Abstracts

Rationale: Extended-release antiepileptic drugs are designed to reduce dosing frequency and maintain consistent drug plasma concentrations, which may improve treatment adherence, reduce breakthrough seizures, and minimize adverse events. Once-daily (QD) USL255― Qudexy® XR (topiramate) extended-release capsules―was designed to provide equivalent plasma exposure (AUC) to twice-daily immediate-release topiramate (BID TPM-IR), with an improved pharmacokinetic profile (eg, lower maximum plasma concentrations [Cmax] and higher minimum plasma concentrations [Cmin]). Clinical study results demonstrating these characteristics, as well as other unique features and efficacy of USL255, are presented here.Methods: Several phase 1 pharmacokinetic (PK) studies and two phase 3 studies were conducted. Phase 1 studies evaluated PK properties unique to USL255, including 1) steady-state PK of QD USL255 vs BID TPM-IR (N=38), 2) food effect on single-dose USL255 PK (N=36), and 3) bioequivalence between USL255 beads sprinkled onto soft food and the intact capsule (N=36). Efficacy and tolerability of USL255 were evaluated in a randomized, double-blind, placebo-controlled phase 3 study (PREVAIL; 3-week titration to 200 mg USL255 [8-week maintenance]; N=249) and its year-long open-label extension study (PREVAIL OLE; ≤400 mg USL255; N=210).Results: Phase 1 evaluations confirmed the PK equivalence of QD USL255 to BID TPM-IR (AUC0-24 90% confidence interval [CI] 1.02-1.05), with reduced plasma fluctuations for USL255 (significantly lower Cmax and higher Cmin vs TPM-IR; P<.001). Further, directly switching between USL255 and TPM-IR did not result in significant changes in Cmax or Cmin, indicating maintenance of topiramate plasma concentrations. Dosing USL255 with a high-fat meal had no significant effect on AUC and Cmax (90% CI for the fed:fasted ratios were between 0.80-1.25%). The USL255 capsule also can be opened and sprinkled onto soft food, as AUC and Cmax were bioequivalent between USL255 beads sprinkled onto soft food and the intact capsule (90% CI: AUC0-∞ 0.98-1.05; Cmax 1.03-1.14). During the phase 3 PREVAIL study, 200 mg USL255 resulted in significantly greater reduction in POS frequency (39.5% vs 21.7%, P<.001) and higher 50% responder rate (37.9% vs 23.2%, P=.013) vs placebo. For the 52-week open-label phase of the OLE, median percent reduction in POS frequency was 59% and the 50% responder rate was 62%, with efficacy observed across all age groups (18-<35, 35-<50, ≥50 y). Treatment-related TEAE incidence during the OLE was 49%, mostly mild to moderate.Conclusions: Once daily USL255—a unique XR formulation of topiramate—provides multiple benefits, including reduced plasma fluctuations vs BID TPM-IR and ability to take with food or sprinkle onto soft food. USL255 demonstrated significant efficacy above placebo, with continued seizure reduction and tolerability during the 1-year OLE across all age groups. USL255 provides an effective and reliable treatment option for the long-term management of epilepsy. Support: Upsher-Smith Laboratories, Inc.