Abstracts

Rationale: NRL-1 (diazepam intranasal solution) has been developed for management of patients with epilepsy who are on stable regimen of antiepileptic drugs (AEDs) and who require intermittent use of diazepam to control bouts of increased seizure activity (i.e. cluster or acute repetitive seizures [ARS]). The comparative bioavailability and safety of diazepam after administration of NRL-1 and diazepam rectal gel (Diastat), with oral diazepam (Valium) as the safety reference compound, were evaluated in a Phase 1 study. The primary objective was to assess the comparative bioavailability of NRL-1 and Diastat in healthy volunteers under fasted conditions. Methods: This was a Phase 1, open-label, randomized, single-dose, three-treatment, three-period, six-sequence crossover study in 48 normal, fasted, volunteers.  There were three diazepam treatments: NRL-1, Diastat®, or oral Valium® (a study reference drug).  NRL-1 and Diastat were dosed as 15 or 20 mg based on subject’s age and body weight. Valium was dosed at 10 mg (oral tablets). Blood samples were collected for 240 hours after dosing.  The inter-period washout was = 28 days. Safety and tolerability were evaluated through adverse events (AEs) monitoring, as well physical examination, vital signs, EKGs, and clinical laboratory tests. Results: A total of 48 healthy male and female volunteers were enrolled and 46 received the study drug. Forty-four (44) volunteers completed the study.  The t_max for NRL-1 was comparable to that of Diastat. Variability in C_max and AUC_0-8 when expressed as %CV (coefficient of variation) geometric mean was lower with NRL-1 when compared with Diastat.Forty-six (46) subjects that received the study drug were included in the safety analysis. No subjects discontinued the study due to adverse events (AEs). The overall frequency of treatment emergent adverse events (TEAEs) was 60.9% in the NRL-1 treatment group, 93.5% in the Diastat group, and 84.8% in the Valium group. Majority of TEAEs were reported mild (>90%) and moderate (<9%). The most commonly reported TEAEs in the study was somnolence (Diastat – 89.1%, NRL-1 – 56.5%, and Valium – 82.6%). There were no serious AEs (SAEs) and no deaths reported in the study. Conclusions: Overall, NRL-1 (15mg and 20 mg) showed comparable exposure to Diastat in all pharmacokinetics parameters. Variability in Cmax and AUC was lower with NRL-1 compared to Diastat. NRL-1 appeared to be safe and well tolerated in this study. These data suggest that NRL-1 has promise in patients who may require intermittent use of diazepam to control bouts of increased seizure activity.  Funding: The study was funded by Neurelis, Inc.