Global phase III study to provide novel extended release of topiramate

Data presented yesterday showed that USL255, a novel extended-release (ER) formulation of topiramate, was associated with less fluctuation in topiramate plasma levels than immediate-release (IR) topiramate in healthy volunteers.  

These and other findings from the USL255 early development program were presented Sunday, Dec. 5, at the 64th annual American Epilepsy Society (AES) meeting in San Antonio, TX.  USL255, developed by Upsher-Smith Laboratories, Inc. and now the subject of a global Phase III clinical study, is designed to provide convenient once-daily dosing with smoother topiramate plasma levels than traditional IR dosage forms.  

"Fluctuation in plasma levels of certain antiepileptic drugs is thought to have the potential to contribute to increased side effects for patients with epilepsy during peak concentrations or to "break-through" seizures at trough concentrations just prior to the next dose.  Therefore, a topiramate formulation that could offer reduced fluctuation in plasma levels is of interest to many clinicians," said Mark Halvorsen, Pharm.D., Senior Director, Clinical Development.  

Abstracts of the poster presentations can be found online at www.aesnet.org. Titles and authors are:

• "Development and Optimization of Extended-Release Formulations of Topiramate." Authors: Lawrence J. Lambrecht, Mark B. Halvorsen, Michael J. Boulware, Wesley M. Todd, John A. Carrithers
• "The Effect of Food on the Bioavailability of USL255, A Novel Extended-Release Formulation of Topiramate." Authors: Wesley M. Todd, Lawrence J. Lambrecht, Michael J. Boulware, Mark B. Halvorsen
• "Pharmacokinetic Equivalence Between Immediate-Release Topiramate and USL255, a Novel Extended-Release Formulation of Topiramate." Authors: Mark B. Halvorsen, Lawrence J. Lambrecht, Michael J. Boulware, Wesley M. Todd

The studies that are the subjects of these posters have been conducted by Upsher-Smith to characterize the pharmacokinetic profile of USL255.  The first poster presented data from numerous internally developed topiramate ER formulations.  The objective of the research presented was to identify a once daily ER formulation with a lower maximum plasma concentration, a higher trough concentration, and an equivalent extent of exposure as compared to IR topiramate.  The PK data from the experimental formulations were compared to IR topiramate, after single doses and/or at simulated steady-state.  Results have aided USL researchers in the formulation selection for USL255.

In another study and second poster presentation, the effect of food on the bioavailability of USL255 was assessed.  In this phase I, randomized, single-dose, crossover study, 36 healthy subjects received three different treatments (200 mg of USL255 under fasting conditions; 200 mg of USL255 with a high fat meal; or 2 doses of 100 mg IR topiramate dosed 12 hours apart).  Based on PK measurements and using standard bioequivalence criteria, the authors determined that the overall extent of absorption of USL255 was not affected by food. However, the presence of food was associated with a delay in the time to maximal plasma concentration of topiramate, a finding that was deemed consistent with the food effect on IR topiramate pharmacokinetics.  

In the third poster, data from the same study compared two 100 mg doses of IR topiramate (administered 12 hours apart) and a single 200 mg dose of USL255 for pharmacokinetic equivalence, using standard bioequivalence criteria.  The authors reported that administration of 200 mg of USL255 in healthy volunteers provided equivalent topiramate exposure as compared with the 100 mg IR topiramate administered twice daily.  USL255 also showed a lower maximum plasma concentration than IR topiramate.  

"We are excited about the progress we have made in our development of USL255 and encouraged that USL255 may offer an improved PK profile compared with IR topiramate," Halvorsen added.  "We are committed to the development of USL255 for patients with refractory partial-onset seizures as part of USL's ongoing commitment to become a leader in providing therapies that empower people suffering from CNS diseases to lead healthy, productive lives."

In a related development, Upsher-Smith recently announced the addition of an open-label extension study of its ongoing global Phase III clinical trial (PREVAIL) for USL255.  The Phase III clinical trial is currently being conducted under a Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA).

Upsher-Smith's Expanding CNS Pipeline

USL255 is the lead investigational drug in Upsher-Smith's expanding central nervous system (CNS) development pipeline, with an anticipated indication for the adjunctive treatment of adult epilepsy patients with partial onset seizures (POS).  USL's pipeline includes a number of other investigational drug programs.  Another program in this pipeline, USL261 (nasal midazolam) is under development for the management of increased bouts of seizure activity, including acute repetitive seizures and seizure clusters, in epilepsy.  Other programs include USL260 (tonabersat), an investigational drug and first-in-class neuronal gap junction modulator for the potential treatment of epilepsy.  Upsher-Smith has previously announced its partnership with Proximagen Group Plc for the PRX1 program for the symptomatic treatment of Parkinson's disease, in which Upsher-Smith is responsible for the world-wide development and commercialization of PRX1 under the direction of a joint steering committee on which there is representation of both Upsher-Smith and Proximagen.