Abstracts

Rationale: Midazolam (MDZ) nasal spray (USL261) is in development as rescue treatment for individuals with intermittent bouts of increased seizure activity; currently, rectal diazepam is the only FDA-approved non-intravenous alternative. USL261 has demonstrated a positive safety and tolerability profile in adolescents, adults, and geriatric individuals. An objective of this study was to characterize the safety and tolerability of USL261 in pediatric subjects with epilepsy to inform its potential use in this population. Methods: This open-label, phase 1 study evaluated single doses of USL261 in pediatric subjects (aged 2 ?" 13) with focal or generalized epilepsy. After screening, subjects were assigned to 5.0, 2.5, or 1.25 mg USL261 by body weight (?-40 to =60 kg, ?-20 to < 40 kg, and ?-10 to < 20 kg, respectively). The safety population consisted of all individuals receiving one dose of study drug. Safety and tolerability assessments included incidence of treatment-emergent adverse events (TEAEs); vital sign measurements; clinical laboratory evaluations; suicidal behavior evaluation (Columbia Suicide Severity Rating Scale); and nasal, physical, and neurological examinations. Results: Thirty-six subjects were enrolled (n=12/cohort) and included in the safety population; all subjects completed the study. Aside from expected age, weight, and BMI differences, demographic and baseline characteristics were generally similar across the three dosing cohorts. A total of 25 subjects (69.4%) had at least one TEAE, with similar TEAE incidence across cohorts (58.3%, 75.0%, and 75.0% each in the 5.0, 2.5, and 1.25 mg cohorts, respectively). Of the 58 reported TEAEs, 82.8% were considered mild and 77.6% were reported as related to study drug. The most common TEAEs (n, % of subjects) were somnolence (21, 58.3%), product taste abnormal (4, 11.1%), and nasal discomfort (3, 8.3%). No treatment-related serious adverse events were reported. Changes in vital signs and clinical laboratory results (hematology and chemistry) revealed no overall patterns of clinical concern. At screening, one individual (5.0 mg cohort) had a suicidal ideation assessment of a wish to be dead during the past 6 months; no subjects had any suicidal ideation or behavior at any time point during the study. There were no clinically significant abnormal nasal results. Physical and neurological examination results were similar between screening and follow-up; the few abnormal neurological findings considered clinically significant were also present at screening. Conclusions: USL261?"MDZ nasal spray?"was generally well tolerated in pediatric subjects across a range of single doses, with no clinically meaningful safety concerns. These safety and tolerability results support the continued development of USL261 in pediatric patients with epilepsy. Funding: Supported by Upsher-Smith Laboratories, Inc.