FDA Accepts NDA for Intranasal Midazolam for Seizure Clusters


Midazolam is expected to receive a decision from the FDA in early 2019. If approved, it would become the first new medication for this indication in more than 15 years.

Jeff Wren

Jeff Wren, the head of neurology and executive vice president at UCB

Jeff Wren

The FDA has accepted a New Drug Application (NDA) for midazolam nasal spray, an investigational therapy for the acute treatment of seizure clusters, according to UCB.

The indication being sought is in patients who require control of intermittent bouts of increased seizure activity. The supporting data includes findings from the phase III ARTEMIS 1 trial, which evaluated the therapy compared to placebo in 292 patients, finding it to be safe and tolerable.1

“Managing seizure clusters remains a challenge for thousands of patients and caregivers, in the US and beyond, who live their lives each day with this debilitating condition,” Jeff Wren, the head of neurology and executive vice president at UCB, said in a statement.2 “There is an unmet need for effective and convenient acute treatment of seizure clusters that can rapidly end ongoing seizures and potentially prevent or delay their reoccurrence."

In ARTEMIS 1, patients were given the therapy in a test dose phase (TDP), then randomized 2:1 to either the 5 mg midazolam (n = 134) or placebo (n = 67) in a comparative phase (CP). In total, 16 patients discontinued the study due to an adverse event (AE) during the TDP, 13 of which were deemed related to the study drug—most associated with the route of administration or protocol defined withdrawals. During the CP, no patients discontinued due to AEs.

The overall incidence of treatment-emergent AEs was 51% for midazolam during the TDP, and 28% during the CP compared to 22% for placebo. Most AEs were considered mild or moderate. The most commonly reported treatment-emergent AEs were nasal discomfort, somnolence, lacrimation increased, abnormal product taste, and throat irritation. All told, 4.8% (n = 14) and 1% (n = 2) patients reported ≥1 treatment-emergent AE that was deemed serious, 3 of which were considered related to midazolam.

Seizure clusters are unpredictable in nature and remain so even when patients are adherent to antiepileptic therapies, making acute care plans for these clusters immensely important. For that reason, in ARTEMIS 1, patients were able to have a second 5-mg dose of midazolam administered between 5 minutes and 6 hours post-first dose to adjust for persistent or recurrent activity.

“With midazolam nasal spray, UCB hopes to expand and diversify the treatment choices we provide to the epilepsy community, complementing our already strong epilepsy portfolio and providing additional solutions to help patients,” Wren said.

Previously, in a 2015 study, midazolam was evaluated in 75 patients with epilepsy, finding that the nasal spray formulation reduced the incidence of all seizure types for a 12-hour period (P = .031), and generalized tonic-clonic seizures for a 24-hour period (OR, 4.67; 95% CI, 1.41-15.45; P = .009).3 The therapy was also not associated with serious AEs.

The therapy was previously granted both Orphan Drug and Fast Track designations from the FDA, reflecting a clear unmet need for acute seizure cluster care. Midazolam is expected to receive a decision from the FDA in early 2019. If approved, it would become the first new medication for this indication in more than 15 years.

Midazolam was acquired by UCB in June 2018, from Proximagen. The pair has since collaborated to progress the NDA filing.


1. Braun TL, Meng TC, Sequeria DJ, et al. Safety and tolerability of


(usl261; midazolam nasal spray) in subjects with acute repetitive seizures: results from the randomized, phase 3


-1 clinical trial 2017. 71st Annual Meeting of the American Epilepsy Society (AES), December 1-5, 2017; Washington, USA, abs. 3.271.

2. FDA Accepts New Drug Application (NDA) to review Midazolam Nasal Spray, an investigational product for the acute treatment of seizure clusters [press release]. Brussels, Belgium: UCB Pharma. August 13, 2018. ucb-usa.com/stories-media/UCB-U-S-News/detail/article/Press-Release-FDA-Accepts-New-Drug-Application-NDA-to-review-Midazolam-Nasal-Spray-an-investigational-product-for-the-acute-treatment-of-seizure-clusters. Accessed August 13, 2018.

3. Kay L, Reif PS, Belke M, et al. Intranasal midazolam during presurgical epilepsy monitoring is well tolerated, delays seizure recurrence, and protects from generalized tonic-clonic seizures. Epilepsia. 2015;56(9):1408-1414.


: 10.1111/epi.13088

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