Abstracts

Rationale: Evidence from animal models strongly suggests a role of brain inflammation in the perpetuation of seizure foci. Inhibition of the production of the inflammatory mediator IL-1? reduced seizure frequency in models of acute seizures and in one model of chronic and spontaneous AED-resistant epileptic activity. VX-765 is a novel Interleukin-1? -Converting Enzyme/Caspase 1 inhibitor, which reduces the production and release of IL-1?. We performed a proof-of-concept study using VX-765 as adjunctive treatment in subjects with resistant partial onset seizures (POS) to assess safety and initial efficacy.Methods: This was a Phase 2, randomized, double-blind, placebo-controlled study of adjunctive VX-765 in subjects with treatment resistant POS. Subjects were randomized 4:1 to receive VX-765 2700 mg (900 mg TID) or placebo. To receive drug, subjects had to have at least 6 observable POS during the 6 weeks between screening and the start of the Treatment Period (Baseline Period). The 6-week Treatment Period was followed by a 6-week observation period off study drug. The primary endpoint was safety and tolerability. Secondary endpoints included percent reduction in seizure frequency during the Treatment Period relative to the Baseline Period, percent of subjects with 50% or greater reduction in seizure frequency ( responder rate ) during the Treatment Period relative to the Baseline Period, and percent of subjects that become seizure free during the last 2 weeks of the Treatment Period. In pre-clinical models, onset/offset of treatment effect with VX-765 was delayed; therefore, post-hoc analysis also evaluated a hybrid period of final 2 weeks of treatment/2 weeks post-treatment.Results: 60 patients were enrolled in the trial (VX-765=48, Placebo=12). Adverse events occurred in 72.9% (35/48) of subjects taking VX-765 and 83.3% (10/12) taking placebo, with the most common event being dizziness. The only adverse event that led to study drug discontinuation was a rash in a single VX-765 subject. Serious adverse events occurred in 6.3% (3/48) of VX-765 subjects (hernia surgery, pain, and acute worsening of Complex Partial Seizures post-treatment) and 0% (0/12) of placebo subjects. Difference in reduction in seizure rate and 50% responder rates did not meet statistical significance between the two groups; 12.5% of the VX-765 subjects were seizure free during the last 2 weeks of treatment vs. 0% of the placebo group (p=0.333). During the hybrid period, there appeared to be a positive trend towards better 50% responder rate (31.3% in the VX-765 group compared to 8.3% in the placebo group; P=0.153).Conclusions: VX-765 treatment demonstrated a safety and tolerability profile through 6 weeks that warrants further evaluation in this population. These preliminary data indicate a possible beneficial effect of VX-765 may occur after 4 weeks of therapy. Because of the unique mechanism of action, and because there may be a shift in onset of effect, future trials of longer duration are being considered. Sponsored by Vertex Pharmaceuticals Incorporated