Pharmacokinetics and Safety of Valtoco® (NRL-1; diazepam nasal spray) in Patients With Epilepsy During Seizure (Ictal/Peri-ictal) and Non-seizure (Inter-ictal) Conditions: Results from a Phase 1, Open-Label Study (1981)

Objective: To assess the pharmacokinetics and safety of NRL-1 (Valtoco®) in patients with epilepsy during ictal/peri-ictal and inter-ictal periods. Background: NRL-1 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. Design/Methods: Patients were diagnosed with partial or generalized epilepsy with motor seizures or seizures with clear alteration of awareness. Open-label intranasal NRL-1 was administered during two periods (ictal/peri-ictal and inter-ictal) ≥14 days apart. In both periods, one dose was administered (5, 10, 15, or 20 mg; based on weight), with a second dose permitted if seizures persisted. Blood samples were taken at pre-specified timepoints after dosing, analyzed for diazepam, and pharmacokinetic measures were calculated. Safety was assessed. Results: The study enrolled 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. A total of 49 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. 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 an acceptable safety profile. Disclosure: Dr. Hogan has received research support from UCB Pharmaceuticals, Neurelis Inc, Biogen Inc, and Engage Therapeutics. Dr. Tarquinio has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Marinus and Avexis. Dr. Sperling has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant/advisor: Medtronic (fee to institution); consultant: NeurologyLive. Dr. Sperling has received research support from (to institution): Eisai, Medtronic, Neurelis, Pfizer, SK Life Science, Inc., Takeda, UCB, Xenon. Dr. Klein has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting: Alliance, Aquestive, UCB Pharma, SK Life Science, Abbott. Ad Boards: Aquestive, Speaker’s honoraria: Aquestive, Eisai, Sunovion, UCB Pharma Research: Eisai. Dr. Klein has received compensation for serving on the Board of Directors of Alliance (medical advisory board). Dr. Klein has received research support from Yes, Eisai. Dr. Miller has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GW Pharmaceuticals, TS Alliance, DS Foundation, lnsys, Biomarin, Upsher-Smith, Visualase, Neuroblate, Zogenix, and Ultragenix. Dr. Miller has received personal compensation in an editorial capacity for Insys pharmaceuticals, GWPharma, TS Alliance, DS Foundation, Visualase, Neuroblate, Zogenix, and Ultragenix. Dr. Miller has received research support from GW Pharmaceuticals, TS Alliance, DS Foundation, lnsys, Biomarin, Upsher-Smith, Visualase, Neuroblate, Zogenix, and Ultragenix. Dr. Segal has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Eisai, Lundbeck, Nurticia, Novartis, Greenwich; Consultant: Greenwich, Epitel, Encoded Therapeutics, Qbiomed. Dr. Rabinowicz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Neurelis, Inc.. Dr. Rabinowicz has received compensation for serving on the Board of Directors of Neurelis, Inc.. Dr. Carrazana has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Neurelis, Inc.; Avekshan; Marinus; Zogenix, Hawaii Biotech. Dr. Carrazana has received compensation for serving on the Board of Directors of Neurelis, Inc.. Dr. Carrazana holds stock and/or stock options in Neurelis, Inc. which sponsored research in which Dr. Carrazana was involved as an investigator. Dr. Study Group has nothing to disclose.