Primary data from Phase 3 study evaluating brivaracetam as adjunctive treatment of partial-onset seizures in epilepsy announced
UCB has announced the primary efficacy and safety data from the latest Phase 3 study evaluating brivaracetam (fixed doses of 100 and 200 mg/day with no up-titration) as adjunctive treatment in adult epilepsy patients with partial-onset seizures.1 This study with brivaracetam represents the largest Phase 3 study conducted in epilepsy patients with partial-onset seizures. Brivaracetam is an investigational antiepileptic drug (AED) and is not approved by any regulatory authority worldwide.
This study showed statistical significance for the two primary endpoints (p<0.001 for brivaracetam 100 and 200 mg/day). The primary efficacy endpoint in the US was the percent reduction in partial-onset seizure frequency per 28 days over placebo. The primary efficacy endpoint in the EU was the responder rate, i.e., the proportion of patients showing a 50% or greater reduction in partial-onset seizure frequency. The most frequent treatment-emergent adverse events were somnolence, dizziness and fatigue. Data was presented at the 68th Annual Meeting of the American Epilepsy Society in Seattle, Wash. (5-9 December 2014).1
“Improving the lives of people with epilepsy and addressing unmet medical needs is a priority for UCB. In our latest study, brivaracetam used as adjunctive therapy significantly reduced partial-onset seizure frequency for many patients. Over 80% of patients in this study had a history of taking two or more AEDs and almost half had a history of taking five or more AEDs,” said Professor Dr. Iris Loew-Friedrich, Chief Medical Officer and Executive Vice President UCB. “We are now focused on the next important step for brivaracetam with applications to US and EU regulatory authorities planned for early 2015.”
“This first presentation of primary study results from the latest Phase 3 brivaracetam study is anticipated by the epilepsy community. The two primary outcomes in this study evaluating adjunctive brivaracetam in the treatment of partial-onset seizures in adults with epilepsy were statistically significant and clinically relevant.” said Dr. Pavel Klein, Director, Mid-Atlantic Epilepsy and Sleep Center, Bethesda, MD.
- Both brivaracetam doses (100 and 200 mg/day) demonstrated statistically significant percent reductions in partial-onset seizure frequency per 28 days over placebo (22.8% [n=252] and 23.2% [n=249] for 100 and 200 mg/day, respectively, p<0.001)
- The 50% responder rate for brivaracetam 100 and 200 mg/day were 38.9% (98/252) and 37.8% (94/249), compared with 21.6% (56/259) for placebo, p<0.001 for both dose arms. The odds ratios vs. placebo were 2.39 (95% Confidence Interval: 1.6,3.6) and 2.19 (95% Confidence Interval:1.5,3.3) for brivaracetam 100 and 200 mg/day, respectively
- Treatment-emergent adverse events occurred in 68.4% (173/253) and 66.8% (167/250) of patients in the brivaracetam 100 and 200 mg/day groups, respectively, and in 59.4% (155/261) of patients in the placebo group
- The most commonly reported adverse events (?5%) for the combined brivaracetam groups (n=503) and the placebo group (n=261) were somnolence (18.1% vs. 7.7%), dizziness (12.3% vs. 5.0%), fatigue (9.5% vs. 3.8%) and headache (7.4% vs. 8.4%)
- Study-discontinuation rates (for any reason) were 11.4% and 10.4 % for brivaracetam 100 and 200 mg/day, respectively, vs. 6.5% for placebo
About the Phase 3 study1
This Phase 3, multicentre, randomized, double-blind, placebo-controlled study enrolled adults (?16-80 years) with refractory partial-onset seizures whether or not secondary generalized, and not fully controlled despite treatment with one or two concomitant AEDs. In the study, 768 epilepsy patients with partial-onset seizures, were randomized (1:1:1) to adjunctive brivaracetam (100 or 200 mg/day) or placebo for a 12-week Treatment Period after having completed an 8-week prospective Baseline Period. Patients taking levetiracetam, either as concomitant antiepileptic drug or within 90 days prior to Visit 1 were excluded. The primary efficacy outcome in the US was the percent reduction over placebo in 28-day adjusted partial-onset seizure frequency. The primary endpoint in the EU was the 50% responder rate based on percent reduction in partial-onset seizure frequency from Baseline to end of the Treatment Period.
About brivaracetam and the clinical development program
Discovered and developed by UCB, brivaracetam is a selective synaptic vesicle protein 2A ligand.2,3 The phase 3 clinical development plan for brivaracetam consisted of the following studies:
N01252: an evaluation of the efficacy and safety/tolerability of adjunctive brivaracetam 20, 50, and 100 mg/day compared with placebo over 12 weeks, in 399 randomized patients (16 to 70 years) with partial-onset seizures not fully controlled despite treatment with 1-2 concomitant AEDs.4
N01253: an evaluation of the efficacy and safety/tolerability of adjunctive brivaracetam at doses of 5, 20, and 50 mg/day compared with placebo over 12 weeks, in 400 randomized patients (16 to 70 years) with partial-onset seizures, not fully controlled despite treatment with 1-2 concomitant AEDs.5
N01254: an evaluation of the safety and tolerability of adjunctive brivaracetam given at individualized tailored doses between 20 and 150 mg/day, compared with placebo over 16 weeks, in 480 randomized patients (?16 to 70 years) with uncontrolled epilepsy (up to 20% could be patients with generalized epilepsy), not fully controlled despite treatment with 1-3 concomitant AEDs.6
N01358: an evaluation of the efficacy and safety of adjunctive brivaracetam 100 and 200 mg/day compared with placebo over 12 weeks in 768 randomized patients (?16 to 80 years) with partial-onset seizures, not fully controlled despite treatment with 1-2 concomitant AEDs.1
1. Klein P., et al. A Randomized, Double-blind, Placebo-controlled, Multicenter, Parallel-group Study to Evaluate the Efficacy and Safety of Brivaracetam in Adult Patients with Partial Onset Seizures. Presented at AES 2014
2. Kenda, B.M., et al., Discovery of 4-Substituted Pyrrolidone Butanamides as New Agents with Significant Antiepileptic Activity. Journal of Medicinal Chemistry, 2004. 47(3): 530-549.
3. Gillard, M., et al., Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: relationship to anti-convulsant properties. Eur J Pharmacol, 2011. 664(1-3): 36-44
4. Ryvlin, P., et al., Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial. Epilepsia, 2014. 55(1):47-56
5. Biton, V., et al., Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a phase III randomized, double-blind, placebo-controlled trial. Epilepsia, 2014. 55(1): 57-66
6. Kwan, P., et al., Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial. Epilepsia, 2014. 55(1):38-46