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(Abst. 2.235), 2018

Long-Term Safety Experience of Nayzilam™ (USL261; Midazolam Nasal Spray) in Subjects With Seizure Clusters: Safety Results From the Open-Label, Phase 3 Extension of the ARTEMIS-1 Study
Authors: Tze-Chiang Meng, Proximagen, LLC; David J. Sequeira, Proximagen, LLC; Peter J. Van Ess, Proximagen, LLC; and William E. Pullman, Proximagen, LLC
Content: 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 and can easily be given by caregivers when patients are experiencing an episode. The safety and efficacy of MDZ NS was evaluated in a randomized, double-blind, placebo-controlled, Phase 3 study (ARTEMIS-1; NCT01390220). This open label extension to ARTEMIS-1 was conducted to evaluate long-term safety and efficacy of repeated treatment of SC episodes (ARTEMIS-2, NCT01529034). Efficacy data are reported in a separate abstract (Sequeira 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 criterion. 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. Safety evaluation included collection of adverse events, caregiver recorded respiration rates, vital signs, physical exams including neurologic and nasal exams, laboratory tests, Columbia-Suicide Severity Rating Scale (C-SSRS), and Brief Smell Identification Test (B-SIT). Results: A total of 1998 episodes were treated in 161 patients. There were no deaths. Of 45 serious treatment emergent adverse events (TEAEs) in 18 patients, 4 events (status epilepticus, convulsion, upper gastrointestinal hemorrhage, and dysesthesia) in 4 patients were observed but were considered unlikely related. Two patients discontinued for 2 related TEAEs (nasal discomfort and somnolence). Two patients had a TEAE of acute central respiratory depression; neither event was considered related to study drug and the patients remained on study. TEAEs were reported by 40.4% of patients. TEAEs reported by =2% of patients included nasal discomfort (12.4%), somnolence (9.3%), headache (6.2%), rhinorrhea (4.3%), fatigue (4.3%), sneezing (3.7%), convulsion, dizziness, nausea, lacrimation increased, and product taste abnormal (all 2.5%).  Regarding nasal safety, the available B-SIT data and observed TEAEs did not indicate clinically significant concerns regarding olfactory toxicity. There were no changes over time indicative of any safety trends in laboratory tests, vital signs measurements, physical, neurological, or nasal examination findings, or C-SSRS scores. Conclusions: The open-label ARTEMIS-2 study supports the long-term safety of repeated usage of MDZ NS in the outpatient setting to treat SCs. MDZ NS potentially offers caregivers a novel and reliable means of rescue treatment for patients experiencing SCs. Funding: Proximagen, LLC