OBJECTIVE:Age of symptom onset is highly variable in familial frontotemporal lobar degeneration (f-FTLD). Accurate prediction of onset would inform clinical management and trial enrollment. Prior studies indicate that individualized maps of brain atrophy can predict conversion to dementia in f-FTLD. We used a Bayesian linear mixed-effect (BLME) prediction method for identifying accelerated brain volume loss to predict conversion to dementia. METHODS:Participants included 234 asymptomatic or prodromal carriers of C9orf72, GRN, or MAPT mutations (including 21 dementia converters) with ≥3 longitudinal magnetic resonance imaging (MRI) T1-weighted scans. The BLME models established individual voxel-wise gray matter trajectories using the first 2 scans. Person-specific clusters of accelerated volume loss were estimated in subsequent scans and tested as predictors of dementia conversion compared with other approaches in time-varying Cox proportional hazard models covarying for age. Receiver-operating characteristic (ROC) curves estimated utility of cluster volume in discriminating which participants converted to dementia within 24 months. RESULTS:The BLME cluster volume predicted conversion to dementia in f-FTLD mutation carriers overall and separately in C9orf72, GRN, and MAPT, with comparable hazard ratios observed for atrophy W-maps and regional volumes. Within a 24-month timeframe, BLME cluster volume discriminated dementia converters from non-converters with larger areas under the curve (AUCs) than other approaches. INTERPRETATION:Bayesian-modeled individualized atrophy scores predict dementia progression among asymptomatic f-FTLD mutation carriers and may have increased utility compared with other structural imaging methods when studying individuals over shorter timeframes that align with clinical trial design. ANN NEUROL 20269999:n/a-n/a.

Background and Objectives Identification of fluid biomarkers for progressive supranuclear palsy (PSP) is critical to enhance therapeutic development. We implemented unbiased DNA aptamer (SOMAmer) proteomics to identify novel CSF PSP biomarkers. Methods This is a cross-sectional study in original (18 clinically diagnosed PSP-Richardson syndrome [PSP-RS], 28 cognitively healthy controls]), validation (23 PSP-RS, 26 healthy controls), and neuropathology-confirmed (21 PSP, 52 non-PSP frontotemporal lobar degeneration) cohorts. Participants were recruited through the University of California, San Francisco, and the 4-Repeat Neuroimaging Initiative. The original and neuropathology cohorts were analyzed with the SomaScan platform version 3.0 (5026-plex) and the validation cohort with version 4.1 (7595-plex). Clinical severity was measured with the PSP Rating Scale (PSPRS). CSF proteomic data were analyzed to identify differentially expressed targets, implicated biological pathways using enrichment and weighted consensus gene coexpression analyses, diagnostic value of top targets with receiver-operating characteristic curves, and associations with disease severity with linear regressions. Results A total of 136 participants were included (median age 70.6 +/- 8 years, 68 [50%] women). One hundred fifty-five of 5,026 (3.1%), 959 of 7,595 (12.6%), and 321 of 5,026 (6.3%) SOMAmers were differentially expressed in PSP compared with controls in original, validation, and neuropathology-confirmed cohorts, with most of the SOMAmers showing reduced signal (83.1%, 95.1%, and 73.2%, respectively). Three coexpression modules were associated with PSP across cohorts: (1) synaptic function/JAK-STAT (beta = -0.044, corrected p = 0.002), (2) vesicle cytoskeletal trafficking (beta = 0.039, p = 0.007), and (3) cytokine-cytokine receptor interaction (beta = -0.032, p = 0.035) pathways. Axon guidance was the top dysregulated pathway in PSP in original (strength = 1.71, p < 0.001), validation (strength = 0.84, p < 0.001), and neuropathology-confirmed (strength = 0.78, p < 0.001) cohorts. A panel of axon guidance pathway proteins discriminated between PSP and controls in original (area under the curve [AUC] = 0.924), validation (AUC = 0.815), and neuropathology-confirmed (AUC = 0.932) cohorts. Two inflammatory proteins, galectin-10 and cytotoxic T lymphocyte-associated protein-4, correlated with PSPRS scores across cohorts. Discussion Axon guidance pathway proteins and several other molecular pathways are downregulated in PSP, compared with controls. Proteins in these pathways may be useful targets for biomarker or therapeutic development.

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.

A sequential pharmacokinetic‐pharmacodynamic (PK‐PD) modeling approach was used to quantify the effects of a single dose of topiramate (100 or 200 mg) on working memory, attention, and psychomotor speed as measured by the Symbol‐Digit Modalities Test (SDMT). Established on data pooled from 3 randomized, crossover studies in healthy subjects (19–55 years of age), using both oral and a novel stable‐labeled intravenous (IV) formulation of topiramate, an inhibitory E max model was found to characterize the topiramate concentration‐SDMT score relationship well. At the EC50 of 2.85 μg/mL, this topiramate plasma concentration value was estimated to be associated with a 25.5% reduction of SDMT score relative to baseline. Age was an important determinant of the baseline SDMT score, with an estimated decrease of 1.13% in baseline SDMT score with every year of age. Moreover, this approach enabled the quantification of the practice effect observed with repeated administration of the neuropsychological test over shorter testing intervals than have previously been reported in the literature. The finding of a significant effect following a single dose of topiramate in the range widely used to treat migraine and epilepsy needs to be evaluated in a broader patient population undergoing chronic treatment, as the narrow range of resultant concentrations limits the generalizability of the findings.

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.

OBJECTIVE: Review potential considerations regarding generic antiepileptic drugs (AEDs) through an exploratory literature review and evaluation of pharmacy use. BACKGROUND: Potential economic advantages of generics drive the market such that generics make up 80[percnt] of prescriptions dispensed in the US. Most generics are approved by the FDA based on pharmacokinetic studies demonstrating bioequivalence to brand products. However, efficacy and safety of generics within specific therapeutic areas, including epilepsy, continue to be a topic of debate. DESIGN/METHODS: A PubMed search was conducted on generic AEDs. Systematic reviews, meta-analyses, surveys, and pharmacokinetic studies published within the last 6 years were identified. Additional data on generics and pharmacy use were gathered through public databases (eg, FDA Orange Book, PubMed). RESULTS: Over 40 publications on AED switching were evaluated; the majority being of retrospective design. There was no consensus on AED switching; some studies suggested switching increased risk for seizures and adverse effects, while others reported no risk/benefit differences. Generics/pharmacy use data demonstrated that currently there are >240 approved generic formulations of 17 AEDs and in 2009 29[percnt] of 13,612 people surveyed used 蠅3 pharmacies. CONCLUSIONS: The current literature offers evidence suggesting that AED switching may not be tolerated by some patients, though further prospective studies are required to provide more definitive data. Additionally, the large number of available generic AEDs and patients’ use of multiple pharmacies may contribute to some of the reported negative outcomes with AED switching, though no direct link has been demonstrated. As individual patient characteristics may play a role in the AED switching debate, minimizing factors that can be controlled may reduce clinical concerns associated with generics. Two potential ways to address these concerns may be to decrease generic switching and reduce variability by ensuring patients receive generic AEDs from the same manufacturer. Study Supported by: Upsher-Smith Laboratories, Inc. Disclosure: Dr. Nguyen has received personal compensation for activities with Upsher-Smith Laboratories as an employee. Dr. Clark 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. Holmay has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee. Dr. Gilmet has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee.

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

AIMS:The aim was to develop a quantitative approach that characterizes the magnitude of and variability in phonemic generative fluency scores as measured by the Controlled Oral Word Association (COWA) test in healthy volunteers after administration of an oral and a novel intravenous (IV) formulation of topiramate (TPM).METHODS:Nonlinear mixed-effects modelling was used to describe the plasma TPM concentrations resulting from oral or IV administration. A pharmacokinetic-pharmacodynamic (PK-PD) model was developed sequentially to characterize the effect of TPM concentrations on COWA with different distributional assumptions.RESULTS:Topiramate was rapidly absorbed, with a median time to maximal concentration of 1 h and an oral bioavailability of ~100%. Baseline COWA score increased by an average of 12% after the third administration on drug-free sessions. An exponential model described the decline of COWA scores, which decreased by 14.5% for each 1 mg l(-1) increase in TPM concentration. The COWA scores were described equally well by both continuous normal and Poisson distributions.CONCLUSIONS:This analysis quantified the effect of TPM exposure on generative verbal fluency as measured by COWA. Repetitive administration of COWA resulted in a better performance, possibly due to a learning effect. The model predicts a 27% reduction in the COWA score at the average observed maximal plasma concentration after a 100 mg dose of TPM. The single-dose administration of relatively low TPM doses and narrow range of resultant concentrations in our study were limitations to investigating the PK-PD relationship at higher TPM exposures. Hence, the findings may not be readily generalized to the broader patient population.

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.

SummaryObjectiveEvaluate the pharmacokinetics (PK), safety, and tolerability of single doses of once‐daily USL255, Qudexy XR (topiramate) extended‐release capsules, over a wide dosing range.MethodsTwo single‐dose, phase I studies in healthy adults were used to evaluate the PK profile and maximum tolerated dose (MTD) of USL255 from 25–1,400 mg. Standard PK parameters assessed included area under the plasma concentration‐time curve (AUC) and maximum plasma concentration (Cmax). Dose proportionality, linearity, and intersubject and intrasubject variability (coefficient of variation [%CV]) of AUC and Cmax were evaluated. Investigator‐reported adverse events (AEs) were obtained throughout the studies.ResultsAfter the initial increase in plasma concentration levels immediately following administration of USL255 25–1,400 mg, plasma topiramate concentration‐time profiles were flat up to 24 h after dosing. AUC was dose proportional from 25–1,400 mg, and Cmax was dose proportional from 50–1,400 mg; both AUC and Cmax were linear across the entire dose range. Low intersubject and intrasubject %CV values were observed for AUC0−t, AUC0−∞, and Cmax (intersubject %CV: 20.2, 19.6, and 22.4%, respectively; intrasubject %CV of dose‐normalized mean values: 10.8, 8.2, and 13.2%, respectively). USL255 was generally safe and well tolerated with MTD established at 1,200 mg.SignificanceThese results demonstrate that USL255 provides consistent plasma topiramate exposure across an extended‐dosing interval and predictable plasma topiramate concentrations over a wide dosing range. Overall, the favorable safety profile and consistency of exposure suggest once‐daily USL255 can be a useful treatment option for patients with epilepsy.A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

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