Evaluation of Drug-Drug Interactions between VX-765 and Common Anti-Epileptic Medications in Subjects with Treatment-Resistant Partial-Onset Epilepsy (P02.216)

OBJECTIVE: To evaluate drug-drug interactions between VX-765 and anti-epileptic medications in subjects with treatment-resistant partial-onset epilepsy. BACKGROUND: Studies have shown that the interleukin 1 beta (IL-1β) signaling pathway mediates inflammatory responses that play an important role in establishing seizures and causing epilepsy. VX-765 is an investigational orally bioavailable pro-drug of a selective and reversible interleukin 1 beta-converting enzyme (ICE) inhibitor (VRT-043198) and is a novel therapeutic approach for subjects with treatment-resistant partial-onset epilepsy. Clinically, VX-765 would be commonly administered with anti-epileptic drugs (AEDs) which contain many cytochrome P450 inducers and substrates. Drug-drug interactions could potentially occur between VX-765 and AEDs, although in vitro studies showed that the cytochrome P450 enzyme system is unlikely to play a major role in VX-765 metabolism. DESIGN/METHODS: In this phase 2a study, VX-765 was co-administered (900 mg 3 times per day for 6 weeks) with 1 to 4 concomitant AEDs to 48 subjects with treatment-resistant partial-onset epilepsy. Concentrations of VX-765 one hour post-dose alone with trough concentrations on Day 1 and Day 28 were compared with historic data in which the same dose of VX-765 was given to healthy subjects. In addition, bioequivalence tests were conducted to compare the trough concentrations of AEDs at baseline and in the treatment period (with VX-765 co-administered). RESULTS: There were no substantial differences in VX-765 and VRT-043198 concentrations between the current study and historic data, indicating that VX-765 and VRT-043198 were unlikely affected by co-administration with common AEDs. Although the study was not statistically powered for these effects, the bioequivalence tests showed no significant changes in AED concentrations before and after co-administration with VX-765. The results suggest that AED concentrations were not affected by either VX-765 or VRT-043198. CONCLUSIONS: These findings indicate that VX-765 has minimal potential for drug-drug interactions with commonly administered AEDs. Supported by: Vertex Pharmaceuticals Incorporated. Disclosure: Dr. Chen has received personal compensation for activities with Vertex Pharmaceuticals as an employee. Dr. Chen holds stock and/or stock options in Vertex Pharmaceuticals, which sponsored research in which Dr. Chen was involved as an investigator. Dr. Huang has received personal compensation for activities with Vertex Pharmaceuticals as an employee. Dr. Huang holds stock and/or stock options in Vertex Pharmaceuticals. Dr. Paskavitz has received personal compensation for activities with Vertex Pharmaceuticals Incorporated as an employee. Dr. Paskavitz holds stock and/or stock options in Vertex Pharmaceuticals Incorporated. Dr. Hoock has received personal compensation for activities with Vertex Pharmaceuticals as an employee. Dr. Hoock holds stock and/or stock options in Vertex Pharmaceuticals. Dr. Wright has received personal compensation for activities with Vertex Pharmaceuticals as an employee. Dr. Wright holds stock and/or stock options in Vertex Pharmaceuticals.