Authors :
Presenting Author: Jurriaan Peters, MD PhD – Boston Children's Hospital
Eric Segal, MD – Hackensack University Medical Center and Northeast Regional Epilepsy Group and Hackensack Meridian School of Medicine
Author: James Wheless, BScPharm, MD, FAAP, FACP, FAAN, FAES, FCNS – University of Tennessee Health Science Center and Le Bonheur Children's Hospital
Steven M Wolf, MD – Westchester Medical Center, Hawthorne, NY, United States
Muhammad Zafar, MD – Duke University School of Medicine
Charles Davis, PhD – CSD Biostatistics, Inc.
Leock Ngo, PhD – Neurelis, Inc.
Miguel Lopez-Toledano, PhD – Neurelis, Inc.
Adrian Rabinowicz, MD – Neurelis, Inc., Center for Molecular Biology and Biotechnology (CMBB) in the Charles E. Schmidt Collage of Science at Florida Atlantic University
Enrique Carrazana, MD – Neurelis, Inc., John A. Burns School of Medicine; University of Hawaii, Honolulu, HI
Rationale:
Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥2 years. In a post hoc analysis of a previous phase 3, long-term, safety study of diazepam nasal spray in patients aged 6-65 years, the days between treated seizure clusters (SEIzure interVAL [SEIVAL]) approximately doubled at 1 year when assessed in 90-day periods. Here, we examined SEIVAL in children aged 2-5 years enrolled in a phase 1/2a, open-label pharmacokinetics study of diazepam nasal spray that included a 180-day open-label safety period and an optional extension period (NCT05076838).Methods:
Caregivers administered diazepam nasal spray to patients aged 2-5 years (0.5 mg/kg) for the treatment of seizure clusters. SEIVAL was determined for all patients with ≥2 treatments (ie, ≥1 SEIVAL), as well as for those with ≥1 SEIVAL in consecutive 90- and 70-day periods (consistent cohorts). SEIVAL in consistent cohorts was evaluated in consecutive periods including ≥5 patients, and the 70-day period was based on a reanalysis of SEIVAL data from the phase 3 safety study in patients aged 6-65 years and evaluated a priori in the present study. Safety outcomes were recorded.Results:
Of the 36 patients enrolled, 19 (52.8%) were aged 2-3 years and 17 (47.2%) were 4-5 years; 27 (75%) completed the optional extension. Across all patients in the study, mean (SD) SEIVAL increased from 13.2 (14.5) days in Period 1 (days 1-90) to 26.4 (40.7) days in Period 4 (days 271-360, Figure 1). Seven patients had at least 1 SEIVAL in each of the first three 90-day periods (270 days total). In this 270-day consistent cohort (Figure 2), mean SEIVAL increased from 13.8 (13.7) days in Period 1 (days 1-90) to 19.4 (19.9) days in Period 3 (days 181-270). Eight patients had at least 1 SEIVAL in each of the first three 70-day periods (210 days total). In this 210-day consistent cohort (Figure 2), mean SEIVAL increased from 9.2 (9.2) days in Period 1 (days 1-70) to 12.7 (14.6) days in Period 3 (days 141-210). Treatment emergent adverse events (TEAEs) and treatment-related TEAEs were reported by 66.7% and 19.4% of patients in the safety period and 88.9% and 3.7% in the extension period. Respiratory depression, acute respiratory failure, and respiratory failure occurred in 1 patient each and none were considered treatment-related.
Conclusions:
In children aged 2-5 years who used diazepam nasal spray to treat seizure clusters, the interval between treated seizures substantially lengthened over time in these small groups. The increase in SEIVAL in young children is consistent with results reported in older patients aged 6-65 years enrolled in a phase 3 study of diazepam nasal spray. These findings suggest a beneficial long-term treatment effect of diazepam nasal spray as an intermittent seizure medication.Funding: Neurelis, Inc.