Safety and Pharmacodynamics of USL261, a Novel Intranasal Formulation of Midazolam, in Subjects with Epilepsy (P3.277)

OBJECTIVE: To assess the safety and degree/duration of sedation and psychomotor performance impairment following a single dose of USL261 in subjects with epilepsy on a stable antiepileptic drug regimen. BACKGROUND: USL261 is an investigational formulation of midazolam optimized for intranasal delivery for outpatient treatment of patients requiring control of intermittent bouts of increased seizure activity (eg, seizure clusters, or acute repetitive seizures). DESIGN/METHODS: This randomized, phase 1, open-label, inpatient study enrolled 90 subjects (12-65 years old) administered a single dose of USL261 2.5, 5.0, or 7.5 mg by a unit-dose nasal-spray device. Sedation was assessed pre- and up to 12 hours post dose using the Stanford Sleepiness Scale (SSS) and Observer’s Assessment of Alertness/Sedation Scale (OAA/S); psychomotor performance impairment was evaluated using the Digit Symbol Substitution Test (DSST). Safety, including respiratory rate and pulse oximetry, was monitored. RESULTS: Signs of sedation were evident 10 min after dosing, with mean peak sedation scores occurring between 1 and 2 hr for SSS and in 10% of subjects) being dysgeusia, oropharyngeal pain, rhinalgia, and burning sensation. CONCLUSION: USL261 at a single dose of up to 7.5 mg was well tolerated without prolonged/excessive sedation or psychomotor performance impairment effects in adult and adolescent subjects with epilepsy. Onset of pharmacodynamic effects was rapid (as early as 10 minutes post dose) with return to baseline function by 4 hours post dose, supporting further development for treatment of patients with intermittent bouts of increased seizure activity. STUDY SUPPORTED BY: Upsher-Smith Laboratories, Inc. Disclosure: Dr. Hayes has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee. Dr. Bancke has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee. Dr. Dworak has received personal compensation for activities with Upsher-Smith Laboratories, Inc.