Abstracts

Rationale: Valtoco™ (NRL-1; diazepam nasal spray formulated with Intravail® A3) provides a rapid and non-invasive route of diazepam administration for individuals with epilepsy who experience seizure emergencies despite stable regimens of antiepileptic drugs. Aspects of tolerability related to nasal administration and to diazepam are of clinical interest. Methods: Subjects had a clinical diagnosis of partial or generalized epilepsy with motor seizures or seizures with clear alteration of awareness. Two doses of open-label intranasal NRL-1 were administered at 5, 10, 15, or 20 mg based on body weight – one dose during the ictal/peri-ictal period and a second inter-ictally; minimum interval between doses was 14 days. Safety and tolerability included treatment-emergent adverse events (TEAEs), clinical laboratory tests, vital signs, and ECGs. Other safety/tolerability outcomes include nasal irritation and sedation, both measured objectively using 6-point scales, and olfactory changes on the NIH Toolbox Odor Identification Test. Results: A total of 57 subjects (54.4% female; mean±SD age 28.1.0±15.3 years; 80.7% white) were enrolled and received ≥1 dose of study drug. Seventeen subjects (29.8%) reported TEAEs; none of the TEAEs resulted in discontinuation, and there were no treatment-related serious TEAEs. The most common TEAEs (≥2 subjects) were dysgeusia (5.3%), seizure (3.5%), nasopharyngitis (3.5%), and nasal discomfort (3.5%). The few reports of nasal irritation were mild and were more frequent under ictal/peri-ictal administration (Table 1). There were no reported TEAEs of somnolence, and while sedation scores indicated small increases in sedation overall, there was variability among the patients (Table 2). There were no clinically significant abnormalities noted for vital signs; specifically, there were no changes in respiratory rate in either the ictal/peri-ictal period or in the inter-ictal period with intranasal diazepam administration. Smell tests showed no clinically relevant olfactory changes. Conclusions: NRL-1 was well tolerated. Adverse events of specific relevance to clinicians or patients (sedation, nasal irritation, olfactory changes) were generally minor and transient. This compares favorably with rectal administration of diazepam, which is associated with sedation rates of 9% to 21%. Additionally, changes in respiratory rate and heart rate were not observed. Funding: Neurelis, Inc.