Phase III data on carisbamate, an investigational compound recently filed with the FDA for the adjunctive treatment of partial onset seizures (POS) in patients 16 years of age and older, was presented during the poster sessions of the 32nd Annual Meeting of the American Epilepsy Society.
Results from two identical placebo-controlled clinical trials investigating the efficacy, safety and tolerability of carisbamate as an adjunctive treatment for patients with POS were presented along with results of a pharmacokinetic/ pharmacodynamic (PK/PD) analysis.
"Although several new antiepileptic drugs have become available in the past decade, there is still unmet patient need. Long-term treatment success is not only determined by seizure control, but equally by tolerability, which is reflected by a patient's ability to remain on medication," said Michael Sperling, M.D. of Thomas Jefferson University and an investigator in the trials. "The carisbamate data presented at AES not only demonstrate benefit of carisbamate in reducing seizure frequency in some patients with partial onset seizures, but also shows an impressive tolerability profile."
Adjunctive Therapy of Partial Onset Seizures in Adults
Two identically designed, randomized, double blind, placebo-controlled global studies were presented in the first poster. Patients with an established diagnosis of uncontrolled POS for one year or more were eligible. The subjects remained on stable doses of a prescribed antiepileptic drug (AED) for 8-weeks (baseline phase) and were then randomized to receive carisbamate 200 mg/day, carisbamate 400 mg/day, or placebo on top of these existing AEDs. Efficacy endpoints were median percent reduction in seizure frequency in the double blind phase compared to the baseline phase, and the proportion of patients with 50% or greater reduction in POS frequency during the 12-week double blind phase.
Carisbamate was well tolerated, with minimal central nervous system-related adverse events and a low discontinuation rate. The most common adverse events were dizziness and somnolence. The rate of treatment-emergent adverse events resulting in discontinuation from carisbamate was 3% in each study. Results showed that treatment with carisbamate 400 mg resulted in significant improvement in both efficacy measures compared with placebo in study 1, but not in study 2. Carisbamate 200 mg/day did not differ from placebo in either study. In both studies, concomitant use of enzyme-inducing AEDs lowered plasma levels of carisbamate by up to 44% (40% in study 1 and 44% in study 2). As a result, there were greater percentage reductions in POS frequency among patients treated with carisbamate who received concomitant non-enzyme inducing AEDs.
PK/PD Modeling of the Effect of Carisbamate
A second poster showed results of an analysis of three studies, which evaluated the efficacy of carisbamate, using a PK/PD model to predict the effect of carisbamate over a dose range of 400 mg/day to 1200 mg/day. The relationship between percent reduction of POS from baseline and steady state trough concentration was investigated.