It's been a rough year for Northstar Neuroscience (Seattle) – from January when its lead stroke therapy failed in a clinical trial to July when a major shareholder pressured the company to either sell or liquidate – but perhaps the tide is about to turn.

Northstar said in mid-October that the FDA had granted conditional approval of a second clinical study of its Renova cortical stimulation system for the treatment of major depressive disorder. With this approval, the company said it expects to begin enrolling patients into its PROSPECT II study this quarter, with preliminary results anticipated during the second half of 2009.

The approval came less than three months after Northstar said it would move away from stroke rehabilitation therapy and instead focus on its cortical stimulation for depression, putting all other clinical programs on hold.

The PROSPECT II study is a prospective, double-blinded, sham-controlled study designed to build on the positive safety profile and promising efficacy observed in the PROSPECT I feasibility trial, Northstar said. The trial will be conducted at up to six sites and will include up to 24 subjects.

"Major depressive disorder affects millions of people who are not adequately treated today and who suffer greatly. Targeted stimulation of the cerebral cortex has shown promise in relieving depressive symptoms where drugs and other therapies have not been effective," said President/CEO John Bowers. "This is an important milestone for our depression program, and we are excited to move forward with our clinical collaborators to begin study enrollment."

Cortical stimulation involves a neurosurgical procedure to place an electrode – which he describes as a flat and flexible device "a little bigger than a postage stamp" – over the outermost layer of the brain, called the cerebral cortex. The electrode is then connected via a lead wire to a neurostimulator in the patient's chest. The pacemaker-sized neurostimulator and lead wire are implanted under the skin and are capable of continuously delivering electrical stimulation to the brain, Northstar said.

"The objective is to be able to provide very precise targeted stimulation and be able to provide stimulation on a continual basis," Bowers told Biomedical Business & Technology.

He said Northstar is targeting the area of the brain that regulates things like feelings and decision-making. In the brains of people suffering from severe, intractable depression, he said, the activities that are frequently seen in that area is different from the activities seen in the same area of a healthy person's brain.

"We're looking to intervene in a really targeted way to that area of the brain to affect neuroactivity," Bowers said.

In August, when the company reported that it was dropping its clinical work on stroke to focus on depression, Bowers told analysts during a conference call that the company had conducted a "thorough evaluation" of its clinical opportunities and that "based on our findings, we determined that increasing focus on our existing depression program and putting our other clinical programs on hold is the best course to achieving a viable therapy for the millions of patients suffering from treatment resistant depression, while also conserving our financial assets and striving to enhance overall shareholder value."

In July Northstar turned down an unsolicited takeover bid from Tang Capital Partners (San Francisco) that valued the company at $58 million. Then, RA Capital Biotech Fund (Boston), in a letter, asked Northstar either to find a buyer or make a cash distribution.

The company's value fell after its lead therapy – which sought to stimulate the brain to improve motion in stroke survivors – failed in a clinical trial in January.

Bowers told BB&T that the "huge clinical need" for a new depression therapy makes it an important area of focus, and he noted results from the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study, funded by the National Institute of Mental Health, which found that 33% of all depressed patients do not have satisfactory sustained responses after four antidepressant treatments. The STAR*D trial, which evaluated more than 4,000 depressed patients, is known as the largest clinical study for depression ever conducted in the U.S.

Another treatment option that just became available earlier in October from a private company, Neuronetics (Malvern, Pennsylvania) is a device that uses transcranial magnetic stimulation (TMS) to treat major depressive disorder when antidepressant medication fails to work. Neuronetics said last week that the FDA has cleared its NeuroStar TMS system for the treatment of depression.

The obvious difference between the two therapies is that one involves a series of 40-minute treatment sessions in a psychiatrist's office in which the doctor uses a coil to deliver magnetic pulses to the patient's brain, while the other involves a permanently implanted brain "pacemaker."

Another less-obvious difference is the patient population. The NeuroStar device is available to patients who have failed to achieve satisfactory improvement from one prior antidepressant medication or above at or above the minimal effective dose and duration in the current episode. The inclusion criteria for Northstar's PROSPECT II trial are even more selective. "To be included in this study, patients need to have failed four previous therapies," Bowers said.

Magnetic device cleared for depression

Also working in the depression segment is privately-held Neuronetics (Malvern, Pennsylvania), which last month received FDA clearance of its NeuroStar TMS (transcranial magnetic stimulation) system for the treatment of depression.

Mark Demitrack, MD, chief medical officer at Neuronetics, told BB&T that there were primarily two driving factors behind the development of the NeuroStar system.

"One is, quite frankly, the fact that major depression as an illness is an illness that remains substantially underserved," Demitrack said.

Most patients treated with pharmaceutical antidepressants don't get better, Demitrack said. In fact, he added, only one in three patients treated with pharmaceutical antidepressants do get better. He said side effects and intolerability is a big reason why these drugs don't work for many patients, while a significant number don't work simply because they don't work.

"Usually what the doctor will do is attempt to mix and match treatments, it's a trial and error, often months will elapse and a patient is still in middle of an illness," Demitrack said.

Another major driving force behind the development of NeuroStar, he said, is the fact that the therapy is noninvasive (no surgery required) and non-systemic – meaning it doesn't circulate the blood so patients don't experience the array of side effects that often accompany pharmaceutical antidepressants, such as weight gain and sexual dysfunction.

The NeuroStar system consists of power electronics, a touch-screen control panel, an electromagnetic coil, a single-use treatment link that is placed between the coil and the patient's scalp, and a treatment chair that looks a lot like a dentist's chair. During a treatment session the TMS coil is placed over the patient's left pre-frontal cortex – an area of the brain involved in mood regulation – and repeatedly energized. Each time the coil is energized an MRI-strength magnetic pulse enters the cortex and briefly introduces an electric current to flow, according to Neuronetics.

The treatment, prescribed by a psychiatrist, is usually administered daily for four to six weeks in a psychiatrist's office. Each treatment session lasts about 40 minutes, the company noted.

The NeuroStar system is indicated for the treatment of major depressive disorder in adult patients who have failed to achieve satisfactory improvement from one prior antidepressant medication at or above the minimal effective dose and duration in the current episode.

"Depression is a debilitating illness, and existing treatment options are frequently ineffective or intolerable due to side effects," said Bruce Shook, president/CEO of Neuronetics. "The availability of NeuroStar TMS therapy means that patients suffering from this disease now have an entirely new non-systemic and non-invasive treatment option that has been proven safe and effective."

CartiMesh may be next best knee repair

Among the emerging technologies and companies featured at the late-September Georgia Life Sciences Summit was an innovative living implant for healing damaged knee cartilage — a concept pioneered by Genzyme (Cambridge, Massachusetts) with its cell therapy known as Carticel. But researchers from Georgia Institute of Technology (Georgia Tech; Atlanta) have added a nanotechnology enabled twist to the concept, producing what could be the next best solution for millions of aching knees.

"We came up with this idea because of the Carticel products from Genzyme," Yash Kolambkar, a PhD candidate at Georgia Tech and co-inventor of CartiMesh, told BB&T. "The problems associated with Carticel are that you don't know how long the solution of cells stays there. We use a nanofiber mesh — a thin membrane to cover the defect site and keep it in place to create a dual-layered construct."

Damage to knee cartilage — caused by injury, obesity or simply repetitive use over time (aka, getting older) — is permanent and leads to osteoarthritis, since that tissue has little capacity to regenerate. Until now, that is, with a little help from science.

CartiMesh consists of engineered tissue integrated with a biodegradable polymeric scaffold. To create the implant, articular cartilage cells are first isolated from either the patient's own cartilage or from a donor. Cells are then culture-expanded to the large numbers necessary for the implant. Then the cells are seeded on electrospun nanofiber meshes and cultured with certain biochemical cues for two weeks.

The meshes are scaffolds that mimic the extracellular matrix to which the cells in the body are accustomed. At the end of the culture period, the resulting CartiMesh is a dual-layered construct with a layer of cartilaginous tissue produced by the cells and a layer of nanofiber mesh with strong mechanical integration of the two layers.

"Even if we use donor cartilage cells, no specific processing is required because cartilage is immune-privileged tissue, eliminating rejection issues." Kolambkar said. "Nanofiber mesh has been around a long time. We just invented the dual construct."

Genzyme's Carticel uses a procedure known as autologous chondrocyte implantation (ACI) and was the first cell therapy to be approved by the FDA in the mid-1990s. It is used by orthopedic surgeons to treat patients who have clinically significant articular cartilage lesions on the thigh bone part of the knee caused by acute or repetitive trauma that have not responded to a prior cartilage repair procedure.

The surgeon provides Genzyme with a biopsy of healthy cartilage taken from a patient's knee in an arthroscopic procedure. Technicians at Genzyme's cell culture lab then grow millions of cells from the biopsy, and the cells then are delivered to the hospital, where the surgeon implants them into the patient's knee defect.

Studies had indicated good results for a term of up to seven years, but longer-term data on Carticel is still in the works.

FDA approves Gore's EMBOLDEN study

W. L. Gore & Associates (Flagstaff, Arizona) said in mid-October that the FDA had approved its EMBOLDEN study to evaluate the safety and efficacy of its Embolic Filter for neuroprotection during carotid artery stenting (CAS) in high-risk patients. The primary endpoint is a composite major adverse event rate of death, stroke, and heart attack at 30 days post-procedure, Gore said.

"In the EMBOLDEN clinical study, we will continue to advance carotid stenting and improve care for patients with carotid disease," said William Gray, MD, of Columbia University Medical Center (New York), national principal investigator for the study. "Based on the demonstrated filter efficiency of the GORE Embolic Filter, we hope to produce positive results and progress the field even further."

EMBOLDEN is a prospective, multi-center, non-randomized, single-arm study. The study will enroll about 250 patients, which is expected to take between 18 and 24 months, Donald Harkness, leader for clinical affairs stroke interventions at Gore, told BB&T.

While some patients have a relatively straight artery that virtually any embolic filter can easily be maneuvered through, he said it is "not terribly unusual" to encounter some "twists and turns" in the vessel. That's where Gore believes its device will stand out against the competition, he said. "We think that it tracks very well through tortuous anatomy," Harkness said. The difference, he noted, is in the design of the device.

"The Gore Embolic Filter enhances traditional filter designs by using a unique diamond frame to minimize the risk of emboli passing between the filter frame and the vessel wall, even in tortuous anatomy," said Mary Mulder, PhD, product specialist at the company. "To take full advantage of improved filter efficiency, the filter is designed to easily navigate tortuous vessels with small landing zones and tight curves, similar to a bare guidewire."

Gore says its Embolic Filter joins its "unique flow reversal technology" to augment its carotid embolic protection solutions.

"The Gore Embolic Filter is a promising addition to Gore's expanding carotid portfolio. Having multiple embolic protection options will allow clinicians to customize the neuroprotection decision for each CAS patient," Gray said.

Datascope wins appeal on patent

A federal judge overturned a patent infringement lawsuit early last month that does not seem to have set any resounding precedents for future legal scholars to scrutinize, but the decision seems to suggest that a claim of infringement had better involve devices that at least look somewhat alike in order to survive an appeal.

In an Oct. 2 decision, a majority of judges in the U.S. Court of Appeals for the Federal Circuit in Washington kicked back to a lower court a suit filed against Datascope (Montvale, New Jersey) by Johns Hopkins University (Baltimore) and Arrow International (Reading, Pennsylvania) over a device used to fragment blood clots during dialysis procedures.

Writing for the 2-1 majority, Judge Rya Zobel wrote that the jury's finding of infringement in the first trial "was not supported by substantial evidence," citing contradictory testimony offered by an expert witness hired by the plaintiff.

The lower court had awarded about $460,000 to Arrow and about $230,000 to Hopkins as a result of the jury's verdict.

According to court documents, Hopkins was the owner and Arrow the licensee of a trio of patents for a "percutaneous mechanical fragmentation catheter system" involving "a fragmentation cage or basket at the distal end of the catheter [that] expands to conform to the inner lumen of the vascular conduit." Upon deployment, the device's "fragmentation cage is rotated at a speed high enough to homogenize the thrombotic material obstructing the vascular conduit."

Datascope, which was defending its ProLumen product, argued that its device was not identical by pointing out that the ProLumen "uses a single 'S' shaped wire, which is rotated to break up thrombotic material." In her opinion, Zobel wrote that the plaintiff's case was based partly on the requirement of the lawsuit that the debris-removing part of the device "expand to conform" to the geometry of the blood vessel prior to rotating to debride the blockage.