Diazepam Nasal Spray Significantly Extends Time Between Seizure Clusters

Adrian Rabinowicz, MD

Results from an exploratory analysis of a 12-month study demonstrated that treatment with diazepam nasal spray (Valtoco; Neurelis) significantly increased the time between interseizure cluster intervals (ISCIs), which may reflect a salutary effect of cluster treatment.^1,2

From period 1 to period 4, the mean ISCIs for the 76-patient cohort increased significantly, from 12.2 days to 25.7 days (P <.01). Presented at the 2nd North American Epilepsy Congress, held virtually May 5-8, 2022, the study investigators concluded that these findings "raise the possibility that intermittent treatment alters the underlying biology of clusters, which should be evaluated in further studies."²

The phase 3 open-label, repeat-dose study included 163 patients with seizure clusters (SCs), aged 6 to 65 years, who received at least 1 dose of diazepam nasal spray. ISCIs were evaluated using 90-day periods for patients treated with at least 2 doses across period 1 and the following 3 periods. Of 151 patients with ISCI data, 120 had data in period 1 and another period, while 76 individuals had at least 1 ISCI in periods 1 to 4, or across the 1-year stretch.

In the 120-patient cohort, ISCIs increased from 14.8 days in period 1 (0-90 days; n = 120) to 35.8 days in period 4 (271-360 days; n = 87), which was statistically significant (P <.001). No effects of age, treatment duration, change in concomitant medications, or quality of life were observed.²

"Valtoco and other rescue therapies play a critical role in treatment plans for people with poorly controlled epilepsy and seizure clusters," study investigator Adrian Rabinowicz, MD, senior vice president, Clinical Development and Medical Affairs, Neurelis, said in a statement.¹ “These latest SEIVAL (SEIzure InterVAL) results lend themselves to a hypothesis that intermittent treatment should be further studied to investigate potential biological and behavioral changes that may impact the natural course of seizure clusters."

The long-term safety of diazepam was evaluated in a separate analysis using the same cohort of patients. Here, patients received 5- to 20-mg doses of diazepam based on age (≤11 years and ≥12 years, respectively) and weight, with second doses administered 4 to 12 hours later if needed. Among the 163 treated patients (6-11 years: 27.6%; ≥12 years: 72.4%), 77.8% (35 of 45) of patients aged 6 to 11 years and 83.1% (98 of 118) of patients aged at least 12 years were exposure to treatment for at least 12 months.³

In total, the 6 to 11 years age group had 784 SCs and 90 (11.5%) individuals used a second dose. Of those, 22 patients administered their second dose within 4 hours of their first, 7 between 4 to 6 hours after, 22 between 6 to 12 hours, and 39 between 12 to 24 hours. For the older group, 3069 SCs were recorded, with 395 (12.9%) needing second doses. Similarly, the timing of the second medication varied, with 130 individuals administering diazepam within 4 hours, 65 within 4 to 6 hours, 234 within 6 to 12 hours, and 105 in 12 to 24 hours.

The safety profile of intranasal diazepam was consistent with the rectal form of the medication, with no serious treatment-emergent adverse events (TEAEs) considered treatment related. TEAEs occurred in 91.1% of patients in the 6 to 11 years age group, 40% of which were serious, and 6.7% considered treatment related. For those older than 12 years, 78.8% experienced TEAEs; 27.1% were serious, and 22.9% were considered treatment related. Notably, there was 1 death in the study, but it was not treatment related. Between the 2 groups, the retention rates until study closure were 75.5% and 76.3%, respectively.

"We continue to explore the robust data set generated by the VALTOCO phase 3 study in people with uncontrolled epilepsy that experience episodes of frequent seizure activity," study investigator Sunita Misra, MD, senior medical director, Neurelis, said in a statement.¹ "This data has the potential of evolving the landscape of care for epilepsy patients in the future and we are incredibly encouraged by the exploratory analysis generated thus far."

REFERENCES
1. Data from novel, exploratory analysis of intermittent valtoco (diazepam nasal spray) CIV use indicates more than two-fold increase in mean interval between seizure clusters. News release. Neurelis. May 5, 2022. Accessed May 18, 2022. https://www.prnewswire.com/news-releases/data-from-novel-exploratory-analysis-of-intermittent-valtoco-diazepam-nasal-spray-civ-use-indicates-more-than-two-fold-increase-in-mean-interval-between-seizure-clusters-301541331.html
2. Misra SN, Sperling MR, Rao VR, Peters JM, Carrazana E, Rabinowicz AL. Examining change in the inter-seizure cluster interval across time from a phase 3, long-term, open-label, repeat-dose study of diazepam nasal spray for the treatment of seizure clusters. Presented at 2nd North American Epilepsy Congress, held virtually May 5-8; Poster 35.
3. Wheless JW, Hogan RE, Sperling MR, et al. Safety and time to second doses in pediatric and adult patients with seizure clusters treated with diazepam nasal spray in phase 3, open-label, repeat-dose safety study. Presented at: 2nd North American Epilepsy Congress, held virtually May 5-8; Poster 44.