Brivaracetam Phase IIb Studies As Adjunctive Treatment In Partial-Onset Epilepsy Show Promising Results

Main Category: Epilepsy
Also Included In: Clinical Trials / Drug Trials
Article Date: 14 Jul 2007 - 1:00 PDT

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Results from two phase IIb, double blind, randomized, parallel-group, placebo controlled dose ranging studies examining brivaracetam as adjunctive therapy in refractory partial-onset epilepsy were reported this week at the 27th International Epilepsy Congress (IEC) in Singapore 1,2. These phase IIb studies confirmed high responder rates and placebo-like tolerability for brivaracetam.

In one phase II trial (N01193) 208 patients1, aged 16-65 years, whose partial-onset epilepsy was uncontrolled on one or two concomitant AEDs1, the frequency of weekly partial-onset seizures was significantly reduced in a dose-dependent way with brivaracetam 5mg-50mg/day1.

In patients treated with brivaracetam 50mg/day for 7 weeks, there was a median 53.1% (p<0.001) reduction in partial-onset seizure frequency from baseline, compared to reductions of 42.6% (p=0.014), 29.9% (p=0.086) and 21.7% with brivaracetam 20mg/day, 5mg/day and placebo respectively1. With brivaracetam 50mg/day, 55.8% (p<0.001) of patients were classed as responders (achieving a 50% reduction in seizure frequency), and 7.7% of patients were seizure free during treatment. This compared with 16.7% responders in the placebo group, and 1.9% seizure free.1

Brivaracetam was well tolerated at all doses, with a similar adverse event profile to that of placebo.1 The most commonly reported adverse events were headache, somnolence, influenza, dizziness, neutropenia and fatigue1.

"Today treatment-resistant patients make up about one third of the total epilepsy population. We need the continued development of new antiepileptic drugs to address the needs of these people with epilepsy. The developmental compound brivaracetam demonstrated a good balance of efficacy and tolerability in Phase II studies and we now look forward to the Phase III results." said Professor Jacqueline French, from Penn Epilepsy Centre, University of Pennsylvania, Philadelphia, USA.

In the second phase II trial (N01114) in 157 patients2 (aged 16-65 years) with refractory partial-onset epilepsy2, brivaracetam 50 mg/day showed a 38.2% (p=0.017) median reduction in partial-onset seizures from baseline during the 7 week maintenance period of the study, compared to reductions of 30% (p=0.113) and 18.9% with brivaracetam 150mg and placebo respectively 2. In this study, increasing the dose to 150 mg/day did not add therapeutic efficacy.

With brivaracetam 50mg/day, 39.6% of patients were responders and 9.4% became seizure free. This compared with 23.1% and 1.9% respectively in the placebo group.2 The tolerability profile for brivaracetam was similar to that of placebo.2 The most commonly reported adverse events were headache, fatigue and nausea, nasopharyngitis, somnolence and dizziness2.

"The efficacy of brivaracetam which we saw in these Phase II trials is promising especially as these studies included patients who had not achieved seizure control with Keppra®. In addition, the tolerability profile was favourable at all doses studied. We look forward to advancing to Phase III studies within the coming months." said Dr Peter Verdru, Vice-President, Clinical Research, Neurology/Psychiatry, UCB.

Brivaracetam has distinct pharmacological differences as well as having some structural similarity to Keppra®. In preclinical studies brivaracetam was shown to have a 10-fold higher affinity for synaptic vesicle protein 2A (SV2A) than Keppra®3. Brivaracetam also has inhibitory activity at neuronal voltage-dependent sodium channels whose abnormal function is understood to contribute to electrical discharges associated with seizures4.These differences may be important for brivaracetam's antiepileptic activity, clinical efficacy and tolerability.

About UCB Pharma SA

Headquartered in Brussels (Belgium), UCB Pharma SA (www.ucb-group.com) is a leading global biopharmaceutical company dedicated to the research, development and commercialisation of innovative pharmaceutical and biotechnology products in the fields of central nervous system disorders, allergy/respiratory diseases, immune and inflammatory disorders and oncology - UCB focuses on securing a leading position in severe disease categories. Employing more than 8400 people in over 40 countries, UCB achieved revenue of 2.5 billion euro in 2006. UCB is listed on the Euronext Brussels Exchange and owns 87.6% of Schwarz Pharma.

http://www.ucb-group.com

References

1. French JA, von Rosenstiel P on behalf of the Brivaracetam NO1193 Study Group. Efficacy and tolerability of 5, 20 and 50mg/day brivaracetam (ucb 34714) as adjunctive treatment in adults with refractory partial-onset seizures. Presented at the 27th International Epilepsy Congress, Singapore, 8-12 July 2007.

2. van Paesschen W, von Rosenstiel P on behalf of the Brivaracetam NO1114 Study Group. Efficacy and tolerability of 50 and 150 mg/day brivaracetam (ucb 34714) as adjunctive treatment in adults with refractory partial-onset epilepsy. Presented at the 27th International Epilepsy Congress, Singapore, 8-12 July 2007

3. Kenda BM, Matagne AC, Talaga PE et al. Discovery of 4-substituted pyrrolidone butanamides as new agents with significant antiepileptic activity. J Med Chem 2004; 47: 530-549.

4. Zona C, Pieri M, Klitgaard H et al. UCB 34714 (brivaracetam) a new pyrrolidone derivative inhibits Na2+ currents in rat cortical neurons in culture. Presented at the 58th Annual Meeting of the American Epilepsy Society, New Orleans, 2004.

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