Safety and Tolerability of NRL-1, an Intranasal Formulation of Diazepam, in Relationship to Usage Frequency in Subjects With Epilepsy: Interim Results From a Phase 3, Open-label, Repeat Dose Study

Objective: To evaluate long-term safety and tolerability of NRL-1 (Valtoco®, diazepam nasal spray formulated with Intravail A3) among patients having moderate or frequent monthly usage. Background: NRL-1 provides a rapid and non-invasive route of diazepam administration for individuals with epilepsy who experience seizure emergencies despite stable regimens of antiepileptic drugs. Design/Methods: This open-label, Phase 3 study included adults and children/adolescents with epilepsy. NRL-1 was administered at 5, 10, 15, or 20 mg based on patient weight, with a second dose administered if needed 4 to 12 hours later. This interim analysis evaluated safety and tolerability stratified by frequency of use (moderate [1–2 doses/month]; 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%) and frequent in 67 (50.8%) patients. At the time of this analysis, the study retention rate was ≥90%. No trends were observed for TEAEs or clinical/laboratory tests with higher usage frequency; the reports of nasal irritation were mild and transient. Overall, 91 patients (68.9%) had TEAEs, with a numerically higher incidence with frequent (76.1%) relative to moderate use (61.5%). The most common TEAEs generally had a numerically higher incidence with frequent use. The one TEAE-related (not treatment-related) discontinuation was in a frequent user. Smell tests showed minimal, transient olfactory changes that did not appear to be related to usage frequency. Conclusions: In this interim analysis, repeat dosing of NRL-1 demonstrated an acceptable safety/tolerability profile consistent with what may be expected for diazepam administered via other routes and which appeared to be independent of usage frequency.