Abstracts

Rationale: Nayzilam™ (USL261; midazolam nasal spray) has been developed as an alternative to rectal diazepam, the only FDA-approved non-intravenous treatment for patients with intermittent bouts of increased seizure activity (ie, acute repetitive seizures [ARS], seizure clusters [SC]). This novel nasal spray formulation of midazolam provides convenient, easy-to-use, non-invasive drug administration in the outpatient setting by caregivers or medical personnel.  Although midazolam is FDA approved for induction of general anesthesia and for preoperative sedation, anxiolysis, and amnesia, it is not indicated as a treatment for seizures. Therefore, the safety and efficacy of Nayzilam were evaluated in a randomized, double-blind, placebo-controlled, global, phase 3 study (ARTEMIS-1; NCT01390220). Methods: In ARTEMIS-1, subjects with a history of SC receiving a stable regimen of antiepileptic drugs (AED) were randomized (2:1) to receive Nayzilam 5 mg or placebo (PBO). The subject’s caregiver administered the double-blind study drug when the subject experienced a seizure cluster meeting study criteria. Primary and secondary efficacy endpoints included the proportion of subjects with Treatment Success (defined as achieving termination of the seizure(s) within 10 minutes and no recurrence from 10 minutes to 6 hours after study drug administration), proportion of subjects with recurrence of seizure(s) from 10 minutes to 4 hours after study drug administration, and time to next seizure with a start time >10 minutes after study drug administration. Results: Of the 262 subjects randomized to treatment, 201 treated a seizure cluster with double-blind study drug (n=134 Nayzilam; n=67 PBO) and were included in the modified intent-to-treat population. The proportion of subjects with Treatment Success was significantly greater in the Nayzilam group (53.7%) as compared with the PBO group (34.4%; p=0.0109). The proportion of subjects with recurrence of seizure(s) from 10 minutes to 4 hours after study drug administration was significantly lower in the Nayzilam group (38.1%) as compared with the PBO group (59.7%; p=0.0043). The time to next seizure with a start time >10 minutes after study drug administration was statistically significant (p=0.0124) with clear separation seen between the Nayzilam and PBO groups within 1 hour and maintained for the duration of the 24-hour observation period. Conclusions: The ARTEMIS-1 phase 3 clinical trial demonstrated that Nayzilam (midazolam nasal spray) was efficacious for the treatment of SC, and significantly terminated seizure activity and prevented seizure recurrence for 24 hours. The ARTEMIS-1 clinical trial provides evidence to suggest that Nayzilam may be a viable alternative to rectal diazepam. Funding: Proximagen, LLC