Abstracts

Rationale: USL255, Qudexy® XR (topiramate) extended-release capsules, is approved in patients ≥2 years of age as monotherapy and adjunctive therapy for the treatment of various seizure types. Two phase 3 studies, PREVAIL (NCT01142193) and PREVAIL open-label extension (OLE; NCT01191086), demonstrated that USL255 was well tolerated and efficacious as an adjunctive treatment in patients with refractory partial-onset seizures (POS). As cognitive adverse events (AEs) are of concern with antiepileptic drugs (AEDs), presented here are post hoc analyses of neurocognitive AE incidence during PREVAIL and PREVAIL OLE.Methods: In PREVAIL, adults with POS were randomized to placebo (n=125) or USL255 (n=124), titrated over 3 weeks (50 mg/week), and maintained at 200 mg/d for 8 weeks. OLE began with a 3-week blinded-conversion phase, where patients randomized to placebo in PREVAIL were titrated to 200 mg/d USL255 (50 mg/week; PBO-USL subgroup), and those randomized to 200 mg/d USL255 in PREVAIL maintained treatment and were given matching placebo (USL-USL subgroup). OLE continued with a 52-week open-label treatment phase. Incidence (new onset) of neurocognitive treatment-emergent AEs (TEAEs) for the first 11 weeks of USL255 treatment in both studies and for the duration of the OLE are detailed here.Results: Of the 217 patients who completed the 11-week double-blind phase in PREVAIL (USL255 n=103; placebo n=114), 96.8% entered the OLE. A total of 148 patients (70%) completed the OLE, with 9.5% of discontinuations due to TEAEs. Individual neurocognitive TEAEs leading to discontinuation in both studies were ≤1% of total participants. During the first 11 weeks of both studies, overall incidence of neurocognitive TEAEs in patients newly-exposed to USL255 were 8.1% (PREVAIL n=99) and 9.9% (OLE n=111 [PBO-USL]). Incidence rates were relatively consistent as patients continued treatment during the year-long OLE, though were slightly higher for patients newly exposed to USL255 in the OLE (10.1% for PBO-USL [last 44 weeks] and 6.1% for USL-USL [55 weeks]). Only aphasia occurred in >2% of patients during either study (OLE [PBO-USL] incidence: 6.3% first 11 weeks; 4% last 44 weeks). Incidence of other neurocognitive TEAEs during PREVAIL and the OLE—amnesia, bradyphrenia (slowed thinking), cognitive disorder, confusional state, disturbance in attention, dysarthria, memory impairment, psychomotor slowing, and speech disorder—was ≤2% in all groups. Incidence of disturbances with speech (aphasia, dysarthria, and/or speech disorder) following USL255 exposure was similar to results for aphasia (PREVAIL: 3% [11 weeks]; OLE [PBO-USL]: 6.3% first 11 weeks and 5.1% last 44 weeks; OLE [USL-USL]: 2% [55 weeks]).Conclusions: In this 1-year open-label extension study, once-daily USL255 (up to 400 mg/d) was generally well tolerated in patients with refractory POS, with a low incidence of neurocognitive AEs. These data suggest a potential benefit of USL255 for the long-term management of epilepsy. Support: Upsher-Smith Laboratories, Inc.