Abstracts

Rationale: Nayzilam™ (USL261; midazolam nasal spray) is being developed for the treatment of patients with intermittent bouts of increased seizure activity (ie, acute repetitive seizures [ARS], seizure clusters [SC]).  Currently rectal diazepam is the only FDA-approved non-intravenous treatment for this condition. The safety and efficacy of Nayzilam were evaluated in a randomized, double-blind, placebo-controlled, global, phase 3 study (ARTEMIS-EMU; NCT 01999777). Methods: ARTEMIS-EMU evaluated the safety and efficacy of Nayzilam 5 mg compared to placebo (PBO) in subjects with an established diagnosis of epilepsy who were admitted to the epilepsy monitoring unit (EMU) for seizure characterization or presurgical evaluation. Eligible subjects who presented with 2 or more seizures in the 6-hour window immediately preceding study drug administration or for whom the administration of study drug was appropriate based on the judgement of the investigator were randomized (1:1) to receive a Nayzilam 5 mg or PBO. Efficacy objectives included the proportion of subjects who were seizure-free within 6 hours of dosing and the time to first seizure following treatment (TFSFT). Safety and tolerability were evaluated through adverse event (AE) monitoring, vital sign measurements, and clinical laboratory evaluations. Results: Sixty-two subjects were enrolled (n=31 Nayzilam; n=31 PBO), received study drug, and completed the study. The percentage of seizure-free subjects in the Nayzilam group (54.8%) was higher than the percentage of seizure-free subjects in the PBO group (38.7%); however, the difference of 16.1% between the groups was not statistically significant (p=0.1972, primary endpoint). The Kaplan-Meier curve of TFSFT showed clear separation of the 2 groups beginning at ~1.5 hours post-dose and throughout the entire 6-hour observation period in favor of the Nayzilam group (p=0.1388, secondary endpoint).Post-hoc analyses were performed evaluating covariates including age, gender, BMI, geographic region, and effect of AED inducers. Evaluation of the per-protocol (PP) US population demonstrated a statistically significant higher percentage of seizure-free subjects (68.4% vs 33.3%; p=0.0227) and a statistically significant longer TFSFT (p=0.0167) in the Nayzilam group.Nayzilam was well tolerated in the study. There were no deaths, serious AEs, or discontinuations due to AEs. Adverse events in the Nayzilam group were generally comparable to those in the PBO group.  Conclusions: Although a clinically meaningful effect size of 16.1% was observed in this study, statistical significance on the primary and secondary endpoints were not demonstrated due to limitations in power.  These data and post hoc analyses are supportive of continued Nayzilam development and suggest that Nayzilam 5mg may provide improvement over placebo and maintained efficacy for at least 6 hours post dose. Nayzilam was well tolerated in this population. Funding: Proximagen, LLC