The Food and Drug Administration (FDA) has accepted a new drug application (NDA) filing for midazolam nasal spray (USL261; UCB, Atlanta, GA) for the treatment of persons with epilepsy who experience acute repetitive seizures (ARS). The FDA previously granted orphan drug and fast track status to midazolam nasal spray reflecting that there is a high unmet need for control of intermittent bouts of increased seizure activity.
In the US, an estimated 44% of patients in the US who are currently being treated for epilepsy still have seizure activity at least once per year. An estimated 150,000 people with epilepsy refractory to treatment also experience ARS, resulting in repeated emergency department visits and hospitalizations.
The only acute seizure treatment approved for use outside the hospital at present is administered rectally, and while this is effective for many patients and situations, there are social barriers to administration for many patients. If approved, midazolam nasal spray will provide another treatment option for patients with ARS—a treatment that can be taken anytime and anywhere. If approved, midazolam spray will also be the first new medication for ARS in 17 years.
The application is supported by data from the phase 3 clinical study (ARTEMIS 1) that evaluated the safety and efficacy of midazolam nasal spray in 292 patients. In this study, primary endpoints were met, including termination of seizures within 10 minutes of drug administration and freedom from seizure for at least 6 hours after seizure termination.
“This is encouraging news for the estimated 150,000 people in the U.S. with refractory epilepsy who experience seizure clusters,” said Mike Davis, Head of U.S. Neurology Patient Value Unit at UCB. “UCB recognizes the challenges these patients and their caregivers face and is committed to working with the FDA as they review our application, in the hopes of addressing an unmet need with a new treatment option, if approved.”
American Epilepsy Society
Annual Meeting Abstracts https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/349298
(Abst. 3.269), 2017
EFFICACY OF NAYZILAM™ (USL261; MIDAZOLAM NASAL SPRAY) IN SUBJECTS WITH ACUTE REPETITIVE SEIZURES: RESULTS FROM THE RANDOMIZED, PHASE 3 ARTEMIS-1 CLINICAL TRIAL
Authors: David J. Sequeira, Proximagen, LLC; Peter J. Van Ess, Proximagen, LLC; Tricia L. Braun, Proximagen, LLC; Annie C. Clark, Proximagen, LLC; and William E. Pullman, Proximagen, LLC
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).
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.
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.
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.
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