Long-term safety and sustained efficacy of USL255 (topiramate extended-release capsules) in patients with refractory partial-onset seizures.

OBJECTIVE: The 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. METHODS: Patients 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 48weeks]). 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 55weeks of treatment and efficacy by patient age and drug-resistant status. RESULTS: Of 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 ≥50years of age. Improvements in CGI-C and QOLIE-31-P were also observed. SIGNIFICANCE: The results of PREVAIL OLE are consistent with those from PREVAIL and demonstrate that adjunctive treatment with up to 400mg/day of USL255 may be a safe and effective treatment option for a variety of adult patients with refractory POS.

Pharmacokinetics, pharmacodynamics, and safety of USL261, a midazolam formulation optimized for intranasal delivery, in a randomized study with healthy volunteers.

OBJECTIVE: To compare the pharmacokinetics, pharmacodynamics, and tolerability of USL261, a midazolam formulation optimized for intranasal delivery, versus midazolam intravenous (IV) solution administered intranasally (MDZ-inj IN) or intravenously (MDZ-inj IV) in healthy adults. METHODS: In this phase 1, five-way crossover, open-label study, 25 healthy adults (aged 18-42 years) were randomly assigned to receive 2.5, 5.0, and 7.5 mg USL261; 2.5 mg MDZ-inj IV; and 5.0 mg MDZ-inj IN. Blood samples were collected for 12 h post dose to determine pharmacokinetic profiles. Pharmacodynamic assessments of sedation and psychomotor impairment also were conducted. Adverse events, oxygen saturation, and vital signs were recorded. RESULTS: Increasing USL261 dose corresponded with increases in midazolam area under the concentration time curve (AUC) and maximum observed plasma concentration (Cmax ), with all doses demonstrating rapid median time to Cmax (Tmax ; 10-12 min). USL261 also demonstrated increased absorption, with a 134% relative bioavailability, compared with the same MDZ-inj IN dose. USL261 was associated with dose-dependent increases in sedation and psychomotor impairment (p < 0.05); however, these effects lasted <4 h and generally did not differ from MDZ-inj IN or MDZ-inj IV at comparable doses. No serious adverse events (SAEs) or deaths were reported, and no treatment-emergent adverse events (TEAEs) led to study discontinuation. SIGNIFICANCE: Compared with intranasal delivery of a midazolam formulation intended for IV delivery, USL261, optimized for intranasal administration demonstrated improved bioavailability with similar pharmacodynamic effects. Therefore, USL261 may be a preferable alternative to the currently approved rectal diazepam treatment for intermittent bouts of increased seizure activity.

Efficacy of once-daily extended-release topiramate (USL255): a subgroup analysis based on the level of treatment resistance.

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.

Once-daily USL255 as adjunctive treatment of partial-onset seizures: randomized phase III study.

OBJECTIVE: To 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. METHODS: In 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. RESULTS: Across 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. SIGNIFICANCE: The 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.

USL255 extended-release topiramate: dose-proportional pharmacokinetics and tolerability in healthy volunteers.

OBJECTIVE: Evaluate the pharmacokinetics (PK), safety, and tolerability of single doses of once-daily USL255, Qudexy XR (topiramate) extended-release capsules, over a wide dosing range. METHODS: Two 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. RESULTS: After 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. SIGNIFICANCE: These 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.

Comparative steady-state pharmacokinetic evaluation of immediate-release topiramate and USL255, a once-daily extended-release topiramate formulation.

PURPOSE: Compare the pharmacokinetic (PK) profiles of immediate- and extended-release formulations of topiramate (TPM) in healthy subjects following multiple dosing, and evaluate maintenance of topiramate exposures after switching formulations. METHODS: A randomized, open-label, single-center, two-way crossover, multiple-dose study comparing the steady-state PK profile of once-daily extended-release topiramate (USL255) to immediate-release topiramate (TPM-IR) administered twice-daily. The TPM PK profile was evaluated using standard PK parameters (e.g., AUC0-24 , Cmax , Cmin ) as well as less common PK criteria such as fluctuation index (FI), peak occupancy time (POT), and percent coefficient of variation (%CV). In addition, partial AUC (AUCp ) analyses provided comparisons of the AUC profiles over predetermined time intervals between TPM-IR and USL255. Pharmacokinetic equivalence between formulations was defined as containment of the 90% confidence intervals (CIs) of the USL255/TPM-IR geometric least-squares mean (GLSM) ratio within the equivalence limits of 80-125%. The effect of switching between treatments was assessed by evaluating equivalence of PK parameters between the day prior to formulation switch and the day immediately following formulation switch. Maintenance of steady state after switching formulations was also evaluated by comparing the slope between Cmin values at formulation switch and 24 h postswitch. Tolerability was evaluated through adverse event monitoring, vital sign measurements, and clinical laboratory evaluations. KEY FINDINGS: USL255 was well tolerated and provided TPM plasma exposure equivalent to TPM-IR at various time intervals. USL255 also demonstrated a significantly lower Cmax (p < 0.001) and higher Cmin (p < 0.001), longer tmax , lower %CV, and 26% decreased FI, as compared with TPM-IR. Further, switching between TPM-IR and USL255 did not affect TPM concentrations, including Cmin , immediately after transitioning and at steady state. SIGNIFICANCE: As compared with TPM-IR, USL255 provided equivalent plasma exposure with an extended absorption profile. Therefore, USL255 offers a once-daily alternative to twice-daily TPM-IR, with reduced TPM fluctuations.

Comparative pharmacokinetic analysis of USL255, a new once-daily extended-release formulation of topiramate.

PURPOSE: To compare the pharmacokinetics of USL255, a once-daily extended-release (ER) formulation of topiramate (TPM), with Topamax (immediate-release TPM) in healthy subjects after oral dosing and evaluate the effect of food on USL255 bioavailability and pharmacokinetics. METHODS: This randomized, single-center, open-label, cross-over design study had three dosing periods separated by 21 days of washout between treatments. Thirty-six volunteers received single doses of USL255 (200 mg) in fasted and fed conditions and two doses of Topamax (100 mg) administered 12 h apart. TPM plasma samples were analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetic parameters were calculated by noncompartmental methods. KEY FINDINGS: USL255 fasted pharmacokinetic parameters [point estimate (90% confidence interval, CI) compared to Topamax] were: relative bioavailability (F) 91.2% (84-99%), peak plasma concentration (C(max)) USL255/Topamax-ratio 59% (53-65%), time to reach C(max) (t(max)) 19.5 ± 7.2 h, accumulation ratio (R(ac)) 3.9 ± 1.2, effective half-life (t(1/2,eff)) 55.7 ± 19.9 h, terminal half-life (t(1/2,z)) 80.2 ± 14.2 h, and peak-occupancy-time (POT) 12.1 ± 4.0 h. Although the F and C(max) were unaffected by food, R(ac) and t(1/2,eff) increased to 4.9 ± 0.9, and 72.5 ± 15.4 h, respectively. In contrast to t(1/2,z,) t(1/2,eff) reflects absorption rate; therefore, USL255's t(1/2,eff) was significantly longer than Topamax's t(1/2,eff) (37.1 ± 6.5 h). SIGNIFICANCE: Although bioequivalent to Topamax in extent of absorption, USL255 had a slower absorption rate as reflected in its lower C(max) and longer t(max), larger POT and longer t(1/2,eff), and similar R(ac) values to that of Topamax (q12 h). This relative flat plasma profile allows for once-daily dosing with diminished fluctuations in TPM plasma levels. In addition, neither USL255's peak nor extent of plasma exposure of TPM was affected by food.

Estradiol gel 0.1% relieves vasomotor symptoms independent of age, ovarian status, or uterine status.

OBJECTIVE: Data from a pivotal efficacy trial have been reanalyzed to explore the impact of age, uterine status, and ovarian status on the efficacy of estradiol gel 0.1% (Divigel) for the treatment of moderate to severe vasomotor symptoms associated with menopause. METHODS: Post hoc analyses were performed on data from a phase III clinical trial of estradiol gel 0.1%. These analyses explored the effects of age (<50, 50-59, ≥60 y) and uterine and ovarian status (intact or absent) on the change from baseline to week 12 in the frequency and severity of moderate to severe vasomotor symptoms. The effects of age, uterine status, and ovarian status were investigated for each individual dose (1.0, 0.5, and 0.25 g) of estradiol gel 0.1% (separately and pooled) compared with those of placebo. RESULTS: Treatment with any dose of estradiol gel 0.1% reduced both the frequency and severity of moderate to severe vasomotor symptoms from baseline regardless of age, uterine status, or ovarian status. Women 50 years or older, regardless of uterine or ovarian status, treated with estradiol gel 0.1% showed improvement in vasomotor symptoms compared with women given matched placebo. No interactions were detected between estradiol gel 0.1% treatment and age, uterine status, or ovarian status on vasomotor symptom frequency or severity. CONCLUSIONS: Estradiol gel 0.1% treatment numerically decreased the frequency and severity of vasomotor symptoms in healthy, postmenopausal women independent of age, uterine status, or ovarian status. To our knowledge, these data are the first to directly explore the effects of age, hysterectomy, and oophorectomy on the efficacy of transdermal estrogen therapy.

Transdermal estradiol gel 0.1% for the treatment of vasomotor symptoms in postmenopausal women.

OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of three doses of estradiol gel 0.1% (Divigel, a novel formulation consisting of 1 mg estradiol per 1 g transdermal gel) to reduce the frequency and severity of vasomotor symptoms and signs of vulvar and vaginal atrophy associated with menopause. DESIGN: A total of 488 postmenopausal women were evaluated in a 12-week study comparing placebo with estradiol gel 0.1% at doses of 1.0, 0.5, and 0.25 mg/day, with estimated daily deliveries of 0.027, 0.009, and 0.003 mg of estradiol, respectively. Primary endpoints were the change from baseline in daily frequency and severity of moderate to severe vasomotor symptoms. Change from baseline in the signs of vulvar and vaginal atrophy (vaginal pH and percentage of superficial cells) was also assessed. RESULTS: Treatment with estradiol gel 0.1% showed statistically significant reductions in frequency and severity of vasomotor symptoms from baseline compared with placebo as early as Week 2 that were maintained throughout treatment. Signs of vulvar and vaginal atrophy were also significantly improved from baseline with all three doses of estradiol gel 0.1% compared with placebo. CONCLUSIONS: Low-dose transdermal estradiol gel 0.1% is an effective treatment for relief of vasomotor symptoms, as well as signs of vulvar and vaginal atrophy, associated with menopause. Estradiol gel 0.1% offers multiple dosing options to individualize patient therapy, including the lowest available effective dose (0.25 mg estradiol, delivering 0.003 mg/d estradiol) to treat the vasomotor symptoms of menopause.