Abstracts

Is Disease Modification in Seizure Clusters Possible? Results from the Long-term Safety Study of Diazepam Nasal Spray

Abstract number : 1.41
Submission category : 7. Anti-seizure Medications / 7B. Clinical Trials
Year : 2024
Submission ID : 988
Source : www.aesnet.org
Presentation date : 12/7/2024 12:00:00 AM
Published date :

Authors :
Presenting Author: Michael Sperling, MD – Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

Jurriaan Peters, MD PhD – Boston Children’s Hospital, Harvard Medical School
Charles Davis, PhD – CSD Biostatistics, Inc
Adrian Rabinowicz, MD – Neurelis, Inc.; Center for Molecular Biology and Biotechnology, Charles E. Schmidt College of Science, Florida Atlantic University
Enrique Carrazana, MD – Neurelis, Inc; John A. Burns School of Medicine, University of Hawaii

Rationale: Historically, immediate-use seizure medications (ISMs; also called rescue treatments) have been evaluated based on short-term control of seizure clusters (eg, across 24 h). Although seizure frequency and interval are commonly measured for daily antiseizure medications (ASMs), their meaning for ISMs is unclear. Additionally, disease modification remains a key unmet need. Using data from a long-term safety study, we explored the hypothesis that diazepam nasal spray may have a role in disease modification for seizure clusters. Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years.


Methods: Drug administration from the long-term, open-label safety study of diazepam nasal spray was recorded in diaries of 163 treated patients. Data from the subset of 76 patients who received ≥2 doses of diazepam nasal spray during each of four 90-day periods (~1 y) were included in exploratory analyses of mean interval between treated seizure clusters (SEIVAL) over time. Statistical significance was assessed by 2-sided paired t-test and by 2-sided Wilcoxon signed rank test. Outcomes from the overall SEIVAL analysis and from subanalyses of specific subgroups were compared to test whether they were similar and to investigate the hypothesis of disease-modifying potential in a broad group of patients.

Results: When examining seizure clusters treated with diazepam nasal spray in the overall study population with SEIVAL data, a post hoc analysis found increasing mean duration between seizure clusters with as-needed use over a 1-year period; there was a doubling in time between mean SEIVAL for the first 90-day period compared with that for the last 90-day period (to day 360). The same pattern was seen whether or not data for re-treatments for the same seizure were included (both P≤0.001 [t-test] period 4 mean compared with period 1). The pattern from that overall analysis was used as baseline for comparison of patterns found in subanalyses of the SEIVAL metric (Fig). SEIVAL results were found to be consistent with the baseline pattern in patient age subgroups (pediatric and adults), by patient sex, whether there were changes to concomitant ASMs, in patients with developmental epileptic encephalopathies (DEEs), and in seizures that were ongoing and treated in 5–15 min (ie, prolonged seizures), as well as in patients who reported self-administering diazepam nasal spray.

Conclusions: In the long-term safety study of diazepam nasal spray, analyses of the SEIVAL metric demonstrated strikingly similar increases in time between treated seizure clusters in all analyses. Although the underlying cause of this observation is unknown and the natural history of SEIVAL is yet to be defined, these consistent findings, even in patients with DEEs, suggest that the reduction is not a statistical artifact and may reflect a disease-modifying process with administration of diazepam nasal spray as needed over 1 year. Additional studies to help elucidate the measuring of SEIVAL are needed.

Funding:
Neurelis, Inc.




Anti-seizure Medications