Abstracts

Rationale: NRL-1 (Valtoco™; 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. As frequency of NRL-1 use will likely vary among patients, it is important to determine whether long-term safety and tolerability are related to monthly usage frequency.  Methods: In this interim analysis of an ongoing study, patients are adults and children/adolescents with epilepsy who provided written informed consent. Caregivers and patients were trained in the use of the intranasal sprayer. During patient follow-up of up to 1 year, NRL-1 was administered at 5, 10, 15, or 20 mg based on patient's weight, with a second dose administered if needed 4 to 12 hours later. Doses could be adjusted by the investigator for efficacy or safety. The current analysis evaluated safety and tolerability stratified by frequency of use based on average number of doses/month, defined as moderate (1-2 doses/month) and frequent (>2 doses/month). Treatment-emergent adverse events (TEAEs) are reported. Tolerability included nasal irritation measured objectively on a 6-point scale and olfactory changes on the NIH Toolbox Odor Identification Test.  Results: Among 132 enrolled subjects (6 to 65 years old; 53.8% female; 82.6% white), 2485 seizure episodes were treated with NRL-1. Use was moderate in 65 (49.2%) patients and frequent in 67 (50.8%) patients. Overall, 91 patients (68.9%) had TEAEs, with a numerically higher incidence with frequent (76.1%) relative to moderate use (61.5%). One TEAE-related discontinuation (major depression and anxiety) was in a frequent user; 37 patients (28.0%) had serious TEAEs, none of which was deemed related to treatment. The most common TEAEs generally had a numerically higher incidence with frequent use relative to moderate use (Table). While there were relatively few treatment-related TEAEs overall, the most common of these (nasal discomfort, headache, epistaxis, and rhinalgia) were numerically higher in frequent users (Table). The single report of TEAE of sedation was with moderate usage. No clinically relevant trends were observed for usage frequency effects on clinical or laboratory parameters. The few reports of nasal irritation were mild (maximum grade 1B; superficial mucosal erosion) with a slightly higher incidence in frequent users. Smell tests showed minimal olfactory changes that did not appear to be related to usage frequency. The study retention rate is >=90%.  Conclusions: In this interim analysis of long-term safety and tolerability, repeat dosing of NRL‑1 demonstrated a safety/tolerability profile consistent with what may be expected for diazepam and which appeared to be independent of usage frequency. No trends were observed for TEAEs, clinical/laboratory tests, or olfactory changes with higher usage frequency; nasal irritation was mild.  Funding: Neurelis, Inc.