Abstracts

Rationale: NRL-1 (ValtocoTM) is a diazepam nasal spray formulated with Intravail® A3 that is being investigated as a rapid, non-invasive, and socially acceptable route of administration in patients with epilepsy who experience seizure emergencies despite stable regimens of antiepileptic drugs. The purpose of this study was to assess the pharmacokinetics and safety of NRL-1 (intranasal diazepam) in patients with epilepsy during ictal/peri-ictal and inter-ictal periods. Methods: This was a Phase 1, open-label study. Enrolled patients were diagnosed with partial or generalized epilepsy with motor seizures or seizures with clear alteration of awareness. Informed consent was provided for all patients. A single dose of intranasal NRL-1 was administered during each of two periods (ie, ictal or peri-ictal conditions and inter-ictal conditions); dosing could be made in either order (ictal/peri-ictal or inter-ictal could be the first dose) with ≥14 days between as a washout. In both periods, the dose was administered based on weight (5, 10, 15, or 20 mg), with a second dose permitted if needed for treatment of seizures. Blood samples were taken at prespecified timepoints after dosing, with following diazepam pharmacokinetic measures. Safety was assessed. Results: The safety population included 57 patients aged 6–59 years. The median age was 31 years (age 6–11 years, n=11; 12–16 years, n=6; >16 years, n=40), 54.4% were female, and 80.7% were white. NRL-1 dose assignments were: 5 mg, n=0; 10 mg, n=13; 15 mg, n=19; and 20 mg, n=25. A total of 47 patients had complete pharmacokinetic data and were included in the primary pharmacokinetic analyses. Pharmacokinetic values were similar under ictal/peri-ictal and inter-ictal conditions (Table). The Figure shows mean plasma concentrations versus time curves for ictal/peri-ictal and inter-ictal conditions. Among all 57 patients, 17 (29.8%) had ≥1 treatment-emergent adverse event (TEAE). Of these, 8 patients (14%) had treatment-related TEAEs with those reported in ≥2 patients being dysgeusia (n=3; 5.3%) and nasal discomfort (n=2; 3.5%); no local toxicity was observed. One patient had serious TEAEs (recurrent seizures, toxic encephalopathy), which were deemed unrelated to study treatment. No patient required a second dose for persistent seizures. Conclusions: In this study, the epileptic condition (ictal/peri-ictal, inter-ictal) appeared to have minimal impact on intranasal NRL-1 diazepam pharmacokinetics in patients with epilepsy. NRL-1 demonstrated a good safety profile. Funding: Neurelis, Inc.