principal investigator of the Xience DES for Abbot, Eberhad Grube, Peter Fitzgerald, Renu Virmani ? pathologist who spearheads the concept that inflammation and fibrin growth, and lack of endothelialisation is causing stent thrombosis.

Issues that were highlighted and debated in the conference :

1)                  The biolimus/PLA formulation has been used across 4 different stent platform, with the same consistent excellent results of low MACE rates (eg 3.7 for Nobori vs 5.6 for Taxus), low Binary Restenosis rate(eg 0.7 for Nobori vs 5.4 for Taxus), low neointimal hyperplasia volume (eg 2.7 for Nobori vs 13.4 for Taxus) and low Instent Late Loss (eg 0.11 for Nobori vs 0.32 for Taxus).

The conference went on to note that the combined number of patients across the 4 different were about 2,100 patients ? a good enough number to gauge the efficacy and safety of the formulation. (I think that is what they say)

2)                  Presentation of the XTENT DES was impressive ? the only stent in the world right now that can customize the length of the stent, as well as the diameter, while in the patient?s body.

3)                  Also, as the XTENT is a stent that comprises of 6mm pieces that are interdigitated together, it is able to conform to the movement and bending of the blood vessel, without danger of stent fracture, etc. (imagine that the stent is like a caterpillar with many 6 mm segments forming its body, and imagine what other conventional stent will look like, if it is contorted while in the blood vessel,especially stents that are crushed together )

It is also the only DES stent in the world where you can treat multiple lesions with a single insertion of the carthethar, including inflation of the balloon to ensure that the stent is well opposed against the vessel wall. (In other DES, you probably have to insert at least 3 times to perform all of the above function, causing more time, money, and more complications)

4)                  .The question was asked by Greg Stone ? Can the Xtent DES be the workhorse DES stent of the future ? Some answers ? Only when larger clinical trials are done, with tracking going into a larger number of years of follow-up. Eberhad Grube is of the opinion that the Xtent will be a specialty DES that will be used for long lesions and multi-lesions, as the current technique of using multiple stents and crushing them together at the ends results in much higher MACE rates and restenosis rates.(Current DES stents longest length is at  most 36-40 mm long, while the XTENT is 60 mm long)

5)                  Renu Virmani presented clinical trials using porcine models that shows that the old generation DES like Cypher, Taxus cause fibrin deposition, inflammation and lack of endothelialization  (These 3 factors will contribute to late stent thrombosis),as opposed to to the Biolimus/PLA formulation that seems to be better in those 3 aspects.

6)                  Eberhad Grube was of the opinion that the DEVAX bifurcation DES is the answer to the problems of bifurcation lesions, as the clinical trials shows low MACE rates, low restenosis, etc, compared to the conventional method of again crushing stents.

7)                   He expressed frustration, on why the medical authorities have NOT YET approved this DES, even with a 3 year follow-up with good results.

The above are my interpretation of the TCT2007 audio conference of the symposium held by Biosensors. You are encouraged to listen to the conference call yourself (in Biosensors? website).

Not a call to buy/sell. Besides the fundamentals, the technical picture as well as the overall bearishness of the mkt has to be considered as well.

Next-generation drug-eluting stents tackle shortcomings of Cypher, Taxus

 

February 7, 2006  Shelley Wood

New York, NY - With several new drug-eluting stents (DES) already available in Europe and in pivotal clinical trials in the US, interventional cardiologists are starting to hope that the innovative newcomers will resolve many of their concerns or complaints about the Cypher (Cordis/Johnson & Johnson) and Taxus (Boston Scientific) devices.

Dr Mitchell Krucoff (Source: Duke University Medical Center)

"With any breakthrough technology that changes the landscape of medical therapeutics, the reality is, the first version is always the worst version," Dr Mitchell Krucoff (Duke Clinical Research Institute, Durham, NC) told heartwire.

 "In the case of first-generation DES, these are essentially bare-metal stents that have been spray-painted with plastic."

Liberté (Source: Boston Scientific)

While next-generation versions of both the Cypher and Taxus, known as the Cypher Select and Taxus Liberté, are already CE Mark approved and poised for US approval, both have focused primarily on easier deliverability, a major buzzword of the early DES era.

 Elsewhere, companies have tried to emulate or improve on the success of the Cypher by developing new macrolide immunosuppressive ("limus") drugs, such as biolimus A9 (Biosensors), everolimus (Guidant), tacrolimus (Sorin, Abbott), and zotarolimus (Abbott, Medtronic) for stent-based delivery.

 Likewise, innovation in stent composition and design continues, with many second-generation drug-eluting stents available outside North America doing away with stainless steel for the base stent, replacing it with alloys that maintain radiopacity and strength but permit thinner, more flexible struts.

Indeed, Cordis/J&J has its own cobalt-chromium stent, the Cypher Neo, still several years away from US approval.

  Cypher Select (Source: Cordis/J&J)

Perhaps the biggest and most contentious flurry of activity centers on the actual mechanics of drug-delivery and the need for a polymer coating. Polymers have been hailed by some as essential to controlled drug elution and maligned by others as a ticking time bomb: the potential cause of increased late thrombosis and other adverse tissue responses.

 The polymer has also been blamed for stent-delivery glitches; in particular, the increased friction, or "stickiness," between the delivery balloon and the stent itself.

 Although the original Taxus and Cypher stents both have polymer coatings, other DES developed at the same time, such Cook Inc's drug-eluting stent program, did not make it through clinical testing, having failed to demonstrate superiority over bare-metal stents?a fault blamed largely on the inability to regulate elution of the drug.

Puzzling over polymers

 

Dr Marie-Claude Morice

New stents, however, are revisiting the concept of polymer-free stents or at least trying to develop polymers that will disappear over time. As Dr Marie-Claude Morice (Institut Cardiovasculaire Paris Sud, Massy, France) emphasized to heartwire, operators have enough years of experience with bare-metal stents to feel confident that a metal stent can remain in the coronary system without causing late adverse effects.

 

 The same cannot be said for the polymer.

 

"It's a very important issue," Morice said. "The polymer coatings currently used reflect the early phase of DES development. The long-term outcome of bare stents is well known, whereas that of polymer coatings is not."

 

Dr Adnan Kastrati (Deutsches Herzzentrum, Munich, Germany) agrees: "Why would you have something on the stent that you don't need?

 

 There are not enough data to show that polymers are risky over the long term, but there are still some concerns," Kastrati said.

 

Dr Adnan Kastrati

 Those concerns stem from a number of sources, experts say. For one, says Krucoff, even a polymer that is not loaded with drug can cause localized reactions in the artery.

"In the preclinical work with the Cypher stent in pigs, for instance, it was very dramatic that once the sirolimus had eluted, there was an intense subsequent inflammatory response at the cellular level that generated profound late in-stent restenosis," Krucoff explained

 

. "Now, it's very clear we're not seeing that in humans, but on the other hand, this does give us an animal model that alerts us to the fact that, once the drug has eluted, if the polymers persist, these are not inert substances."

....... 'Deleted portion of the article (Too long)'

While not everyone agrees on the absolute need for a polymer, most concede that the best-of-both-worlds strategy would be to have a polymer that disappears after it has done its job.

 

 Sahajanand Medical Technologies' (SMT) Infinnium stent elutes paclitaxel via a proprietary biodegradable polymer, while Conor Medsystem's has its own PLGA bioabsorbable polymer that it is testing on its CoStar stent.

 Other front-runners in the field are Guidant, Biosensors, and Terumo, whose Champion, BioMatrix, and Nobori stent programs, respectively, all use Biosensor's proprietary bioresorbable polymer.

 Last year, however, Guidant announced that it would first be moving forward with its Xience (previously known as the Vision) DES program, which uses a durable polymer, instead of its Champion stent program, as a result of "link fractures" seen in the Champion's stent platform during testing.

Reva (Source: Reva Medical)

Still, as Krucoff pointed out to heartwire, second-generation stent manufacturers focusing on bioresorbable polymers are for the most part basing their technologies on elements that are already well established in the coronary stent world: antiproliferative drugs delivered via metal stents.

Beyond these are the devices he believes are best described as "third-generation" devices, namely fully bioresorbable stents, made completely out of dissolving polymers or magnesium. Companies like Reva, Endovasc/TissueGen, and Igaki-Tamai have all presented or published data in recent years on stents made completely out of biodegradable polymers that elute drug as they dissolve.

 Taking another tactic, Biotronik is working away on a drug-eluting magnesium-based alloy that degrades over the course of approximately two months and, in 2004, signed an agreement with Conor to develop a fully absorbable magnesium-based DES.

 Maybe it's enough to have a bare-metal stent with a good drug on it. 

 

This is "an entirely new domain," Krucoff says. "There are some totally novel questions that will have to be answered to make these fully bioresorbable stents usable and government approved in the US," he says. "What is the difference between the rate in which you deliver drug and the rate at which the stent ultimately loses its physical properties that are a part of the scaffolding?

 And is that different if that is a metal scaffolding vs a plastic scaffolding? The answers to all of these questions really have to be worked out.

The second-generation stents, like the Conor stent, can come forward very quickly because the components they are using are all very well known.

 Third-generation, fully bioabsorbable stents, will enter a new domain in such fundamental ways that they're certainly going to have to do a lot more work."

 

Kastrati, likewise, called the whole field of bioabsorbable platforms "an interesting idea" but pointed out that it is one that has been around from the dawn of bare-metal stents, when people were first concerned about leaving bare metal in coronary arteries. Those fears, he points out, have largely disappeared

. If the polymer problems can be solved and the stent design doesn't pose late hazards, having the stent disappear altogether might not be necessary.

 

 "If we can get a good drug," says Kastrati, "maybe it's enough to have a bare-metal stent with a good drug on it."

 

Yes... Bull vs Bear tussle... 

But I think bears have the upper hand now...