Objective: For extended-release drugs with multi-compartment kinetics, such as topiramate, effective half-life (toe) may be a more clinically relevant parameter than elimination half-life (tip,). Using topiramate as a real-life example, the objective was to compare these half-life values for immediate-and extended-release topiramate (TPM-IR and USL255, respectively) to understand how drug pharmacokinetics may impact drug dosing recommendations.Methods: The t(1/2z) and t(1/2z) for USL255 and TPM-IRwere compared using data from a phase I study (N = 36) of 200 mg USL255 administered once daily (QD) or TPM-IR twice daily (BID); effect of sampling duration on t(1/2z) was investigated. To further explore the relationship between half-life and dosing, steady-state Pk was simulated for USL255 and TPM-IR.Results: As previously reported, mean tip, was similar between USL255 (80.2 h) and TPM-IR (82.8 h); TPMIR tip, was 4 times longer than reported in the Topamax label (21 h). In contrast, USL255 displayed a 1.5 fold longer t(1/2z) (55.7 vs 37.1 h for TPM-IR). When tip, was calculated from 48 to 336 h, values ranged from 28.8 to 82.8 h. Simulated steady-state Pk profiles of USL255 QD exhibited reduced plasma fluctuations during a dosing interval vs TPM-IR QD or BID.Significance: As expected for the same moiety, tip, of USL255 and TPM-IR were similar; however, the longer t(1/2z) for USL255 better approximates differences in recommend dosing (QD USL255 vs BID TPMIR). Further, sampling duration impacted tip,, diminishing its predictive value for determining dose regimens; sampling-time differences may also explain tip, discrepancy between TPM-IR here versus Topamax label. As expected, steady-state simulations confirm that although TPM-IR has a long tip,, taking TPM-IR QD would lead to large plasma fluctuations. These data demonstrate that t(1/2z) may be less clinically meaningful than t(1/2z), and using tip, for some drugs may lead to erroneous conclusions regarding dosing regimens. (C) 2016 The Author(s). Published by Elsevier B.V.

ObjectiveThe aim of this study was to evaluate long-term safety, efficacy, and quality of life (QOL) of ≤400-mg/day USL255, Qudexy® XR (topiramate) extended-release capsules, as adjunctive therapy for partial-onset seizures (POS) in adults.MethodsPatients who completed the 11-week double-blind treatment phase of the phase 3 PREVAIL study were eligible to enroll in this 1-year open-label extension (OLE) study (PREVAIL OLE). The primary objective was to evaluate the safety and tolerability of USL255 (including treatment-emergent adverse events [TEAEs]). The secondary objective was to assess seizure frequency in patients (e.g., median percent reduction from baseline in weekly POS frequency, responder rate [proportion of patients with ≥25%, ≥50%, ≥75%, or 100% reduction from baseline in POS frequency], and seizure-free intervals [proportion of patients who were seizure-free for 4, 12, 24, 36, or 48 weeks]). Exploratory clinical-status endpoints included the Global Impression of Change (CGI-C) and Quality of Life in Epilepsy—Problems (QOLIE-31-P) questionnaires. Post hoc analyses evaluated neurocognitive TEAE incidences during the first 11 and entire 55 weeks of treatment and efficacy by patient age and drug-resistant status.ResultsOf the 217 patients who completed PREVAIL (USL255, n = 103; placebo, n = 114), 210 (97%) enrolled in PREVAIL OLE and were included in the ITT population. Across the entire 55-week treatment period, USL255 was generally safe and well tolerated, with low individual neurocognitive TEAE incidences. Seizure reduction was sustained across the year-long study and observed in patient subgroups, including those with highly drug-resistant seizures and those ≥50 years of age. Improvements in CGI-C and QOLIE-31-P were also observed.SignificanceThe results of PREVAIL OLE are consistent with those from PREVAIL and demonstrate that adjunctive treatment with up to 400 mg/day of USL255 may be a safe and effective treatment option for a variety of adult patients with refractory POS.

Objective: The objectives of these two studies were to determine if beads from extended-release topiramate capsules sprinldecl onto soft food are bioequivalent to the intact capsule and if beads from the capsule can be passed through enteral gastrostomy (G-) and jejunostomy (J-) feeding tubes.Methods: Bioequivalence of 200-mg USL255 (Qudexy (R) XR [topiramate] extencleckelease capsules) sprinkled onto soft food (applesauce) versus the intact capsule was evaluated in a phase 1, randomized, single-dose, crossover study (N 36). Pharmacokinetic evaluations included area under the curve (AUC), maximum plasma concentration (C-max), time to C-max (T-max), and terminal elimination half-life (t(1/2)). If 90% confidence intervals (CI) of the ratio of geometric least-squares means were between 030 and 125, AUC and C-max were considered bioequivalent. In separate in vitro experiments, 100-mg USL255 beads were passed through feeding tubes using gentle syringe pressure to develop a clog-free bead-delivery method. Multiple tube sizes (14- to 18-French [Fr] tubes), dilutions (5 mg 15 mL-25 mg/15 mL), and diluents (deionized water, apple juice, Ketocal, sparkling water) were tested.Results: Area under the curve and C-max for USL255 beads sprinkled onto applesauce were bioequivalent to the intact capsule (GLSM [90% CI]: AUC(0-t) 1.01 [0.97-1.04], AUC(0-infinity) 1.02 [0.98-105]; C-max 1.09 [1.03-1.14]). Median T-max was 4 h earlier for USL255 sprinkled versus the intact capsule (10 vs 14 h; p 0.0018), and t(1/2) was similar (84 vs 82 h, respectively). In 14-Fr G-tubes, USL255 beads diluted in Ketocal minimized bead clogging versus ionized water. Recovery of USL255 beads diluted in cleionized water was nearly 100% in 16-Fr G-, 18-Fr G-, and 18-Fr j-tubes.Significance: For patients with difficulty swallowing pills, USL255 sprinkled onto applesauce offers a useful once daily option for raking topiramale. USL255 beads were also successfully delivered in vitro through >= 14-Fr G- or j-tubes, with tube dogging minimized by portioning the close and using gliclant diluents for smaller tubes. (C) 2016 Upsher-mith Laboratories, Inc. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nc1/4.0/).

Background: Noncompliance with medication regimens, whether due to side effects or difficulty adhering to the proper dosing schedule, has been shown to contribute to increased seizure frequency and morbidity/mortality in patients with epilepsy. Immediate-release topiramate (TPM-IR) is an efficacious treatment option for the management of epilepsy; however, twice-daily dosing, required for TPM-IR, can lead to large fluctuations in drug plasma concentrations throughout the day and reduced compliance, which may increase the risk of adverse events (AEs) and breakthrough seizures. USL255, Qudexy™ XR (topiramate) extended-release capsules, was developed as a once-daily treatment option. USL255 was recently approved by the FDA (March 2014) as initial monotherapy for partial-onset seizures (POSs) or primarily generalized tonic–clonic (PGTC) seizures (patients ≥ 10 years of age) and adjunctive therapy for POSs, PGTC seizures, or seizures associated with Lennox–Gastaut syndrome (patients ≥ 2 years of age). In phase 1 studies, USL255 was pharmacokinetically equivalent to TPM-IR in total exposure (AUC), maximal plasma concentration (Cmax), and minimal plasma concentration (Cmin), with a reduced mean plasma fluctuation index of up to 26%. Presented here are efficacy and safety data from a multicenter (66 centers), multinational (16 countries), phase 3 study (PREVAIL; NCT01142193) of USL255 for the adjunctive treatment of refractory POSs.

April 20, 2015April 6, 2015Free AccessInvestigations of USL255, Qudexy™ XR (Topiramate) Extended-Release Capsules, Sprinkled onto Soft Food or Delivered via Enteral Feeding Tubes (P1.248)Mary Holmay, Annie Clark, Bob Anders, and John PellockAuthors Info & AffiliationsApril 6, 2015 issue84 (14_supplement)https://doi.org/10.1212/WNL.84.14_supplement.P1.248 Letters to the Editor

Objective: Describe different half-life measures and compare immediate- and extended-release topiramate (TPM-IR [Topamax®] and USL255 [Qudexy™ XR]) Background: Clinicians frequently use elimination half-life (t1/2z; time to decrease drug concentration by half after absorption and redistribution) to determine dosing frequency and time to steady state. However, t1/2z may not always be appropriate because XR formulations can exhibit prolonged absorption, and most drugs, including topiramate, redistribute into multiple tissue compartments. A more appropriate parameter to predict multidose drug accumulation may be effective half-life (t1/2eff), rate of drug loss over a dosing interval. Design/Methods: Half-lives were compared using data from a phase 1, randomized (N=36), open-label, single-dose crossover study of 200mg USL255 QD and 100mg TPM-IR BID. Plasma concentrations were measured for 336h using an assay with 10ng/mL lower limit of quantification. Pharmacokinetic parameters included t1/2z, t1/2eff, and time to maximum plasma concentration (Tmax). t1/2z was calculated using the terminal phase slope whereas t1/2eff accounted for dosing interval and accumulation index. Results: t1/2z was similar for USL255 (80h) and TPM-IR (83h); however, t1/2eff was markedly different (56 vs 37h). USL255 Tmax was longer than TPM-IR, indicating slower absorption. TPM-IR t1/2z observed here is longer than reported in the Topamax product information (83 vs 21h), likely due to longer sampling time and increased assay sensitivity. Conclusions: Despite differences in recommended dosing, t1/2z of USL255 and TPM-IR were similar, which may lead to the assumption that changes in plasma concentration over 24h are similar. In contrast, USL255 displayed a longer t1/2eff versus TPM-IR, predictable for a measure that takes into account absorption. This difference in t1/2eff better reflects the once- vs twice-daily dosing that is recommended for USL255 and TPM-IR. Though half-life is a commonly recognized drug-elimination parameter, t1/2eff may be more clinically relevant for XR drugs. Study Supported by: Upsher-Smith Laboratories, Inc.

OBJECTIVE: Evaluate efficacy, safety, and impact on quality of life (QoL) of adjunctive treatment with USL255 in adults with refractory partial-onset seizures (POS). BACKGROUND: USL255, Qudexy™ XR (topiramate) extended-release capsules, is approved for the once-daily treatment of epilepsy. USL255 demonstrated efficacy and favorable tolerability for adjunctive treatment of refractory POS in the phase 3 PREVAIL study (NCT01142193). Long-term use of USL255 was evaluated in a 1-year PREVAIL open-label extension (OLE; NCT01191086) study. DESIGN/METHODS: Patients who completed PREVAIL (N=217) were eligible to enroll in the OLE, which consisted of a 3-week blinded-conversion (to 200 mg/d USL255), 52-week open-label phase, and down titration. Changes in USL255 dosage (≤400 mg/d) and concomitant antiepileptic drugs were allowed after 11 weeks. Efficacy endpoints included median percent reduction from baseline in weekly POS frequency and 50[percnt] responder rate. Safety (treatment-emergent adverse events [TEAEs], laboratory findings, physical/neurological exams) and the Quality of Life in Epilepsy-Problems (QOLIE-31-P) and Clinical Global Impression-Change (CGI-C) scale were evaluated. Efficacy calculations used the original PREVAIL study baseline. RESULTS: Of the 210 patients who enrolled, 148 patients (70[percnt]) completed the OLE. Over the 52-week open-label phase, median percent reduction in POS frequency and 50[percnt] responder rate were 59[percnt] and 62[percnt], respectively. Incidence of treatment-related TEAEs was 49[percnt]; 9.5[percnt] of discontinuations were due to TEAEs. New individual neurocognitive/neuropsychiatric TEAEs were reported in <3[percnt] patients, except for aphasia (5.2[percnt]) and depression (3.8[percnt]). There were no abnormal trends in laboratory evaluations. At study end/early termination, 49[percnt] of patients (45/92) were rated as ‘very much’ or ‘much improved’ using CGI-C; improvements from baseline in overall QOLIE-31-P score were reported (mean change, 5.0; n=88). CONCLUSIONS: In this OLE study, treatment with ≤400 mg/d USL255 was associated with reductions in seizure frequency, functional benefits, and was safe and well-tolerated in patients with epilepsy. Study Supported by: Upsher-Smith Laboratories, Inc. Disclosure: Dr. Hogan has received personal compensation for activities with Upsher-Smith Pharmaceuticals as a consultant. Dr. Hogan has received research support from Eisai Pharmaceuticals and Upsher-Smith Pharmaceuticals. Dr. Blatt has received personal compensation for activities with Upsher-Smith Laboratories, Inc. Dr. Clark has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee. Dr. Anders has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee. Dr. Halvorsen has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee. Dr. Chung has received personal compensation for activities with UCB Pharma, Supermus, Esai Inc., Lundbeck Research USA, Inc., Upshire-Smith, and SK Life Science.

OBJECTIVE: Assess the efficacy of USL255, once-daily extended-release topiramate, in patients subdivided by baseline seizure type and antiepileptic drug (AED) use. BACKGROUND: Seizure type, concomitant AED use, and the number of previous AEDs may influence responsiveness of a patient to AED treatment. These analyses attempt to identify effectiveness of USL255 in treatment-resistant patient subgroups. DESIGN/METHODS: In this double-blind, phase 3 study (PREVAIL; NCT01142193), patients with partial-onset seizures (POS) on 1-3 concomitant AEDs were randomized to placebo (n=125) or USL255 (n=124), titrated over 3 weeks (50 mg/week), and maintained at 200 mg/day for 8 weeks. Efficacy assessments included median percent reduction from baseline in weekly POS frequency and 50% responder rate. Subgroup analyses included efficacy by 1) POS seizure type, 2) concomitant AED use, 3) lifetime AED use, and 4) refractory status (‘highly refractory’, 蠅2concomitant AEDs and 蠅4 lifetime AEDs; ‘less refractory’, 1 concomitant AED or <4 lifetime AEDs), although PREVAIL was not powered for statistical analyses in these subgroups. RESULTS: In subjects experiencing disabling seizures (complex partial with/without secondary generalization), USL255 significantly reduced weekly seizure frequency (40.6% vs 17.7%; P P =.001) vs placebo. Both seizure reduction and responder rate were significantly improved in patients concurrently taking 蠅3 AEDs ( P P =.001 and .007, respectively). In patients deemed ‘highly refractory’, reduction in seizure frequency was 2-fold higher with USL255 vs placebo (40.4% vs 18.1%; P =.004) and responder rate was significantly improved (38.5% vs 19.0%; P =.023). CONCLUSIONS: USL255 was efficacious as an adjunctive treatment for POS, with a variety of concomitant AEDs, and in highly refractory patients. Results from the PREVAIL study demonstrate broad and consistent efficacy of USL255, which may provide a significant benefit to patients with epilepsy. Study Supported by: Upsher-Smith Laboratories, Inc. Disclosure: Dr. Blatt has received personal compensation for activities with Upsher-Smith and GlaxoSmithKline, Inc. Dr. Nagaraddi has received personal compensation for activities with Upsher-Smith Laboratories as a consultant, and with UCB Biosciences as a speaker. Dr. Nagaraddi has received research support from Upsher-Smith Laboratories and UCB Biosciences. Dr. Hogan has received research support from Eisai Inc., and Upsher Smith. Dr. Arnold has received personal compensation for activities with UCB Pharma, Upsher-Smith, and Eisai Inc. as a consultant. Dr. Lawson has received personal compensation for activities with Upsher-Smith Laboratories as a consultant. Dr. Lawson has received research support from Upsher-Smith Laboratories. Dr. Anders has received personal compensation for activities with Upsher-Smith Laboratories, Inc. Dr. Clark has received personal compensation for activities with Upsher-Smith Laboratories, Inc. Dr. Halvorsen has received personal compensation for activities with Upsher-Smith Laboratories, Inc. Dr. Halvorsen holds stock in Medtronic Inc., Stryker, Elan Corp., Teva Neuroscience, Gilead, Pfizer Inc., and Amgen Inc. Dr. Chung has received personal compensation for activities with UCB Pharma, Supermus, Esai Inc., Lundbeck Research USA, Inc., Upshire-Smith, and SK Life Science.

OBJECTIVE: To compare the adverse event (AE) profile of USL255, once-daily extended-release (XR) topiramate, with those of commonly prescribed immediate-release (IR) antiepileptic drugs (AEDs): lacosamide (LCM), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC) and topiramate IR (TPM-IR). BACKGROUND: The goal of XR AEDs is to reduce dosing frequency and maintain constant plasma drug concentrations so that concentration-related adverse events are minimized. Once-daily USL255 is pharmacokinetically equivalent to twice-daily TPM-IR, but with reduced plasma fluctuations and peak dose concentrations. DESIGN/METHODS: AEs reported in the Prescribing Information for LCM (200-400mg/day), LTG (up to 500mg/day), LEV (up to 3000mg/day), OXC (600-1200mg/day) and TPM-IR (200mg/day) were compared with those of USL255 (200mg/day) reported in a double-blind, phase 3 study (PREVAIL; NCT01142193). Risk ratios (RR) were calculated using methods described in the Cochrane Handbook for Systematic Reviews of Interventions (2005). To calculate RR for AEs with zero-cell counts, a continuity correction of 0.5 was used. RESULTS: AEs with a particularly high risk compared to placebo (RR>10) were balance disorder (LCM, RR=29.6), speech disorder (LTG, RR=25.7), emotional lability (LEV, RR=18.1), arthralgia (LTG, RR=17.4), and weight decrease (USL255, RR=16.0). Somnolence, dizziness, and diplopia were the only AEs for which incidences were reported for all six drugs. Compared to placebo, all AEDs had a greater risk for somnolence (USL255, RR=6.0; LTG and OXC, RR=2.0; LEV, RR=1.9; TPM-IR, RR=1.7; LCM, RR=1.4) and dizziness (LCM, RR=3.1; LTG, RR=2.9; LEV, RR=2.3; OXC, RR=2.2; TPM-IR, RR=1.8; USL255, RR=1.2). All AEDs except USL255 had an increased risk for diplopia versus placebo (LCM, RR=4.5; OXC, RR=4.4; TPM-IR, RR=4.3; LTG, RR=4.0; LEV, RR=2.0 vs RR=0 for USL255). CONCLUSIONS: These data suggest that USL255 has an overall favorable AE profile compared with commonly prescribed AEDs, but additional studies with head-to-head comparisons are needed to fully delineate differences in AE profiles. Study Supported by: Upsher-Smith Laboratories, Inc. Disclosure: Dr. Meador has received personal compensation for activities with Eisai Inc., NeuroPace, Inc., Novartis, Supernus, Upsher Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals as a consultant for the Epilepsy Study Consortium. Dr. Meador has received research support from Pfizer Inc and UCB Pharma. Dr. Gilliam has nothing to disclose. Dr. Hogan has received research support from Eisai Inc., and Upsher Smith. Dr. Holmay has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee. Dr. Clark has received personal compensation for activities with Upsher-Smith Laboratories, Inc. Dr. Anders has received personal compensation for activities with Upsher-Smith Laboratories, Inc.

OBJECTIVE: Assess seizure misclassification rates following implementation of a seizure training program for investigators and coordinators participating in a phase 3 trial evaluating the efficacy and safety of USL255 as adjunctive therapy in subjects with partial-onset seizures (PREVAIL; NCT01142193). BACKGROUND: As seizure misclassification can negatively impact trial outcomes, The Epilepsy Study Consortium has created a training program for study investigators and coordinators to consistently identify the type of seizure and provide independent verification of seizure classification. DESIGN/METHODS: A seizure identification video, providing detailed descriptions of seizure types and advice for patient interviews, was moderated by a Consortium member at investigator meetings. After the video, a quiz was administered, with answers discussed in real time. PREVAIL was the first trial to implement this quiz with required retraining for scores <70%. Seizure Identification Forms (SIFs) were submitted for each subject, which included subject/caregiver-based seizure descriptions and investigator-based classification(s) of seizure(s). Prior to randomization, the Consortium reviewed and approved all SIFs; misclassifications were communicated to the study team to allow for investigator retraining. Subject diaries were assessed by centralized CRO reviewers to ensure seizure type and counts met protocol-specified criteria. RESULTS: The Epilepsy Consortium reviewed and reconciled 308 SIFs; only 1 subject was deemed unsuitable for PREVAIL. Eleven subjects (3.6%) had 12 misclassified seizures; a rate lower than previously reported (14% [2010], 10% [2013]) for other trials. Complex partial seizures (CPS) were the most commonly misclassified, representing 8 (66.7%) of the 12. The 4 remaining misclassifications included 2 cases each of secondarily generalized tonic-clonic seizures and simple partial seizures w/motor signs. CONCLUSIONS: In conjunction with The Epilepsy Study Consortium, the USL255 PREVAIL trial implemented the use of a novel video-based seizure identification training program, which may have contributed to the improved accuracy of seizure classification by the trial investigators versus historical comparisons. Study Supported by: Upsher-Smith Laboratories, Inc. Disclosure: Dr. DiVentura has received research support from Acorda Therapeutics, Biotie, Aprecia, Convergence, Eisai Inc., and Electroc. Dr. French has received research support from Acorda, Biotie, Eisai Medical Research, GlaxoSmithKline, Inc., Impax, Johnson & Johnson, MAP Pharmaceuticals, Marinus, Novartis, Lundbeck, Pfizer Inc, Sepracor, Sunovion, SK Life Science, Supernus Pharmaceuticals, UCB Inc/Schwarz Pharma, Upsher Smith, and Vertex. Dr. Anders has received personal compensation for activities with Upsher-Smith Laboratories, Inc. Dr. Laine has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee.

OBJECTIVE: Evaluate the adverse event profile of USL255, once-daily extended-release (XR) topiramate, in adults with refractory partial-onset seizures (POS). BACKGROUND: Treatment-emergent adverse events (TEAEs) affecting the central nervous system can be associated with antiepileptic drug (AED) treatment. Immediate-release (IR) topiramate is an AED that is efficacious for the management of epilepsy, but requires twice-daily dosing. USL255 can be given once daily, is pharmacokinetically equivalent to IR topiramate at the same daily dose, and has reduced plasma fluctuations, which may result in decreased incidence of TEAEs caused by high peak drug levels. DESIGN/METHODS: In this double-blind, phase 3 study (PREVAIL; NCT01142193), patients taking 1-3 concomitant AEDs were randomized to placebo (n=125) or USL255 (n=124), titrated over 3 weeks (50 mg/week), and maintained at 200 mg/day for 8 weeks. Incidence of spontaneously-reported TEAEs was assessed by study phase and severity. Neurocognitive adverse events were also summarized. RESULTS: Overall, the incidence of TEAEs was 66% with USL255 and 50% with placebo treatment (P=.015), and the majority were mild-to-moderate in intensity. A higher proportion of patients reported TEAE onset during the 3-week titration phase than during the first or last 4 weeks of the maintenance phase. Somnolence, dizziness, paraesthesia, weight decrease, fatigue, and headache were the most commonly reported TEAEs. The proportion of patients reporting a neurocognitive/neuropsychiatric TEAE (eg, memory impairment, psychomotor slowing) was less than 3% in both treatment groups, with the exception of disturbance in attention (2.4% [USL255]; 3.2% [placebo]). A majority of these events resolved before completion of maintenance. No deaths were reported and none of the serious TEAEs with USL255 were considered treatment related (USL255, 1.6%; placebo, 1.6%). CONCLUSIONS: USL255 demonstrated a favorable adverse event profile in patients with refractory POS with low incidence of neurocognitive adverse events, suggesting USL255 may provide a significant benefit to patients with epilepsy. Study Supported by: Upsher-Smith Laboratories, Inc.

OBJECTIVE: Evaluate interim data from a long-term study of USL255, once-daily extended-release topiramate, for the adjunctive treatment of refractory partial-onset seizures (POS). BACKGROUND: USL255 demonstrated efficacy and favorable safety/tolerability in a double-blind, placebo-controlled, phase 3 study (PREVAIL; NCT01142193). Interim data from the PREVAIL open-label extension (OLE) study (NCT01191086) are presented here. DESIGN/METHODS: Interim analyses (cutoff date 1 July 2013) of an ongoing OLE study of USL255 in adult patients with POS on 1-3 concomitant AEDs were performed. Patients who completed the 11-week double-blind phase from PREVAIL were eligible to enroll in the OLE. The OLE consisted of a 3-week blinded conversion phase (to 200 mg/day USL255), a 52-week open-label treatment phase, and a down titration of at least 3 weeks. USL255 dose adjustments of 50 mg/week were permitted after 11 weeks, until an optimal dose was achieved (maximum 400 mg/day); AED adjustments were also allowed following 11 weeks of treatment. Safety assessments included treatment-emergent adverse event (TEAE) monitoring. RESULTS: Of the 217 patients who completed PREVAIL, 210 (96.8%) elected to continue into the OLE study. As of the interim cutoff date, approximately 33 months after study start, data were available for 209 patients: 91 (43.5%) completed the year-long study, 70 (33.5%) were continuing treatment, and 48 (23%) had discontinued. Mean and median drug exposure for all patients were 283 and 347 days, respectively. A total of 18 (8.6%) patients discontinued due to a TEAE. The most common TEAEs were decreased weight (7.2%), headache (7.2%), somnolence (7.2%), and dizziness (5.7%). A total of 13 patients (6.2%) had at least 1 serious adverse event; of those only cholelithiasis (n=2) and status epilepticus (n=2) occurred in more than 1 patient. CONCLUSIONS: Interim exposure and safety data suggest that USL255, at dosages up to 400 mg/day, is generally well tolerated as an adjunctive treatment for refractory partial-onset seizures. Study Supported by: Upsher-Smith Laboratories, Inc. Disclosure: Dr. Fakhoury has received personal compensation for activities with UCB Pharma, Upsher Smith Laboratories, Supernus, and Sunovion Pharmaceuticals. Dr. Fakhoury has received research support from UCB Pharma, Sunovion Pharmaceuticals, Upsher Smith Laboratories, SK Life Science, and Westward Pharmaceuticals. Dr. Hogan has received research support from Eisai Inc., and Upsher Smith. Dr. Blatt has received personal compensation for activities with Upsher-Smith and GlaxoSmithKline, Inc. Dr. Chung has received personal compensation for activities with UCB Pharma, Supermus, Esai Inc., Lundbeck Research USA, Inc., Upshire-Smith, and SK Life Science. Dr. Anders has received personal compensation for activities with Upsher-Smith Laboratories, Inc.

OBJECTIVE: Gain an understanding of pharmacokinetic effects associated with delayed administration of USL255. BACKGROUND: USL255, a once-daily, extended-release formulation of topiramate, was developed for the treatment of epilepsy. While once-daily formulations may improve patient compliance, delayed dosing may cause steady-state plasma concentrations to decrease below minimum therapeutic concentrations. DESIGN/METHODS: Nonparametric superpositioning was used to simulate steady-state pharmacokinetic profiles from single-dose USL255 200 mg data. A 14-day dose administration (200 mg/day) to achieve steady-state conditions was simulated (full compliance), followed by a 6, 12, 18, and 24 hr (double dose) simulated delay in dosing, with once-daily dosing resuming after the late dose. Mean-predicted topiramate concentrations were calculated for each delayed-dose scenario and compared with full compliance. Simulated minimum (C min ) and maximum concentrations (C max )were evaluated for 96 hr following the late dose. RESULTS: Mean-predicted plasma concentrations prior to the next scheduled dose decreased incrementally as the time delay increased. However, within 24 hr after late-dose administration (followed by compliant dosing), topiramate concentrations for all delayed-dose scenarios were similar by visual comparison to simulated full-compliance concentrations. Concentrations were generally highest 2 days after a USL255 dose was administered 6, 12, 18, or 24 hr late; mean C max values were 2.09%, 4.25%, 6.79%, and 11.85% higher than steady-state concentrations, and corresponding C min values increased by 2.55%, 5.12%, 7.67%, and 10.23%. Three days after delayed-dose administration, C max and C min values were 1.14-7.03% and 1.33-5.31% higher, respectively, as compared with compliant dosing. CONCLUSIONS: After a USL255 dose was administered up to 24 hr late, simulated topiramate concentrations returned to near steady state within one 24-hr interval. These data demonstrate dosing USL255, up to 18 hr after a missed dose (ie, 6 hr before the next scheduled dose), minimizes the time that topiramate concentrations may be below minimum therapeutic concentrations without significant risk of increased (>10%) C max . Study Supported by: Upsher-Smith Laboratories, Inc. Disclosure: Dr. Anders has received personal compensation for activities with Upsher-Smith Laboratories, Inc. Dr. Lu has received personal compensation for activities with Cognigen Corp. as an employee. Dr. Ludwig has received personal compensation for activities with Cognigen Corp. as an employee. Dr. Clark has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee.

OBJECTIVE: Evaluate efficacy, safety, and impact on quality of life (QoL) of adjunctive treatment with USL255, once-daily extended-release (XR) topiramate, in adults with refractory partial-onset seizures (POS). BACKGROUND: Treatment nonadherence, common in patients with epilepsy, can increase seizures and adversely affect QoL. Compared with immediate-release (IR) antiepileptic drugs (AEDs), XR formulations can improve adherence by reducing dosing frequency and may decrease treatment-emergent adverse events (TEAEs) caused by peak-dose toxicity. At the same daily dose, USL255 is pharmacokinetically equivalent to IR topiramate and reduces plasma fluctuations. DESIGN/METHODS: In this double-blind, phase 3 study (PREVAIL; NCT01142193), patients taking 1-3 concomitant AEDs were randomized to placebo (n=125) or USL255 (n=124), titrated over 3 weeks (50 mg/week), and maintained at 200 mg/day for 8 weeks. Primary and key secondary efficacy endpoints were median percent reduction in weekly POS frequency and 50% responder rate following 11 weeks of treatment. Safety (TEAEs, laboratory findings, physical/neurological exams) and treatment effects on the Quality of Life in Epilepsy - Problems (QOLIE-31-P) and Clinical Global Impression-Change (CGI-C) scale were evaluated. RESULTS: USL255 resulted in greater reduction in POS frequency (39.5% vs 21.6%, P<.001) and greater 50% responder rate (37.9% vs 23.2%, P=.013) vs placebo. TEAE incidence was 66% (USL255) and 50% (placebo) (P=.015). Less than 3% of USL255-treated patients reported individual neurocognitive or neuropsychiatric TEAEs. No serious AEs (1.6% each group) were deemed USL255 related, and there were no abnormal trends in safety evaluations. The QOLIE-31-P seizure-worry subscale was significantly improved (14.1 vs 4.1, P<.001) with USL255 vs placebo, though the overall score was not significantly different (5.2 vs 4.5). Almost twice as many USL255-treated patients had improved CGI-C scores (37.8% vs 19.4%; P<.002). CONCLUSIONS: The PREVAIL study demonstrated that once-daily USL255 (200 mg/day) significantly improved seizure control, was well tolerated with few neurocognitive/neuropsychiatric side effects, and may functionally benefit patients with epilepsy. Study Supported by: Upsher-Smith Laboratories, Inc.

OBJECTIVE: Evaluate early efficacy and timing of treatment-emergent adverse events (TEAEs) with USL255, a once-daily extended-release topiramate formulation. BACKGROUND: Since many antiepileptic drugs require titration to achieve effective doses, it may be helpful to understand how quickly patients may experience symptom improvement after starting treatment. DESIGN/METHODS: In this double-blind, phase 3 study (PREVAIL; NCT01142193), participants with partial-onset seizures (POS) on 1-3 concomitant AEDs were randomized to placebo (n=125) or USL255 (n=124), titrated over 3 weeks (50 mg/week), and maintained at 200 mg/day for 8 weeks. Efficacy endpoints included median percent reduction from baseline in weekly POS frequency and 50% responder rate during titration and maintenance phases separately. Post-hoc analyses included weekly seizure reduction and TEAEs by phase. RESULTS: During titration, USL255 was associated with significant reductions in weekly POS frequency vs placebo (34% vs 8.6%; P<.001), which continued through maintenance (46% vs 22%; P=.001). During titration, 50% responder rate was significantly greater following USL255 treatment (34% vs 18%; P=.007); similar results were observed during maintenance (44% vs 31%; P=.048). When evaluated weekly, POS frequency was significantly reduced as early as Week 1 with USL255 (29% vs 9.2%; P<.05). Incidence of TEAEs was highest during titration for both USL255 (50%) and placebo (31%). After the first 4 weeks of maintenance, there was a 2% difference in TEAE incidence between USL255 (26%) and placebo (24%). Similar results were seen for nervous system disorder TEAEs, including neurocognitive and neuropsychiatric events, most of which resolved during maintenance. CONCLUSIONS: USL255 demonstrated significant efficacy as early as the first week of treatment (50 mg/day), with sustained benefit throughout the study. Incidence of TEAEs was higher in the titration than maintenance phase. USL255 demonstrated an early onset of efficacy, with TEAE rates similar to placebo after 4 weeks of maintenance treatment. Study Supported by: Upsher-Smith Laboratories, Inc.

OBJECTIVE: Compare the PK and TEAE profiles of USL255 with immediate-release topiramate (TPM-IR [Topamax ® ]) after multiple-dose administration. BACKGROUND: Extended-release antiepileptic drugs aim to reduce drug plasma fluctuations compared with IR formulations. This reduction may increase efficacy and decrease peak-related TEAEs, including cognitive-related AEs. DESIGN/METHODS: Three pooled phase 1, multiple-dose studies in healthy adults were used to evaluate TEAEs with USL255 (n=105) and TPM-IR (n=109) at 200 - 400 mg/day maintenance doses for up to 14 days. PK data from 1 of these studies (N=38; crossover design) was used to determine equivalence between USL255 and TPM-IR. RESULTS: In the PK study, USL255 was pharmacokinetically equivalent to TPM-IR, as the 90% CIs for the USL255/TPM-IR ratios of AUC 0-24 (1.02-1.05), C min (1.03-1.09), and C max (0.90-0.97) were contained within the 0.8 to 1.25 equivalence limits. USL255 demonstrated significantly lower C max ( P min ( P

Results from a previously conducted global phase III study (PREVAIL; NCT01142193) demonstrate the safety and efficacy of once-daily USL255, Qudexy™ XR (topiramate) extended-release capsules, as adjunctive treatment of drug-resistant partial-onset seizures (POSs). In this study, we report a post hoc analysis of PREVAIL data according to patient level of treatment resistance (based upon the number of concomitant antiepileptic drugs [AEDs] and lifetime AEDs) at baseline, with patients defined as either having “highly” drug-resistant seizures (≥2 concurrent AEDs and ≥4 lifetime AEDs) or having “less” drug-resistant seizures (1 concurrent AED or <4 lifetime AEDs) at baseline. For each subgroup, median percent reduction in POS frequency (primary endpoint), responder rate, Clinical Global Impression of Change (CGI-C), and Quality of Life in Epilepsy — Problems (QOLIE-31-P) survey were assessed. Of 249 PREVAIL patients, 115 were classified as having highly drug-resistant seizures (USL255: n=52, placebo: n=63), and 134 were classified as having less drug-resistant seizures (USL255: n=72, placebo: n=62) at baseline. For the primary endpoint, USL255 resulted in significantly better seizure outcomes compared with placebo regardless of drug-resistant status (P=.004 and P=.040 for “highly” and “less”, respectively). Responder rate was also significantly improved in patients with highly drug-resistant group (P=.023). The CGI-C scores indicated significant improvement in both subgroups (P=.003 and P=.013 for “highly” and “less”, respectively). On the QOLIE-31-P, a significant improvement on the seizure worry subscale for the group with less drug-resistant seizures was noted in USL255-treated patients compared with placebo-treated patients (P=.003); the overall score and all other subscales were not significantly different for both subgroups. We conclude that USL255 led to significant improvements across multiple outcomes compared with placebo, including in those classified as having highly drug-resistant seizures to prior treatment, making it a valuable treatment option for patients with epilepsy.

SummaryObjectiveTo evaluate the efficacy and safety of USL255, Qudexy™ XR (topiramate) extended‐release capsules, as an adjunctive treatment for refractory partial‐onset seizures (POS) in adults taking one to three concomitant antiepileptic drugs.MethodsIn this global phase III study (PREVAIL; NCT01142193), 249 adults with POS were randomized 1:1 to once‐daily USL255 (200 mg/day) or placebo. The primary and key secondary efficacy endpoints were median percent reduction in weekly POS frequency and responder rate (proportion of patients with ≥50% reduction in seizure frequency). Seizure freedom was also assessed. Safety (adverse events, clinical and laboratory findings), as well as treatment effects on quality of life (QOLIE‐31‐P) and clinical global impression of change (CGI‐C), were evaluated.ResultsAcross the entire 11‐week treatment phase, USL255 significantly reduced the median percent seizure frequency and significantly improved responder rate compared with placebo. Efficacy over placebo was observed early in treatment, in patients with highly refractory POS, and in those with the most debilitating seizure types (i.e., complex partial, partial secondarily generalized). USL255 was safe and generally well tolerated with a low incidence of neurocognitive adverse events. USL255 was associated with significant clinical improvement without adversely affecting quality of life.SignificanceThe PREVAIL phase III clinical study demonstrated that once‐daily USL255 (200 mg/day) significantly improved seizure control and was safe and generally well tolerated with few neurocognitive side effects.

OBJECTIVE: Evaluate bioequivalence between USL255 beads sprinkled onto soft food compared with the intact USL255 capsule. BACKGROUND: USL255 is a once-daily extended-release formulation of topiramate developed for the treatment of epilepsy. As some patients with epilepsy may have difficulty swallowing tablets or capsules, USL255 was formulated to allow the capsule to be opened and the beads sprinkled onto soft foods. DESIGN/METHODS: Phase 1, randomized, open-label, single-dose, crossover study of 36 healthy adult subjects who received 200 mg USL255 administered as an intact capsule or sprinkled onto 1 tablespoonful of applesauce. Blood samples were collected for 14 days post-dose and pharmacokinetic parameters were calculated, including area under the plasma concentration-time curve (AUC0-∞, AUC0-t), maximum concentration (Cmax), time to Cmax (Tmax), and terminal elimination half-life (t1/2). AUC and Cmax were considered bioequivalent if the 90% confidence intervals (CI) for the ratio of geometric least-squares means (GLSM) were contained between 0.80 - 1.25. Tolerability was evaluated through adverse event (AE) monitoring, vital sign measurements, and clinical laboratory evaluations. RESULTS: AUC and Cmax were bioequivalent between USL255 200 mg administered as an intact capsule and sprinkled onto soft food (GLSM [90% CI]: AUC0-t, 1.01 [0.97 - 1.04]; AUC0-∞, 1.02 [0.98 - 1.05]; Cmax,1.09 [1.03 - 1.14]). Median Tmax was between 10 - 14 hours and t1/2 was similar for both administration methods (81.5 hr intact; 83.6 hr sprinkled). USL255 was generally well tolerated, with similar types and numbers of AEs reported in both groups. CONCLUSIONS: USL255 beads sprinkled onto soft food demonstrated bioequivalence for AUC and Cmax compared with the intact capsule. Therefore, USL255 can be a useful treatment option for individuals with difficulty swallowing. Study Supported by: Upsher-Smith Laboratories, Inc.