Rapid administration of diazepam improves cessation of cluster seizures and shortens seizure duration

This article was originally published on Neurology Live. It has been lightly edited.

New post hoc data from a recently completed Phase 3 trial (NCT02721069) evaluating Neurelis’ diazepam nasal spray (Valtoco), an FDA-approved antiepileptic drug (ASM), shows that faster dosing times are associated with greater Short epileptic cluster cessation times are associated with shorter epilepsy duration overall. The researchers also noted statistically significant changes in epileptic seizure interval (SEIVAL), or the time between seizure clusters, over a 12-month period that were independent of age with concomitant ASM changes.^1-3

These data are part of 2 poster presentations presented at the 35th International Epilepsy Congress (IEC), September 2-6, 2023, in Dublin, Ireland. In the first analysis, researchers assessed the temporal pattern of epilepsy clusters treated with diazepam nasal spray, while the second analysis characterized SEIVAL in treated individuals. Of the 175 enrolled patients aged 6 to 65 years, 163 patients received at least 1 dose of treatment, and 120 patients had SEIVAL data in Phase 1 and another phase.

To characterize temporal patterns, seizure cluster data were analyzed based on treatment time after seizure onset (0 to 5 minutes, 5 to 15 minutes, and more than 15 minutes). After excluding observations with seizure duration greater than 24 hours, negative duration, and invalid dose date/time values, 3325 observations were included. In the 0 to 5 minute group, the median time from onset of seizure to administration of diazepam nasal spray, time from administration to cessation, and total seizure duration were 1, 2, and 4 minutes, respectively. In the 5- to 15-minute group, the median times were 6, 7, and 15 minutes, respectively. Patients treated after 15 minutes had the least benefit, with median times of 35 minutes, 15 minutes, and 70 minutes.²

“Despite the availability of chronic, daily oral medications to help control seizures, many patients still experience acute recurrent seizures,” Adrian L. Rabinowicz, MD, chief medical officer of Neurelis, said in a statement.¹ “The clinical evidence presented at the IEC further supports the utility of VALTOCO in acute seizure management to minimize the potential negative consequences of seizures and have a meaningful impact on patients with epilepsy.”

The second analysis evaluated SEIVAL over 4 consecutive 90-day periods (total 360 days), paired t Test to assess statistical significance. A total of 76 patients had data for all 4 periods, representing a consistent cohort. In the general population, study results showed that mean SEIVAL increased from 14.8 days to 35.8 days in treated patients from Phase 1 to Phase 4. In the consistent cohort, mean SEIVAL increased from 13.9 days to 26.8 days (ask ≤ .001).

In the subgroup of pediatric participants aged 6 to 17 years (n = 32), mean SEIVAL increased from 13.0 to 25.9 days (ask = .02). In adults (n = 44), mean SEIVAL increased from 14.6 to 27.5 days (ask = .01). Of note, diazepam nasal spray treatment resulted in an increase in mean SEIVAL in patients with concomitant changes in ASM therapy (n = 56), ranging from 13.9 to 25.8 days, compared with 14.1 in patients without changes (n = 20) days increased to 29.6 days. The researchers concluded that these findings may “reflect changes in patient behavior or other factors, including the underlying pathophysiology of epileptic clusters.”

The initial Phase 3 study was an open-label trial consisting of a 12-month treatment period with study visits on day 30 and every 60 days thereafter, after which patients had the option to continue treatment. A total of 81.6% of patients had been exposed to diazepam nasal spray for at least 12 months. Throughout the observation period, there was 1 death due to sudden unexpected death from epilepsy and 1 discontinuation due to treatment-related AEs, both of which were considered unlikely to be related to treatment. Only 13 patients (7.9%) experienced nasal irritation symptoms without associated olfactory changes. The safety profile of diazepam nasal spray was generally similar across subgroups based on age, monthly use, concomitant benzodiazepine therapy, or seasonal allergy/rhinitis.

refer to
1. Neurelis will present an analysis of Valtoco (diazepam nasal spray) CIV at the 35th International Epilepsy Congress, emphasizing the impact on seizure timing. Press Releases. Nurelis. August 31, 2023. Accessed 6 September 2023. https://www.prnewswire.com/news-releases/neurelis-to-present-analysis-of-valtoco-diazepam-nasal-spray-civ-highlighting-effects-on -Seizure time to 35th International Epilepsy Congress
2. Misra SN, Jarrar R, Stern JM, Becker DA, Rabinowicz AL, Carrazana E. Faster treatment of cluster seizures with diazepam nasal spray is associated with faster cessation of cluster seizures: a post hoc analysis. Presented at: International Epilepsy Congress 2023; September 2-6; Dublin, Ireland. Abstract 243.
3. Misra SN, Sperling MR, Rao VR, et al. Significant improvement in SEizure InterVAL (time between seizure clusters) over time: a post hoc analysis of a long-term, open-label study of diazepam nasal spray. Presented at: International Epilepsy Congress 2023; September 2-6; Dublin, Ireland. Abstract 655.
4. Wheless JW, Miller I, Hogan RE, et al. Final results from a Phase 3 long-term, open-label, repeat-dose safety study of diazepam nasal spray for the treatment of cluster seizures in patients with epilepsy. epilepsy.

2021;62(10):2485-2495. doi:10.1111/epi.17041