Abstracts

Rationale: NRL-1 is a diazepam nasal spray being investigated as a rapid, non-invasive, and socially acceptable route of administration in patients (pts) with epilepsy with seizure emergencies despite stable regimens of antiepileptic drugs. The study was designed to assess the pharmacokinetics and safety of NRL-1 in pts with epilepsy. Early safety assessments of change from baseline (CFB) for vital signs and other safety procedures following administration of NRL-1 in the ictal/peri-ictal phase are presented. Methods: In this Phase 1 study, enrolled pts provided informed consent and were diagnosed with partial or generalized epilepsy with motor seizures or seizures with clear alteration of awareness. Intranasal NRL-1 was administered during two separate periods: (1) ictal or peri-ictal conditions and (2) inter-ictal conditions. One dose of NRL-1 (5, 10, 15, or 20 mg based on weight) was administered in each period, with a second dose permitted if seizures persisted. During the ictal/peri-ictal phase, administration was ideally 5 minutes after the onset of the seizure. First vital signs (temperature, respiratory rate, blood pressure, and pulse) assessments at 45 (±5) minutes post-dose are reported here. Acute nasal mucosal pain and nasal examination were assessed at multiple timepoints beginning at 15 and 30 minutes, respectively; timepoints prior to an hour post-dose are reported here. Acute nasal mucosal pain was assessed using a pt-marked, 100-mm visual analogue scale (VAS; 0 mm= no pain) and nasal examination was performed by a trained rater. Results: The safety population included 57 pts aged 6 to 59 years. Median age was 31 years (age 6–11 years, n=11; 12–16 years, n=6; >16 years, n=40), 54% were female, and 81% were white. NRL-1 dose assignments were: 5 mg, n=0; 10 mg, n=13; 15 mg, n=19; and 20 mg, n=25. Ictal/peri-ictal dosing data are available for 41 of 43 pts with seizures, 22 (51%) dosed during the peri-ictal phase and 19 (44%) in the ictal phase. Most common seizure types (≥5%) were absence (n=12 [28%]), tonic (n=10 [23%]), focal onset with impaired awareness and motor manifestations (n=9 [21%]), and tonic-clonic (n=4 [9%]). Regarding vital signs, there were no clinically meaningful differences from baseline at 45 (±5) minutes; respiratory rate was unchanged during the observed period (Table 1). For nasal mucosal pain, CFB on the VAS (mean [standard deviation]) was minimal at 15 (±5) minutes (baseline [n=34], 2.50 mm [13.721]; 15 minutes [n=29], 7.09 mm [21.290]; CFB, 4.33 mm [11.948]) and decreased at 30 minutes (n=29; 4.93 mm [19.539]; CFB, 2.17 mm [7.695]). Nasal examination events reported at 30 (±5) minutes were infrequent and mild, with 1 case of moderate mucosal erythema (redness) (Table 2). Conclusions: In this study, intranasal NRL-1 diazepam administered to pts with epilepsy during the ictal/peri-ictal phase demonstrated a good safety profile immediately post-dose for vital signs, nasal mucosal pain, and nasal examination. Funding: Neurelis, Inc.