Positive results from trial of investigational anti-epilepsy drug Brivaracetam

UCB has announced data demonstrating that anti-epileptic drug (AED) brivaracetam, with the proposed trade name Rikelta, administered as an adjunctive treatment in adults with refractory epilepsy with partial onset seizures, significantly reduced seizure frequency and had a side-effect profile comparable to placebo.

The results of the two Phase IIb (Abstracts C.04 and 3.218), double-blind, randomized, parallel- group, placebo-controlled dose ranging studies were presented today as an oral platform presentation at the 61st annual meeting of the American Epilepsy Society.

"It is exciting to see the promising results that brivaracetam produced in this highly refractory population of epilepsy patients," said Jacqueline French, MD, lead study author and professor of neurology at New York University. "The development of novel anti-epilepsy drugs is vital to addressing the needs of treatment-resistant epilepsy patients. We look forward to seeing the results of our Phase III clinical research."

The two studies involved 365 patients, ages 16-65, with refractory partial onset seizures, which were uncontrolled despite treatment with one to two other AEDs. Patients in the first study (Abstract C.04) were randomized to receive 5 mg/day, 20 mg/day, 50 mg/day or placebo, administered twice-daily without titration over the seven week treatment period. The study found that brivaracetam reduced weekly seizure frequency over placebo by 9.8%, 14.9%, and 22.1% with doses of 5mg/day, 20 mg/day, and 50 mg/day, respectively, suggesting a dose response trend with brivaracetam 5 mg-50 mg/day.

An analysis of the study's secondary endpoints found that brivaracetam:

• Reduced median seizure frequency from baseline by 29.9%, 42.6% and 53.1% for 5mg/day, 20mg/day and 50mg/day, respectively, compared with 21.7% for placebo.
• Reduced weekly seizure frequency from baseline in 32.0%, 44.2% and 55.8% of patients, for 5mg/day, 20mg/day and 50mg/day, respectively, compared to 16.7% for placebo.
• Produced seizure freedom rates of 7.7% for 20 mg-50 mg/day, 8% for 5mg/day and 1.9% for placebo over the treatment period.

Patients in the second study (Abstract 3.218) were randomized to receive 50 mg/day, 150 mg/day, or placebo, administered twice-daily without titration over the 12 week treatment period. The findings for the study's primary endpoint-reduction in weekly seizure frequency over placebo-were not statistically significant. However, an analysis of the study's secondary endpoints demonstrated a clear difference between placebo and the 50 mg/day dose:

• The median difference versus placebo for the percent reduction from baseline in seizure frequency per week was 22.5%.
• There was at least a 50% reduction in weekly seizure frequency from baseline in 39.6% of patients, compared with 23.1% for placebo.
• Seizure freedom rates of 9.4% were seen for 50mg/day, compared with 1.9% for placebo.

Retention rates in both studies were high and similar to placebo, with up to 98% of patients in the treatment group completing the studies. The most commonly reported adverse events were nausea, vomiting, fatigue, nasopharyngitis, anorexia, convulsion, dizziness, headache, somnolence, and insomnia. A dose-response relationship was not observed for the majority of adverse events analyzed in the studies.

Phase III clinical trials of brivaracetam as adjunctive therapy in patients with refractory partial onset epilepsy are already underway. Nearly 1,300 epilepsy patients, ages 16-70, will take part in three multicenter, multinational phase III trials. Two randomized, double-blind, placebo- controlled studies are designed to evaluate the efficacy and safety of brivaracetam (5, 20 and 50 mg/day or 20, 50 and 100 mg/day) over 12 weeks in patients with partial onset epilepsy, not fully controlled despite treatment with one or two other antiepileptic drugs. The third study is a randomized, double-blind, placebo-controlled trial with flexible dosing designed to evaluate the safety and tolerability of brivaracetam in patients with uncontrolled partial onset or primary generalized seizures. First results of these studies are expected in mid 2009.

About Brivaracetam: Brivaracetam has distinct pharmacological differences as well as having some structural similarity to the AED Keppra(R) (levetiracetam). In preclinical studies brivaracetam was shown to have a 10- fold higher affinity for synaptic vesicle protein 2A (SV2A) than Keppra(R). Brivaracetam also has inhibitory activity at neuronal voltage-dependent sodium channels whose abnormal function is understood to contribute to electrical discharges associated with seizures. These differences may explain brivaracetam's antiepileptic activity, clinical efficacy and tolerability.

About Epilepsy: Epilepsy is a chronic neurological disorder affecting more than 2.5 million Americans regardless of race, age or sex. Between 70-80% of individuals are successfully treated with one of the more than 20 antiepileptic drugs now available. However, 20-30% of patients have either intractable or uncontrolled seizures or have significant adverse side effects secondary to medication, highlighting the ongoing need for the development of new antiepileptic drugs.

About Keppra(R) in the U.S.: Keppra(R) tablets and oral solution are indicated as adjunctive therapy in the treatment of partial onset seizures in adults and children 4 years of age and older with epilepsy, myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy, and primary generalized tonic-clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy. Keppra(R) injection is indicated as adjunctive therapy in the treatment of myoclonic seizures in JME and partial onset seizures in adults with epilepsy. Keppra(R)injection is an alternative for adult patients when oral administration is temporarily not feasible.

Keppra(R) tablets and oral solution are associated with the occurrence of central nervous system adverse events including somnolence and fatigue, behavioral abnormalities, and coordination difficulties, as well as hematological abnormalities. In pediatric patients 4 -16 years of age experiencing partial onset seizures, the most common adverse events associated with Keppra(R) in combination with other AEDs were somnolence, accidental injury, hostility, nervousness and asthenia. In adults experiencing partial onset seizures, the most common adverse events associated with Keppra(R) in combination with other AEDs were somnolence, asthenia, infection and dizziness. In patients 12 years of age and older experiencing myoclonic seizures with JME, the most common adverse events associated with Keppra(R) in combination with other AEDs were somnolence, neck pain, and pharyngitis. In patients 6 years of age and older experiencing PGTC seizures with idiopathic generalized epilepsy, the most common adverse event associated with Keppra(R) in combination with other AEDs was nasopharyngitis.

The adverse events that result from Keppra(R) injection use for myoclonic seizures in JME and partial onset seizures in adults include all of those associated with Keppra(R) tablets and oral solution.

Dosing for all Keppra(R) formulations must be individualized according to the patient's renal function status.