Authors :
Presenting Author: James Wheless, BScPharm, MD, FAAP, FACP, FAAN, FAES – LeBonheur Children’s Hospital
Eric Segal, MD – Hackensack University Medical Center, Hackensack Meridian School of Health, and Northeast Regional Epilepsy Group
Evelyn Shih, MD, PhD – Neurelis, Inc.
Muhammad Zafar, MD, FACNS – Duke University Hospital
Leock Ngo, PhD – Neurelis, Inc.
Enrique Carrazana, MD – Neurelis, Inc; John A. Burns School of Medicine, University of Hawaii
Adrian Rabinowicz, MD – Neurelis, Inc.; Center for Molecular Biology and Biotechnology, Charles E. Schmidt College of Science, Florida Atlantic University
Rationale: Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy age ≥6 y with age-based dosing of 0.2 and 0.3 mg/kg. A second dose may be used ≥4 h after the first if needed. The use of a second dose within 24 hours of the initial dose to treat a cluster as a proxy measure of treatment effectiveness has been published in patients aged 6-65 y (Sperling MR, et al.
Epilepsia. 2022;63:836-843). This post-hoc analysis reports the use of second doses in patients aged 2–5 y from an ongoing phase 1/2a study of diazepam nasal spray.
Methods: 35 patients aged 2–5 y with epilepsy and seizure clusters participated in an ongoing phase 1/2a, open-label, pharmacokinetic (PK) and safety study that consisted of a single-day PK assessment period, 180-day open-label safety period, and ≥1-y optional extension period. Caregivers were supplied with diazepam nasal spray (0.5 mg/kg) to administer as needed to treat seizure clusters. Doses were based on body weight, and a second dose could be administered as needed 4–12 hours after the initial dose. Dosage could be adjusted by the investigator for efficacy or safety reasons. Nasal-spray usage and seizure diary data collected during the 180-day open-label safety period were included in this post-hoc analysis.
Results: Of the 35 patients enrolled and treated, 31 (88.6%) completed the 180-day safety period as of October 2023. Mean age was 3.9 y (range: 2.0–5.8 y).
264 doses of diazepam nasal spray were administered during the 180-day period (5 mg, 8 doses [n=3 patients]; 10 mg, 210 doses [n=28]; 15 mg, 46 doses [n=4]). Out of the 264 total doses, 37 (14.0%) were administered as second doses ≤24 hours after the first. Therefore, 86.0% of doses were given without a second dose (
Figure). 10 patients (28.6%) received second doses within 24 hours of the initial dose, of whom 8 (80%) received a second dose in < 4 hours at least once.
Of the total doses, 162 (61.4%) were administered to treat seizure clusters, defined here as ≥2 seizures documented as occurring within a 24-hour period. Treatment-related treatment-emergent adverse events were reported in 7 patients (20.0%); none occurred in >1 patient, and none were serious.
Conclusions: In this interim analysis of diazepam nasal spray for the treatment of seizure clusters in pediatric patients aged 2–5 y, a low proportion of seizure events (14.0%) was treated with a second dose within 24-hours of the first. Rates were comparable to pediatric patients aged ≥6 y in the prior phase 3, long-term, open-label safety study, in which 11.4% of seizure clusters were treated with second doses, with rates of 11.5% and 11.3% in the 6–11 and 12–17 age groups, respectively (
Figure) (Tarquinio D, et al.
Pediatr Neurol. 2022;132:50-55). In the present study, 28.6% of patients received ≥1 second dose compared with 52.6% of patients 6–17 y in the phase 3 study. Together, these results support the effectiveness of the age-based dosing regimen for diazepam nasal spray.
Funding: Neurelis, Inc.