Medical Device Daily Contributing Writer

SAN DIEGO – With the beginning of baseball spring training, we are reminded that it is a new year, full of hopes and dreams that this will be the year when our team becomes a winner.

Similarly, each year at about the same time as spring training begins, the annual International Stroke Conference, sponsored by the American Heart Association (Dallas) takes place, amid hopes that perhaps a much-needed "magic bullet" for stroke therapy will be unveiled.

However, stroke is an extraordinarily complex and heterogeneous disease and it is inconceivable that one approach could singlehandedly provide a solution. Nevertheless, several positive signs of progress were seen here at this year's meeting, although the stroke community remains frustrated that the pace is not quicker.

Acute ischemic stroke (AIS), which accounts for about 85% of the approximately 750,000 strokes that occur annually in the U.S. is severely hampered by a treatment "window of opportunity" that is frustratingly narrow. The only FDA-approved AIS drug, tPA, has a three-hour window.

Because of its previously demonstrated success in treating stroke patients far beyond the current short time window, the results of the NeuroThera Effectiveness and Safety Trial-2 (NEST-2) were eagerly anticipated by the stroke community. They were released last Friday at the last session of the conference, which was titled "Sample of the Best Science of the International Stroke Conference."

Justin Zivin, MD, professor of neurosciences at the University of California San Diego and the principal investigator for the NEST-2 study presented the results, which also were published online last Friday in the February edition of Stroke: Journal of the American Heart Association in an article titled "Effectiveness and Safety of a Transcranial Laser Therapy for Acute Ischemic Stroke."

The article, authored by Zivin and the other NEST-2 investigators, referred to an "urgent unmet need" for stroke therapies that could be administered for an extended period after stroke onset and noted that despite the availability of tPA and newer mechanical thrombectomy catheters that can capture cerebral clots, "fewer than 4% of patients receive any therapy ..."

The developer of the technology, privately-owned, venture capital-backed PhotoThera (Carlsbad, California), had released very promising data from its 120-patient international feasibility trial at this same conference two years ago. Very importantly and impressively, it provided initial evidence of excellent efficacy in a patient population with a mean time to treatment of over 16 hours, with a few patients being treated successfully as far out as 24 hours.

NEST-2 enrolled 660 patients at 53 sites in four countries between January 2007 and April 2008 in a randomized, double-blind, sham-controlled trial. The primary endpoint was a favorable 90-day score of 0-2 using the modified Rankin Scale (mRS). The mRS is a widely used and well-accepted scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke.

Patients were eligible for inclusion in the study if they were between 40 and 90 years of age, had moderate to severe strokes and had not received tPA. Initiation of treatment had to occur within 24 hours after stroke onset.

NEST-2 did not meet its primary endpoint, with a favorable outcome in about 36% of treated patients compared to 31% of patients in the sham group. The mean time to treatment was more than 14 hours. Mortality rates and serious adverse events did not differ between groups, which provided evidence that the procedure is safe. This safety profile had been clearly demonstrated in the earlier, smaller trial.

A post-hoc sub-group analysis of 434 patients who suffered moderate to moderately severe strokes did reveal a favorable outcome in about 52% of patients in the treated group compared to 42% of patients in the sham group. This 10% treatment effect differential was statistically significant and lends credence that it has the potential for significant success in select patient groups.

The procedure, which is sometimes referred to as transcranial laser therapy (TLT), features the non-invasive delivery of 808 nanometers of near-infrared (NIR) laser energy into the brain. The device consists of a mobile cart, a fiber optic cable and a handpiece that a clinician uses to direct the laser energy to 20 pre-determined treatment sites on the scalp. It delivers the laser energy at a controlled power density, in combination with a thermal management system to prevent heat buildup on the patient's head. Each site is treated for about two minutes, with the total procedure lasting about an hour.

The precise mechanism of action of TLT is not fully understood. Possibly the most plausible theory is that cytochrome c oxidase, a photoreceptor in the mitochondria, absorbs the NIR laser energy and drives adenosine triphosphate formation. The effects of the therapy may include improved energy metabolism, the prevention of apoptosis (cell death) and the enhancement of neuro-recovery mechanisms.

In the Stroke article, the authors speculated that near-infrared laser energy may have an anti-apoptotic effect and also that "it is possible that TLT acts in a neuroprotective fashion." Neuroprotection has been one of the Holy Grails in the ischemic stroke field for many years. It has been estimated that nearly 100 neuroprotective compounds have been tried in humans and all have failed to provide meaningful benefit.

In an interview with Medical Device Daily, Zivin said that despite the failure of NEST-2 in meeting its primary endpoint, TLT is "as promising a device technology as I've ever seen for treating acute ischemic stroke."

Werner Hacke, MD, chairman of neurology at the University of Heidelberg (Heidelberg, Germany), who participated in NEST-2 and will be more involved in the future, was equally enthused.

"TLT is one of the most promising new therapies that we've seen in a long time," he said, "especially as it may expand the treatment window for acute ischemic stroke to 24 hours."

PhotoThera is planning to initiate another TLT trial, called NEST-3 later this year. It is expected to enroll about 1,000 patients with some revisions in the entry criteria vs. NEST-2.

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