Abstracts

Rationale: Nayzilam™ (USL261; midazolam nasal spray, MDZ NS) is a novel nasal spray formulation of MDZ specifically developed as an acute rescue treatment for seizures in the outpatient setting for patients who require control of intermittent episodes of increased seizure activity (ie, acute repetitive seizures [ARS], seizure clusters [SC]). This novel nasal spray formulation of MDZ provides convenient, non-invasive drug administration without active inhalation which can easily be administered by caregivers when patients are experiencing a SC. This open label extension to the pivotal Phase 3 ARTEMIS-1 study (NCT01390220) was conducted to evaluate long-term safety and efficacy of repeated treatment of SC episodes (ARTEMIS-2, NCT01529034). Safety data are reported in a separate abstract (Meng et al, AES 2018). Methods: Adult and adolescent patients with a history of SC receiving a stable regimen of antiepileptic drugs who completed ARTEMIS-1 were enrolled. The subject’s caregiver administered MDZ NS 5 mg for a SC episode meeting study criteria. A second 5 mg dose could be administered if seizures did not terminate within 10 minutes or if seizures recurred between 10 minutes and 6 hours after the initial dose.  Treatment success for an episode was defined as termination of the seizure(s) within 10 minutes and no recurrence from 10 minutes to 6 hours after initial study drug administration. Treatment success as a repeated efficacy measurement was fitted into a generalized linear mixed model to assess efficacy over time. Results: The study enrolled 87% (175 of 201) of the subjects that completed ARTEMIS-1.  Of these, 161 treated at least one SC episode during the study (median time on study 16.8 months, range 1 to 55.7 months), for a total of 1998 treated episodes (median episodes per subject 7.0, range 1 to 73). A sustained high rate of treatment success was observed when either a single 5 mg or second 5 mg dose of Nayzilam was administered.  Of the 1998 seizure clusters treated, 1108 (55.5%; 95% CI 53.2%-57.7%) met the criteria for treatment success after a single 5 mg Nayzilam dose was administered; a result comparable to that observed for MDZ NS (53.7%) subjects in the ARTEMIS-1 study. Following all doses (1 or 2 doses of MDZ NS) a consistent therapeutic effect of >80% treatment success was observed. Treatment success rate for the first dose and the proportion of subjects administered a second dose was similar for episodes treated for up to 4+ years, demonstrating consistency of clinical response with repeated administration over the long-term and suggesting that tolerance did not develop with repeat acute use.   Conclusions: The open-label ARTEMIS-2 study supports evidence of efficacy observed in the double-blind ARTEMIS-1 study.  The consistent efficacy of MDZ NS, when used to treat multiple repeat SC in the outpatient setting, is encouraging for its potential use as a new acute rescue treatment option for patients with SC.   Funding: Proximagen, LLC