Medical Device Daily Associate

Two companies developing implantable neuromodulation technology systems reported results yesterday from a couple of preliminary studies.

Advanced Neuromodulation Systems (ANS; Plano, Texas) disclosed a small study that it said showed "promising results" for a method of deep brain stimulation (DBS) in the treatment of depression and Cyberonics (Houston) reported the publication of initial pilot study results from a study of its vagus nerve stimulation (VNS) therapy in patients with bulimia nervosa.

In the first piece of news, ANS reported the publication of an independent research paper in the neuroscience journal Neuron that it said showed promise in the use of its technology in the treatment of depression.

The paper, authored by what it termed "noted clinical researchers" including the inventors of the technology, reported "a striking and sustained remission of depression in four of six patients." ANS acquired the exclusive rights to this intellectual property over a year ago, it said.

The six-month research study, conducted by the investigators at the University of Toronto, independent of participation by or funding from ANS, ANS said, was based on the preliminary observations that a particular region of the brain (the subgenual cingulate region, or Broadmann area 25) is metabolically overactive in treatment-resistant depression.

The investigators studied whether electrical stimulation of the region could reduce the elevated activity and produce clinical benefit. Six patients with refractory depression were implanted and followed for six months.

The study showed that continuous stimulation of these specific brain structures demonstrated that high-frequency DBS of the target area can produce anti-depressive changes in patients with treatment-resistant depression. In addition, the researchers found that "sustained clinical improvement decreased with blinded discontinuation of chronic DBS and were recaptured with reinstitution of stimulation, providing evidence as to the specificity of DBS-mediated changes."

The investigators noted that the antidepressant effects were accompanied by a marked reduction in local cerebral blood flow as well as changes in downstream limbic and cortical sites, as measured using PET scans – meaning that the effects of stimulation can be visually observed and recorded. The investigators stated that the study suggests that disrupting brain circuitry in this region by using electrical stimulation "can effectively reverse symptoms in otherwise treatment-resistent depression [TRD]."

TRD is a disabling disorder with no proven treatment options once multiple medications, psychotherapy and electroconvulsive therapy have failed, according to ANS.

Despite the encouraging results reported in the Neuron article, there were noted limitations to this first study of DBS for TRD. Sample size was small, follow-up was limited and no sham surgery or systematic placebo control arm was used. There were also limitations on identifying markers that might predict response. Differences in electrode targeting and placement may have also contributed to the observed response variance. The mechanisms of action of DBS are incompletely understood.

"We will be quick to caution that these results cover only six patients, follow-up was limited, and no sham surgery or systematic placebo control arm was used," said Chris Chavez, president and CEO of ANS. He said that despite these and the other limitations in this study, "the response rate in these patients is striking given their extreme resistance to other treatments and the well-documented low placebo response in these patients. What is particularly impressive is the sustained response in four of the six patients."

Based on what he called "the strength of this research," Chavez said ANS will pursue a feasibility study to further evaluate the clinical benefit of electrical stimulating Broadmann area 25 in TRD. Additionally, he said that if the expanded study "continues to impress," ANS intends to pursue a pivotal trial for this application.

With regards to competitor Cyberonics' recent panel recommendation for use of its VNS technology as a long-term adjunctive treatment for certain TRD patients (Medical Device Daily, Feb. 4, 2004), Chavez said his company believes that milestone is a "major step forward in the development of neurostimulation as a treatment for this indication." He added: "We intend to learn from Cyberonics' experiences with the FDA and benefit from them as we pursue a DBS therapy."

In the other study, researchers from the University of Minnesota's (Minneapolis) Neuroscience Research Center used Cyberonics' VNS therapy in a pilot study of patients with bulimia nervosa. The study was designed to evaluate VNS therapy's ability to reduce the episodes of bingeing and vomiting, the hallmarks of bulimia, by reversing the physiological changes that occur in vagus nerve function.

The National Institutes of Health (Bethesda, Maryland) provided a $300,000 grant to the University of Minnesota to fund the study. To date, six patients have been treated with VNS therapy. All reported significant reductions in episodes of bingeing/vomiting.

According to Patricia Faris, PhD, associate professor and the principal investigator, "All six patients have experienced dramatic results. What's most impressive about these early results is that the women taking part had severe bulimia and had not responded to numerous traditional treatments. If these results hold up in a larger study, this will be the first real hope for severely ill individuals to have a complete remission of symptoms."

Skip Cummins, CEO and chairman of Cyberonics, said, "Part of Cyberonics' plan to accomplish that mission and become the neuromodulation market leader following final depression approval is to accelerate the development of several new patent-protected VNS indications."

To date, he said the company has completed or has underway several pilot studies in potential new VNS indications such as Alzheimer's Disease, anxiety, chronic headache and bulimia.