Abiomed (Danvers, Massachusetts) last month rolled out plans to develop a new line of ventricular-assist devices, suggesting both a return to its initial development effort and an "inflection point" in its progress with the AbioCor replacement heart program. The proposed expansion of the company's assist device line "is not a change in focus in terms of our overall mission, but a change in redirecting our resources in a more balanced way," said Ed Berger, PhD, vice president for strategic planning and policy. Berger told Cardiovascular Device Update that the VADs to be developed both build on the company's original BVS heart assist system and also will represent new generations of these devices. At least three devices are in the planning stages, the first to be an external assist device. Berger declined to provide details about the other devices in the development pipeline.

"Cash flow is a good thing," Berger said. "Finding ways to grow the heart assist side of our business is a good way to make our business stronger while we're ramping up the AbioCor." And he said that the company had reached an "inflection point in the AbioCor program" which will allow the broader effort in VADs to move forward. Besides unveiling this plan, the company gave more specifics on its plans for the AbioCor. It said it will file for a humanitarian device exemption (HDE) in mid-2004 rather than filing for a premarket approval (PMA) application. An HDE provides for treatment of a patient population of fewer than 4,000 per year, for which no approved alternative devices exist and for which the potential benefits outweigh the risks. Berger said the HDE application strategy is consistent with the company's vision of a controlled rollout for the AbioCor.

In other developments, the company reported the 10th implant of the AbioCor in March. Consistent with past practice, the company gave out no details concerning either the patient or the procedure and, at the same time, it announced even tighter control of information to be released about the ongoing trial, which is slated for the enrollment of 15 patients. With the death of one patient also occurring in March, two patients were still alive and supported by the AbioCor at month's end. "We are very pleased with the rate of enrollment in the AbioCor clinical trial since the beginning of the calendar year," said Dr. Robert Kung, Abiomed's chief scientific officer. "We believe we have recaptured the momentum lost in 2002 and are working diligently to maintain that momentum."

With the announcement of the 10th implant, Abiomed said it is changing the way in which trial information will be released to the public. "Going forward, Abiomed will be providing only monthly updates on the status of the clinical trial in order to keep our investors and the public informed of our progress," said Berger. He told CDU that these updates would include news of significant events that have occurred within a given month, and that it is the company's goal to eliminate special announcement of individual implants and or patient-specific events either positive or negative as they occur.

Berger said that the policy "is really what we would have hoped to have done from the very beginning of the clinical trial." However, he noted that the intense nature of public and media interest "really made it impossible in the early stages of the clinical trial to do that." He said that, early on, the news media obtained information prior to a decision by Abiomed or the hospitals to actually publicize an implant. In those situations, Berger said, "we were therefore sort of acting to keep rumors under control and to keep things accurate."

Medtronic eyes refractory angina relief

Recently, neurostimulation devices have emerged as a promising potential therapy for treating troubling diseases of the brain such as Parkinson's and Alzheimer's, as well as for such chronic clinical conditions as depression, anxiety and headaches. Medtronic (Minneapolis, Minnesota) has added another treatment to the growing list of potential applications, saying it has initiated a clinical study in the U.S. and Canada of neurostimulation for refractory angina pain, and more exciting forays into other cardiovascular therapy modalities could follow in the future.

The company said a 61-year-old man from Indianapolis, Indiana, recently became the first U.S. patient to be implanted with a neurostimulation system in Medtronic's STARTSTIM (Stimulation Therapy for Angina Refractory To Standard Treatments, Interventions and Medications) trial. Angina often is an emergency event requiring immediate attention. It affects an estimated 6.4 million Americans and usually results from coronary artery disease. Patients in the STARTSTIM trial, however, have an intractable form of chronic angina that can cause severe limitations on basic daily activities. According to Joe McGrath, a spokesperson for Medtronic, the use of neurostimulation for the treatment of refractory angina is not a new concept. He told CDU that this treatment "has been available in Europe for several years and also in Canada."

McGrath explained that the system delivers treatment via spinal chord stimulation. "The mechanism of action for neurostimulation as a treatment for chronic pain is to block the pain signals traveling through the spinal chord on their way to the brain, where pain is actually perceived." He said this same technology also has been used to treat chronic low back and leg pain for many years as well as a condition called complex regional pain syndrome (CRPS). So the angina therapy "is really just another application of neurostimulation to treat pain that's entering the spinal chord a little higher up." So the leads with the electrodes are placed "quite a bit lower" down the spine for the lower back and leg applications than they are in the angina pain indication. "That's just a reflection of where the pain signals are entering the spinal chord," he added.

The first U.S. implant, performed by Michael Turner, MD, at Indiana University Hospital, in association with Jeffrey Breall, MD, of the Krannert Institute of Cardiology at the Indiana University School of Medicine (also Indianapolis), marked the beginning of the STARTSTIM trial, approved by the FDA to evaluate the safety and efficacy of neurostimulation to treat the pain of severe, chronic angina that does not yield to traditional medications or standard surgical procedures. Scheduled to last about two years, the study is expected to involve more than 200 patients at 20 North American medical centers. There will be two arms in the study. One group of patients will be treated as soon after implant as possible with neurostimulation, while the other group will not. Both groups will get optimal medical therapy after three months, and the first results should be released after about six months.

McGrath said the study would use two of Medtronic's neurostimulation systems the Synergy Neurostimulation System and the Itrel 3 Neurostimulation System. The Synergy device is a dual-lead, dual-channel system that can accommodate two leads and the Itrel 3 can accommodate one lead. He said the Synergy would probably be used in the study in patients who had a more complex pain syndrome. Electrophysiologist and STARTSTIM principal investigator Douglas Zipes, MD, distinguished professor of medicine and director of the Krannert Institute of Cardiology, hailed the first implant. "Success in this clinical trial would solve a frustrating medical problem and enhance the lives of many patients whose quality of life is restricted by almost constant pain," he said.

According to results published in the Journal of the American College of Cardiology and the European Heart Journal, neurostimulation has shown promise in European studies where chronic angina patients unresponsive to other treatments have experienced pain relief with less medication and fewer visits to the emergency room. Zipes told CDU that while there have been implants in Europe, "the studies have not been prospective randomized [trials] as we're doing." To qualify for the study, he said that patients had to have Class III or IV angina as classified by the Canadian Cardiovascular Society, have significant coronary disease, be on maximal medical management and cannot be revascularizable. Basically, he said, these are patients who "have reached the end of their therapeutic rope to treat their angina." Aside from the primary endpoint of treadmill walk, he said his team also would be looking at quality-of-life issues

McGrath noted that the system couldn't be used to treat all people who suffer from angina, only those with a stable chronic condition. "There's a subset of angina pain patients whose pain is not serving any valuable purpose in terms of signaling that there is something else wrong. This is the kind of angina pain that is chronic and stable and refractory of medication that is not masking some other problem."

Medtronic and others also are working on expanded uses for neurostimulation technology. The company received an FDA clearance in January 2002 to use its Activa system to treat advanced stages of Parkinson's disease. The device serves as a pacemaker for the brain, delivering pulses of electrical stimulation to specific sites in the brain in order to manage the uncontrollable movements associated with the disease. Cyberonics (Houston, Texas), has developed a device that uses vagus nerve stimulation (VNS) to treat epilepsy. The company also is working on an application of the device for the treatment of depression in the U.S. (the device already is approved for sale in Europe and Canada for that application) as well as anxiety disorders, Alzheimer's and chronic headache.

Aside from the neurological applications, Zipes suggested that the use of neurostimulation might also have expanded utility in the treatment of other cardiovascular conditions. He said that he and his colleagues have published a paper that showed this type of spinal chord stimulation "increases vagal activity to the heart and reduces sympathetic activity to the heart." He said such a change was also antiarrhythmic, meaning it could have implications in the treatment of such conditions as ventricular tachycardia and ventricular fibrillation, "but that's not been established [yet]."

MIV Therapeutics to develop HAp coating

The large cardiovascular players have developed some big lead time in the drug-coated stent derby, but that isn't stopping other smaller players from leaping into the race and attempting to provide even better technologies. Thus, MIV Therapeutics (MIVT; Vancouver, British Columbia) reported last month that it has completed two agreements with the University of British Columbia (also Vancouver) to bring development of a hydroxyapatite coating (HAp) in-house, that coating material already part of an ongoing developmental collaboration between the two. The HAp material is bannered by MIVT as offering unique qualities as a coating for metal stents. In particular, it provides both a high level of biocompatibility and also a multi-layer approach to coating stents to provide controlled levels of porosity for drug elution. MIVT is saying that, in itself, HAp also offers a strong alternative to polymer matrices and drug coatings.

"Our coating is not a drug," said Alan Lindsey, president of MIVT, in differentiating his company's activities from those of Cordis (Miami Lakes, Florida), Boston Scientific (Natick, Massachusetts) and the other players in the competition to bring a drug-coated stent to market. Rather, he says HAp "resembles the coating on your bones" and that it is being developed in two phases: the first as a sole substance coating on a metal stent and then as a kind of matrix that can be combined with a drug to release the drug in a multi-layered manner.

The first phase will be directed toward a market which will be looking for a coated stent less expensive than the drug-coated versions, Lindsey said, while the second effort will attempt to integrate HAp with a drug-eluting system. Meanwhile, the company continues its efforts at the development of laser-cut stents. Late last year, it inked an agreement with a joint venture firm, Stentgenix the other partner in the venture being Endovasc (Montgomery, Texas) to supply it with stents. At the time of that announcement, Lindsey tended to position the company's stents as its main priority, but with the agreement with the University of British Columbia, he emphasizes its coating technology as the larger potential opportunity. The company's current emphasis is "on coatings and therapeutics we will be in the stent business, but our focus is to develop a coating that will be universally accepted," Lindsay says.

In its deal with the university, MIVT has obtained exclusive rights to the HAp technology and allowing the firm "to partner up or to end up with another attractive offer" for the system, he says. What UBC receives is the royalties on any commercialized products. UBC also retains the patent rights, Daniel Byrne, head of investor relations for MIVT, told CDU. As a result he said that the agreements "don't constitute a complete technology transfer, per se." The effect of the agreements "is bringing the product into our facility." A key advantage, Byrne adds, is that university researchers often have other priorities and "we won't have to be encumbered by scheduling conflicts with the university."

MITV's research and manufacturing facility offers 17,000 square feet of space, equipped to manufacture the company's laser-cut stents and also the HAp-coated stents. The move to in-house development of the coated stent product "has involved substantial investment in specialized coating equipment and included procurement and commissioning of modern coating chambers and a state-of-the-art industrial oven required to support HAp coating techniques," according to a company statement.

Lindsey describes HAp as a "ceramic-like" material that has not seen its full usefulness yet. "People have tried to develop this technology in the past and have not been able to successfully. It's always peeling or [too] brittle." What MIVT has done, he said, is to engineer a HAp coating that is so thin that it is invisible to the eye, covers a stent uniformly and maintains its protective integrity over the device when it expands or otherwise changes shape. "Stents are metal," he adds. "We believe that with this biocompatible coating it will prevent exposure of the metal to the artery."

While MIVT will use the material on its own stents and will continue to supply stents and HAp to Stentgenix Lindsey says the main opportunity is to provide the HAp technology to a broad range of other stent makers as well as to other device manufacturers in other sectors. The company is targeting receipt of a CE mark in 18 to 24 months "with protocols parallel to the FDA's," he says. Additional products for incorporation with drug/device applications will follow over the next three to four years.

Robotic surgical systems collaboration

Following close on the heels of its proposed merger with surgical robotics rival Computer Motion (Goleta, California), Intuitive Surgical (Sunnyvale, California) last month lined up an agreement with Medtronic's Cardiac Surgery division, a leading developer of minimally invasive cardiac surgical devices. The agreement involves initiatives on several fronts, including training, marketing and product development for cardiac stabilization devices used during beating-heart surgery.

As part of the agreement, Intuitive said it would transfer ownership of its EndoStabilizer System to Medtronic. The EndoStabilizer System is the world's first commercially available stabilization system designed for endoscopic cardiac surgery. The two companies also will embark on co-promotion activity within the field of endoscopic beating-heart surgical procedures in Europe, and following FDA clearance within the U.S., which is expected by the year's end.

Medtronic already has intellectual property in this area "and we didn't want to infringe on their property, so the logical thing to do was work together on this," Gong said. "They get to sell the stabilizer that we have designed and we both get to promote it. We want to be able to enable minimally invasive cardiac surgery using the da Vinci system, and that's what this product does. What [the stabilizer] does is it promotes the use of the da Vinci System." With its November 2002 approval for intracardiac mitral valve repair surgery, the da Vinci system is the only operative robotic system FDA-cleared for performing any type of cardiac surgery.