MAPLE GROVE, Minn., Aug. 13, 2013 /PRNewswire/ -- Upsher-Smith Laboratories, Inc.'s, USL255 (extended-release topiramate), an investigational once-daily formulation for the management of epilepsy, demonstrated equivalent systemic exposure with an improved topiramate (TPM) pharmacokinetic (PK) profile at steady-state, as measured by a significantly lower Cmax (P<0.001) and higher Cmin (P<0.001), when compared to immediate-release topiramate (TPM-IR) administered twice daily in healthy volunteers. Additionally, upon switching from TPM-IR, USL255 maintained steady state topiramate concentrations. Although both study drugs were generally well tolerated in the healthy volunteers, subjects receiving 200 mg/day of USL255 were observed to have fewer side effects related to cognition and memory impairment than those receiving TPM-IR (1/36 for USL255 vs 3/38, and 0/36 for USL255 vs 3/38, respectively). The study was published in the August issue of Epilepsia. (The Journal of the International League Against Epilepsy-ILAE).
"The goal of therapy with antiepileptic drugs is freedom from seizures and absence of side effects. While many individuals with epilepsy are successfully treated with one or more of the currently available AEDs, a substantial number still live with uncontrolled seizures or intolerable side effects," said Meir Bialer, PharmD, lead study investigator. "The results from this study suggest that USL255's improved PK profile, reduced fluctuations in topiramate steady-state plasma concentrations and favorable tolerability findings may offer patients a once-daily alternative to twice-daily commercially available immediate-release topiramate."
About the Study
The comparative study, published in Epilepsia, was designed to compare the steady-state PK profile of USL255 (200 mg QD) to TPM-IR (100 mg Q12h) in the same healthy subjects. The randomized, open-label, single-center, two-way crossover, multiple-dose study consisted of a 12-day up-titration, two 14-day maintenance periods with an immediate crossover between periods, followed by an 8-day down-titration.
Thirty-eight healthy adult subjects between the ages of 18 and 65 were randomized 1:1 to receive either USL255 or TPM-IR during up-titration and Period 1, and were switched to the alternate formulation (without washout) for Period 2, followed by down-titration.
At steady state, USL255 exhibited a smaller fluctuation in topiramate plasma concentration and significantly lower variability in topiramate concentrations over 24 hours compared to TPM-IR.
Because switching from one formulation of an AED to another can lead to potential problems such as varied treatment response, breakthrough seizures, and/or increased adverse events, the study also evaluated the effects of switching TPM formulations on PK parameters. Steady-state topiramate concentrations were maintained after switching topiramate formulations (TPM-IR to USL255 or USL255 to TPM-IR), and the PK parameters of Cmin, AUC and Cmax met criteria for bioequivalence for the two formulations.
USL255 was observed to be generally well tolerated in healthy subjects. The treatment-emergent adverse events (TEAEs) seen in this study were mild in intensity. Although the most common TEAEs occurred with similar frequency in both groups, subjects receiving USL255 were observed to have fewer side effects related to cognition and memory impairment than those receiving TPM-IR.
About Upsher-Smith's Phase III (PREVAIL) Clinical Trial
Upsher-Smith recently announced the successful completion of its global Phase III (PREVAIL) clinical trial for USL255 and that its New Drug Application for USL255 has been accepted for review by the U.S. Food and Drug Administration (FDA).
The PREVAIL trial was a randomized, multicenter, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy and safety of USL255 as adjunctive therapy in patients with refractory partial-onset seizures (POS). Preliminary findings from the Phase III trial will be submitted for presentation at the 2013 Annual Meeting of the American Epilepsy Society (AES), December 6-10 in Washington, D.C.
PREVAIL was conducted under a Special Protocol Assessment (SPA) agreement with the FDA. More information about the trial is available at www.clinicaltrials.gov (NCT01142193).
An open-label extension study to evaluate the safety of USL255 as adjunctive therapy in patients with refractory POS who had participated in PREVAIL is ongoing. The open-label extension study can be found by searching NCT01191086 on www.clinicaltrials.gov.
Epilepsy is a medical condition that causes seizures affecting a variety of cognitive and physical functions. More than two million people in the U.S. are estimated to be affected by epilepsy with about 200,000 new cases of epilepsy diagnosed each year.1 For many people with epilepsy, medication will prevent seizures if taken regularly, but some people continue to have seizures.1 As many as two out of three patients treated for epilepsy have seizures that are refractory to therapy, either because they have incomplete control of their seizures or they experience treatment-related side effects that interfere with their quality of life.2
Upsher-Smith's Epilepsy Pipeline
Upsher-Smith's clinical development pipeline includes three investigational drugs that are being studied for the management of epilepsy. USL255 is an investigational once-daily, extended-release topiramate for the management of epilepsy. The pipeline also includes USL261, an investigational intranasal midazolam for the rescue treatment of seizures in patients who require control of intermittent bouts of increased seizure activity, often called seizure clusters, which is the subject of an ongoing international Phase III clinical trial (ARTEMIS1) with an open-label safety extension study. In addition, USL260 (tonabersat) is in early clinical development as a potential first-in-class neuronal gap junction modulator.
Upsher-Smith, founded in 1919, is an independent and privately-owned specialty pharmaceutical company headquartered in Maple Grove, Minnesota that focuses on product growth and innovation for branded and generic pharmaceuticals. Upsher-Smith has a particular focus on developing therapies to assist people suffering from central nervous system diseases and also markets products relating to cardiology, dermatology, and women's health. For more information, visit www.upsher-smith.com.
SOURCE Upsher-Smith Laboratories, Inc.