Medical Device Daily Associate

After an odyssey of six years, it appears that Cyberonics (Houston) will finally get U.S. approval for use of its Vagus Nerve Stimulation (VNS) therapy system in the treatment of recurrent treatment-resistant depression (TRD).

The FDA brought the company a step closer to attaining true “comeback kid“ status via an “approvable“ letter indicating that the device is eligible to be used as a long-term adjunctive treatment for patients over the age of 18 with chronic or recurrent TRD in a major depressive episode that has not responded to at least four adequate antidepressant treatments.

The company also said during a Thursday conference call to discuss the approvable letter that it expects to gain full approval from the FDA for the indication by May.

The VNS system is a pacemaker-like device implanted in the chest that delivers electrical impulses to the brain through an electrode attached to a nerve in the neck. Cyberonics already sells the system for reducing seizures from epilepsy in the U.S., having received approval for that indication in 1997.

“We believe that FDA's approvable decision could potentially prove to be a transforming event for 4 million Americans with TRD, 200,000 Americans with medically-refractory epilepsy and co-morbid depression, the neuromodulation industry and Cyberonics,“ said Skip Cummins, the company's president and CEO, during the conference call.

In the letter, the FDA indicated that final approval was conditional on final labeling, final protocols for a post-approval dosing optimization study and patient registry, satisfactory compliance with quality system regulations (QSR) and satisfactory resolution of any outstanding bioresearch monitoring issues.

“Cyberonics' goal is to resolve all remaining issues, receive final approval and properly scale our organization to support a potential TRD launch in late May at the annual APA [American Psychiatric Association] and biological psychiatry meeting,“ Cummins said.

He also noted that Cyberonics and the FDA already have agreed on the protocol synopses for the post-approval dosing study and patient registry. The full protocols will be submitted to FDA in the next several weeks, he said.

The FDA is reviewing the labeling, which includes the physician's and patient's manuals, and expects to complete that review in a timely manner. The company said it is aware of only one bioresearch monitoring issue and will work with the FDA to resolve that issue promptly.

Cyberonics also said it submitted its responses to an FDA warning letter, including a list of planned and already implemented corrective actions, on Jan. 21 and expects to meet with the Dallas District Office late this month to resolve any remaining QSR issues.

The FDA's approvable letter reversed its August 2004 rejection of the device (Medical Device Daily, Aug. 13, 2004) and represents a dramatic comeback for the company, which appeared to be reeling on the regulatory ropes, ripe for a knockout. That rejection, according to Cummins, marked the first time the agency had rejected an expedited review premarket approval supplement after one of its panels has given a recommendation for approval of such a device. Just three months earlier, the FDA's Neurological Devices Panel voted 5-2 to recommend the system for agency approval for the depression indication.

The agency's stated reasons for rejecting the approval included worsening depression, potential biases stemming from a non-randomized control and an inability to distinguish one-year VNS effects from placebo and concomitant treatment effects.

To add insult to injury, after Cyberonics' stock plunged on the news of the FDA rejection, rival Advanced Neuromodulation Systems (ANS; Plano, Texas) bought just under 15% of the company's shares and later offered to acquire the rest of the company. Cyberonics repeatedly rejected its rival's offer, and ANS finally withdrew the offer last October (MDD, Oct. 4, 2004).

If Cyberonics had been unable to convince the FDA to change its mind, the company probably would have had to conduct additional costly and time-consuming clinical trials.

If approved, the VNS system, which costs about $20,000, including surgical and hospital expenses, will be the first implantable device-based treatment for depression and the first treatment developed, studied and labeled specifically for patients with treatment-resistant depression. The device is the only product Cyberonics sells, and some analysts estimate the device's market for depression — about 4.4 million people in the U.S. alone for TRD — would be as much as 10 times larger than the one for epilepsy.

“If [the] FDA approves VNS for TRD, the U.S. VNS TRD market opportunity will likely become the largest of the neuromodulation market opportunities,“ said Cummins. He added that the TRD opportunity would more than double the estimated neuromodulation market “and attract the human, scientific and financial capital to accelerate the development of the overall industry.“

Cummins said that if the market expands tenfold as projected, his company has the potential to become the “first billon-dollar annual sales neuromodulation company.“

The Cyberonics VNS Therapy System was approved by the FDA in 1997 for use as an adjunctive therapy in reducing the frequency of seizures in adults and adolescents over 12 years of age with partial onset seizures that are refractory to antiepileptic medications.

The system also is approved for sale as a treatment for epilepsy in all the member countries of the European Economic Area, Canada, Australia and other markets.

VNS already is approved in the European Economic Area and Canada as a treatment for depression in patients with treatment-resistant or treatment-intolerant major depressive episodes, including unipolar depression and bipolar disorder (manic depression).

It is at various levels of investigational clinical study as a potential treatment for anxiety disorders, Alzheimer's disease, chronic headache/migraine and bulimia.