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news.Ortho-McNeil Neurologics, a division of Ortho-McNeil-Janssen Pharmaceuticals, has reported positive Phase III data on carisbamate, an investigational compound recently filed with the FDA for the adjunctive treatment of partial onset seizures in patients 16 years of age and older.
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The company has reported results from two identically designed, randomized, double blind, placebo-controlled global studies. Patients with an established diagnosis of uncontrolled partial onset seizures (POS) for one year or more were eligible. The subjects remained on stable doses of a prescribed antiepileptic drug (AED) for eight-weeks and were then randomized to receive carisbamate 200mg/day, carisbamate 400mg/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.
According to the company, carisbamate was well tolerated, with minimal central nervous system-related adverse events and a low discontinuation rate. 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.
The company has also reported results of an analysis of three studies, which evaluated the efficacy of carisbamate, using a pharmacokinetic/ pharmacodynamic (PK/PD) model to predict the effect of carisbamate over a dose range of 400mg/day to 1200mg/day. The relationship between percent reduction of POS from baseline and steady state trough concentration was investigated.
The model showed that seizure reduction increased with greater drug exposure levels. Carisbamate pharmacokinetics were influenced by the co-administration of enzyme-inducing AEDs, which reduced carisbamate exposure by about 33-40%.
In all three studies separately, a statistically significant positive relationship between seizure rate reduction and steady state trough concentrations was found. The PK/PD simulations predicted that treatment with 400mg/day provides clinically meaningful effects for all subjects, with further increase in effect with dosages of 800mg and 1200mg/day for patients on enzyme-inducing or non-enzyme inducing AEDs.
If approved by the FDA, carisbamate will be marketed by Ortho-McNeil Neurologics, a division of Ortho-McNeil-Janssen Pharmaceuticals. Carisbamate has received provisional approval by the FDA to be marketed under the brand name of Comfyde.