Medtronic Completes Implants in SANTE Trial of Deep Brain Stimulation for Epilepsy

Medtronic, Inc. (NYSE: MDT), today announced the completion of implants in its U.S. pivotal clinical study of deep brain stimulation (DBS) for the treatment of medically refractory epilepsy, a form of the neurological condition that does not respond to antiepileptic drugs. With 110 patients now implanted with the Intercept™ Epilepsy Control System, results of the study – the SANTE (Stimulation of the Anterior Nucleus of the Thalamus in Epilepsy) Trial – are expected to be available during 2008.

Ongoing at 17 medical centers in the United States, the SANTE Trial is using existing Medtronic DBS technology to determine whether bilateral stimulation of the anterior nucleus of the thalamus – the brain’s central message and relay station – can safely and effectively reduce seizure frequency in people with epilepsy. The same technology is approved for treating motor symptoms of Parkinson’s disease and essential tremor – the two most common movement disorders. It has been used by more than 40,000 people worldwide, however, Medtronic’s DBS therapy has not yet been approved for use in medically refractory epilepsy. Unlike other treatments that involve brain surgery, DBS therapy is non-destructive, adjustable and reversible.

All implanted patients in the SANTE Trial will be monitored for 13 months following implant, with long-term follow-up continuing until the device is approved for treating epilepsy or the study is stopped. Trial participants are adults with partial-onset epilepsy for whom at least three antiepileptic drugs have proven ineffective. (Individuals with partial-onset epilepsy have seizures that originate in a localized area of the brain.) To qualify for enrollment, study patients were required to have had an average of six or more seizures per month. They continue to receive their epilepsy medications while participating in the trial.

“Despite best medical management, a significant proportion of people with epilepsy continue to experience seizures that wreak havoc on their lives,” explained the trial’s principal investigator, Dr. Robert Fisher, professor of neurology and director of Stanford Epilepsy Center at Stanford University in Palo Alto, Calif. “For this underserved patient population, deep brain stimulation may represent a promising new treatment option.”

According to the Epilepsy Foundation, epilepsy and seizures affect more than three million Americans of all ages, at an estimated annual cost of $12.5 billion in direct and indirect costs. Despite trying a range of treatment options, about one-third of people with epilepsy continue to experience debilitating, recurring seizures – brief periods of abnormal electrical activity in the brain. The unpredictability of seizures affects daily activities and disrupts school days, work responsibilities and social functioning.

“The SANTE Trial is one of several major studies that Medtronic is sponsoring or supporting to establish compelling clinical evidence for approved and investigational applications of our neuromodulation technologies, which include implantable neurostimulation systems and site-specific drug-delivery systems,” said Dr. Richard E. Kuntz, M.D., senior vice president of Medtronic, Inc., and president of the Neuromodulation business unit. “With this latest milestone complete, we are one step closer to understanding the effectiveness of DBS therapy for patients with medically refractory epilepsy.”

Medtronic developed and leads the field of neuromodulation, the targeted and regulated delivery of electrical pulses and pharmaceuticals to specific sites in the nervous system. The company’s Neuromodulation business offers innovative therapies for chronic pain, movement disorders, spasticity, overactive bladder and urinary retention, benign prostatic hyperplasia, and gastroparesis.

ABOUT MEDTRONIC
Medtronic, Inc. (www.medtronic.com), headquartered in Minneapolis, is the global leader in medical technology – alleviating pain, restoring health, and extending life for millions of people around the world.

New data shows once a day Lamictal XR is effective in treating patients with partial seizures

Data from two clinical trials presented today at the American Academy of Neurology (AAN) meeting suggest that an investigational once daily extended re-lease formulation of Lamictal® (lamotrigine) is effective as add-on treatment in patients with partial epilepsy with and without secondary generalization. Lamictal XR Extended-Release Tablets are currently in development for the treatment of epilepsy. If approved, it will be the first extended release, new generation epilepsy treatment taken once-daily.


Data from the ARMOR study, an international, multi-center, randomized, double-blind, placebo-controlled trial, showed that the new once-daily, extended release formulation reduced partial seizures by 46 percent, while patients taking placebo experienced a reduction of 24 percent over the entire nineteen-week treatment period. The study also showed significant overall reduction in seizure frequency in both the escalation and maintenance treatment phases. In addition, the study showed that 42 percent of patients treated with Lamictal XR reduced their frequency of seizures by at least half by the end of the 19-week treatment period.


The second study, COMPASS, showed that patients could be switched from Lamictal® Immediate Release (IR) to Lamictal XR while maintaining comparable blood levels of lamotrigine.


“These data are important because they show that the extended release formulation of Lamictal reduces the frequency of seizures. The once daily dosing regimen may also provide a more convenient treatment option for patients,” said Dean Naritoku, M.D., Professor of Neurology and Pharmacology, Southern Illinois University, Springfield, IL. “In addition, when compared to Lamictal immediate release, given twice a day, the new investigational formulation demonstrated fewer daily fluctuations in serum concentration and more stable blood levels over time.”


About the ARMOR study
In the ARMOR study, patients naïve to Lamictal, thirteen years of age or older with uncontrolled partial seizures, taking a stable regimen of 1 or 2 AEDs were enrolled in an 8 week baseline phase. Patients having 8 or more partial seizures were randomized to receive either once daily Lamictal XR or placebo. The treatment period consisted of escalation (7 weeks) and maintenance phases (12 weeks) with dosing based on background AEDs. The primary endpoint was percentage change from baseline in weekly partial seizures during the entire treatment phase.


Of 326 patients enrolled, 236 were randomized and included in the intent-to-treat population (116 Lamictal XR, 120 placebo). The median percent decrease from baseline in all partial seizures was 46 percent compared to 24 percent for placebo during the entire treatment phase, 28 percent compared to 16 percent during the escalation phase of treatment and 58 percent com-pared to 27 percent during the maintenance phase of treatment.


Time to ≥50 percent reduction in seizure frequency was analyzed using a two sided log-rank statistic. In patients taking Lamictal XR, 42 percent achieved ≥50 percent reduction in seizure frequency at the end of the treatment period. The time to achieve and maintain ≥50 percent reduc-tion in seizure frequency with Lamictal XR was reached at day 18. During the twelve-week maintenance period, the percent of patients with 100 percent decrease from baseline partial sei-zures were 19 percent and 5 percent (Lamictal XR vs. placebo).


The most common (>5 percent) drug-related adverse events for Lamictal XR and placebo, respectively, were dizziness, 18 vs. 5 percent, headache, 17 vs. 15 percent, somnolence, 7 vs. 4 percent, nausea, 7 vs. 2 percent, and diarrhea, 7 vs. 4 percent. The non-serious rash rate was 2 percent for Lamictal XR and <1 percent for placebo. No serious rash was reported.


About the COMPASS study
The second trial (COMPASS) compared the pharmacokinetics of twice daily, immediate release Lamictal to once daily Lamictal XR in patients thirteen years of age and older with epilepsy. The open label, conversion study consisted of a 2 week base line phase with Lamictal immediate re-lease, a 2 week treatment phase with Lamictal XR and a 1 week treatment phase with Lamictal immediate release. The study outcomes included lamotrigine pharmacokinetics upon conversion and seizure frequency during each treatment phase.


Results showed the steady state trough concentrations for Lamictal XR were equivalent to or higher than those of Lamictal immediate release depending on concomitant AED. In addition, there was no change in the median weekly seizure frequency among the groups.


About epilepsy
Epilepsy, defined by recurrent unprovoked seizures, is a change in sensation, awareness, or behavior brought about by an electrical disturbance in the brain. The kind of seizure a person has depends on which part and how much of the brain is affected by the electrical disturbance that produces seizures. Generalized seizures are seizures that involve the entire brain from the outset. Partial seizures, which are more common, involve a restricted area of the brain. In approxi-mately 70 percent of cases, the cause of epilepsy is unknown. According to the Epilepsy Foundation, more than three million Americans of all ages are living with epilepsy.


About Lamictal Immediate Release (IR) formulation
Lamictal is indicated 1) as adjunctive therapy for partial seizures, primary generalized tonic-clonic seizures, and the generalized seizures of Lennox-Gastaut syndrome in adults and pediatric patients as young as 2 years and 2) for conversion to monotherapy in adults with partial seizures taking carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single AED.


Safety and effectiveness of Lamictal have not been established 1) as initial monotherapy, 2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate, 3) for simultaneous conversion to monotherapy from 2 or more con-comitant AEDs.


Lamictal is also approved for maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in adult patients treated for acute mood episodes with standard therapy. The effectiveness of Lamictal in the acute treatment of mood episodes has not been established.


Serious rashes requiring hospitalization and discontinuation of treatment have been reported in association with the use of Lamictal. The incidence of these rashes, which have included Stevens Johnson syndrome, is approximately 0.8 percent (8 per 1000) in pediatric patients under the age of 16 years receiving Lamictal as adjunctive therapy for epilepsy, and 0.3 percent (3 per 1000) in adults on adjunctive therapy for epilepsy. In clinical trials of bipolar and other mood disorders, the rate of serious rash was 0.08 percent of adult patients who received Lamictal as initial monotherapy and 0.13 percent of adult patients who received Lamictal as adjunctive therapy. In a prospectively followed cohort of 1,983 pediatric patients taking adjunctive Lamictal, there was one rash-related death.



About GlaxoSmithKline
GlaxoSmithKline, with U.S.operations in Philadelphia, P.A. and Research Triangle Park, N.C., is one of the world’s leading research-based pharmaceutical and healthcare companies. GlaxoSmithKline is committed to improving the quality of human life by enabling people to do more, feel better, and live longer. More information on GlaxoSmithKline is available at the company’s Web site at www.gsk.com