BB&T European Editor and Staff Reports

PARIS — There is a lot of talk among medical device makers about the increasingly tough requirements of the FDA for product approval.

In January, PriceWaterhouse Coopers warned that the FDA's “capricious and complex“ approval process is discouraging entrepreneurs, causing them to launch new products elsewhere.

The “FDA attitude“ dominated discussion in December 2010 among the 80 CEOs gathered at the annual Bohemian Medical Device Summit, according to a participant, who said the preferred approach is increasingly to move company headquarters to Europe where a conformité Européen, or CE mark, is easier to win.

This approval in a “home market“ opens doors in emerging markets, especially China.

Still others say the effect of stringent and variable FDA rules for new products is to lock up the U.S. market for grandfathered products that never underwent the rigors of proof now required.

The trials and travails of Vexim (Toulouse, France), a small company with a potentially disruptive treatment for vertical compression fracture (VCF), sharply illustrates the difficulties.

Medtronic (Minneapolis) holds a lock on nearly 75% of the expanding market for VCF, estimated at $1.1 billion, thanks to a 2007 acquisition of Kyphon (Sunnyvale, California).

Kyphoplasty is a minimally invasive procedure where a space is created between verterbrae with the inflation of a balloon and a cement is injected to maintain this separation.

Vexim's SpineJack goes beyond kyphoplasty by restoring post-trauma vertebral height using a five millimeter adjustable titanium implant inserted through two skin incisions into a patient's vertebrae.

With a CE mark approval, SpineJack is sold by both Vexim and Stryker EMEA (Montreux, Switzerland) in Europe.

For the FDA, both SpineJack and kyphoplasty are in a category called vertebral augmentation products.

But where kyphoplasty's approval is grandfathered, SpineJack for the past two years has been subjected to increasingly more demanding scrutiny as a new product.

“We are now up to a requirement for a randomized comparative clinical trial of 450 patients that will cost between $20 million and $30 million,“ said Vexim CEO Bruce La Grange in an interview with BB&T.

“In September last year the FDA said we would need to show equivalence with kyphoplasty, but now they are asking that SpineJack demonstrate clinical superiority for approval,“ he said.

As a result of the delays, La Grange said the company's focus for SpineJack has shifted to rest-of-world (ROW) approvals and sales.

At the same time, the company is seeking FDA 510(k) approval for a “dumbed-down“ VCF product using its cohesion bone cement and an injector.

Though both the cement and the injector are already FDA-approved, the combination of the two elements into a procedure kit requires a new submission for approval.

Elsewhere in the world, SpineJack is gaining approvals, distribution and sales.

Vexim distributes direct in France and Switzerland.

The deal with Stryker, which covers Germany, the UK, Austria and Ireland, saw distribution begin in the second half of 2010, “and sales really got underway in September,“ said La Grange.

The partners sold $1.1 million in 4Q10, he reported.

A new version of the Spinejack implant has been approved in Europe, with Vexim offering a limited release to experienced surgeons.

In early 2010 Vexim signed a distribution agreement for Spain and Italy with MBA Group (West Yorkshire, UK) Europe's largest dealer for orthopedic products.

Portugal came on line for sales at the end of 2009.

Kayacan (Istanbul), a Stryker distributor, has begun distribution in Turkey.

Vexim began shipping Spinejack to South Africa at the end of 2010 and in March to Argentina.

La Grange said Vexim won regulatory approval in Brazil after a two-year process and is now negotiating for a distribution partner in Mexico.

The company recently completed regulatory requirements for India, he said.

These emerging markets are critical for the company's strategic plan.

Only 10% of the 1.4 million fractures reported each year are actually treated, creating a market potential of roughly $9 billion with greater availability for treatment, he said.

“Our strategy is simple,“ said La Grange, explaining the first circle of approach are CE countries, then a second circle of countries accepting the CE mark with additional local requirements, and finally a third circle of countries who take into consideration the CE mark but add a longer review and approval process.

“Moving further out the process becomes more complex for China and then the United States where we are looking at $30 million and between four and five years,“ he said.

Vexim has begun a pilot comparative study in Germany of 40 patients evenly divided between Spinejack and kyphoplasty to test the design of the anticipated FDA trial.

“Before pulling the trigger on $30 million, we want to validate the materials and methods,“ he explained.

Though frustrated by the delays for entering the world's most developed and lucrative market for VCF, La Grange remains confident.

A recently completed financing round of €2.5 million ($3.6 million) from historic investors provides a comfortable runway ahead of the investment that will be required for the FDA trial, he said.

Kuros regains rights from Baxter for KUR

Kuros (Zurich, Switzerland), a company that develops bioactive-biomaterial combination products for trauma, wound and spinal indications, said it has regained its rights to a number of clinical-stage trauma and spinal repair candidates previously licensed to Baxter (Deerfield, Illinois).

Kuros regained rights include the following product candidates: KUR-111, which has met its primary efficacy endpoint demonstrating non-inferiority to autograft in a 183 patient Phase II study in tibial plateau fracture patients; KUR-113 which is in an ongoing Phase II study in which KUR 113 in addition to standard of care was compared to the standard of care alone; and KUR-115 which is being prepared for clinical studies in spinal fusion patents.

Baxter and Kuros will continue to be partners in the development of KUR-211, a product for the treatment of chronic wounds which is currently in a large pan European Phase II study involving patients with diabetic foot ulcers, the company noted. The companies signed the original collaboration and license agreement in 2005.

“We were developing these products with Baxter . . . they got good results, the products haven't failed in any way but they decided this is not for them so we've regained the rights,“ Didier Cowling, CEO of Kuros, told BB&T in a phone interview from Zurich. “It's quite an important development.“

Cowling said that combination products such as the kind Kuros is developing are complex to manufacture and develop and regulatory authorities are still working out how to regulate them. “There are not that many players worldwide but I think that in the future it is going to be a very important area for therapeutics because it is the way our body's work,“ Cowling said. “That's how our bodies work and I think the device and drug industries have been very successful so far.“ He added that there is growing interest in these combination device and biologic products and soon it will be a sough-after market, “much the same way as drug eluting stents have taken the cardiovascular space by storm.“

The company spun out of the University of Zurich about 11 years ago, Cowling noted.

“Kuros now has rights to a portfolio of late stage clinical products with significant clinical efficacy and safety data following Kuros having regained the rights to these product candidates from Baxter. We look forward to developing them further so that both patients and clinicians can benefit from the advantages that they could offer in the treatment of a number of trauma and spine indications,“ Cowling said.

He told BB&Tthat regaining the rights to these product candidates did not come as a total surprise because last year Baxter returned rights to a similar product for soft tissue generation.

Kuros also reported recently that its KUR-113 met its primary efficacy endpoint in a 200 patient Phase IIb clinical trial designed to assess its efficacy and safety in open tibial shaft fracture patients. The primary endpoint of the study is the proportion of patients healed at six months after surgery, comparing KUR-113 in combination with standard of care to the standard of care alone. The use of KUR-113 is designed to improve fracture union and thus reduce the time needed to achieve bone healing as well as the incidence of secondary interventions, the company said.

The Phase II b study is a randomized, controlled, open-label (dose-blinded) dose finding study of the safety and efficacy of KUR-113 in the treatment of patients with acute open tibial shaft fractures. A total of 200 patients were randomized and treated in 31 centers across Europe.

In the intent-to-treat (ITT) population the healing rate at six months after surgery, as assessed by the investigators using radiographic and clinical criteria, was 65% for patients treated with standard of care alone vs. 76%, 80%, and 69% for the 0.133, 0.4 and 1.0 mg/ml KUR-113 groups respectively. In the per-protocol (PP) population, the healing rates were 63% in the standard of care alone group versus 74%, 83%, and 75% for the 0.133, 0.4 and 1.0 mg/ml KUR-113 groups respectively. For both analyses the 0.4 mg/ml group had significantly better healing than standard of care alone group. To date there are no indications of any safety issues, Kuros said. Analysis of the secondary endpoints is ongoing.

According to the company, KUR-113 uszes Kuros' TG-hook technology for binding biologics into a fibrin sealant. The product candidate is composed of a variant of parathyroid hormone (vPTH) and fibrin sealant and is applied directly to the fracture site in the form of a paste. KUR-113 has been designed to deliver vPTH locally at the fracture site and to maintain this via the slow controlled release of vPTH over time from the fibrin matrix. The fibrin matrix also plays a further important role in the bone healing process by providing a physical scaffold for cell ingrowth.

“We have now tested our fibrin–vPTH combination product technology in large Phase II studies in two different indications,“ Cowling said. “Both studies have met their primary endpoint generating further evidence of the efficacy of our TG-hook technology in general and more specifically of our bone regeneration product candidates. Kuros believes that the efficacy and the ease of application of these product candidates means that they could be of significant potential benefit to both patients and clinicians.“

MedShape gets CE mark for Morphix, ExoShape

MedShape Solutions (Atlanta) recently received CE mark approval for its Morphix anchor and ExoShape interference fixation device. The company said it is in discussions with third party distributors across the European region.

Morphix is a suture anchor manufactured from MedShape's shape memory PEEK Altera biomedical polymer. Suture anchors are commonly used in a variety of surgical procedures that require the reattachment of damaged or worn ligaments and tendons to bone. The device received FDA 510(k) clearance in September 2009 and has been fully commercially launched in the U.S.

The ExoShape interference fixation device also utilizes MedShape's PEEK Altera biomedical polymer to provide simple and secure tibial fixation of soft tissue grafts during anterior cruciate ligament reconstruction procedures. ExoShape received FDA 510(k) clearance for that device last November and it is currently being rolled out in a phased launch to select sports medicine surgeons across the U.S.

STAAR wins CE mark for Visian ICL

STAAR Surgical (Monrovia, California), a maker of ophthalmic lenses for refractive surgery, reported CE mark approval for its Visian implantable collamer lens (ICL) V4c design. The V4c design incorporates a proprietary port in the center of the ICL optic of a size determined to optimize the flow of fluid within the eye, and eliminates the need for the surgeon to perform a YAG peripheral iridotomy procedure days before the ICL implant. The result is more comfort for the patient and a more convenient, efficient ICL experience for both the patient and the surgeon, according to STAAR. Both myopic and myopic toric models of the ICL will feature the new design. The company has two issued patents on the technology to enhance flow within the eye and is pursuing additional claims to further broaden its IP position.

Cutera garners CE mark for Excel V system

Cutera (Brisbane, California), a provider of laser- and other energy-based aesthetic systems for practitioners worldwide, in May reported its CE-mark approval and European launch of the Excel V laser system. The Excel V laser system is a next-generation vascular workstation designed specifically for the core market of dermatologists and plastic surgeons.

“The Excel V has received strong interest among the dermatology community since its launch at the American Academy of Dermatology in February. The combination of new high-power green technology, with Cutera's Nd:YAG laser, provides the practitioner the ability to treat the full spectrum of vascular conditions, both superficial and deep. This is very important because vascular treatments are the cornerstone of a laser dermatologist's practice,“ said Kevin Connors, president/CEO of Cutera.

Wildcat now on the prowl in Europe with CE mark

Avinger (Redwood City, California) reported getting CE mark approval for Wildcat – a next-generation catheter used in endovascular procedures for the treatment of peripheral artery disease (PAD). In Europe, Wildcat is intended to create a channel in totally occluded peripheral vessels. The device may also be used to facilitate the placement of conventional guidewires beyond stenotic lesions (including sub and chronic total occlusions) in the peripheral vasculature prior to further percutaneous intervention.

“The CE mark approval for Wildcat is a huge step for Avinger and our dedication to helping the millions of afflicted PAD patients worldwide,“ said Avinger founder, CEO and interventional cardiologist John Simpson PhD, MD. “With the rate of PAD in Europe closely rivaling the U.S., more and more patients are confronted with the threat of amputation and quality-of-life issues resulting from invasive bypass surgery. We are thrilled to be one step closer to our goal of empowering physicians everywhere with the most advanced tools and technologies to perform the least invasive procedures for PAD sufferers around the globe.“

Avinger recently completed enrollment of the CONNECT (Chronic TOtal OcclusioN CrossiNg with thE WildCat CatheTer) study, an 88-patient IDE study evaluating Wildcat for crossing chronic total occlusions in femoropopliteal lesions, in support of a CTO indication. The CONNECT results were presented at this year's EuroPCR Conference in May by John Pigott, MD, of JOBST Vascular Institute (Toledo, Ohio).

The company will begin commercialization of Wildcat in select European countries by the end of 2Q11. Wildcat is commercially available as a guidewire support catheter in the U.S.