Nayzilam (USL261)

Nayzilam (USL261) is a nasally administered midazolam formulation. It was developed by Proximagen; however, UCB acquired the rights to the medication in April 2018.

Midazolam was approved by the U. S. Food and Drug Administration for the induction of general anesthesia and preoperative sedation, anxiolysis (an anti-anxiety agent), and amnesia.

Rescue medicine

Midazolam is not intended for the treatment of seizures, but it is currently being investigated as a rescue medicine to stop acute repetitive seizures.

Currently, Diastat (diazepam rectal gel) is the only FDA-approved nonintravenous medication for the treatment of repetitive seizures. It is effective, but the rectal administration is problematic when it is not used at home.

A nasal spray allows a convenient, easy-to-use, and noninvasive alternative.

Nayzilam has been granted orphan drug and fast drug designation for the treatment of repetitive seizures by the FDA. The administration also accepted the filing of a new drug application (NDA) for Nayzilam in August 2018, which will allow the treatment to be commercialized.

Dravet syndrome patients may need rescue medicines to quickly stop a seizure before it progresses to status epilepticus.

How Nayzilam works

The active component of Nayzilam, midazolam, is a GABA agonist, a molecule that acts in a similar way to GABA.

GABA is a neurotransmitter — a signaling molecule in the brain — that inhibits nerve cell signaling. GABA performs its action by binding to GABA receptors. Midazolam mimics GABA’s action by binding to the same receptors.

In a majority of Dravet syndrome patients, the SCN1A gene, which provides instructions to make the NaV1.1 subunit of sodium channels, is mutated. Sodium channels are essential for the communication between brain cells.

Brain cells communicate with each other through electric signals and sodium channels play a crucial role in the transduction of these signals. The SCN1A mutation is thought to mainly affect brain cells that release GABA, leading to uncontrolled signaling that causes seizures in Dravet syndrome patients.

Midazolam’s action is thought to compensate for the impaired action of GABA-releasing neurons in Dravet syndrome patients, thereby decreasing the frequency of seizures.

Nayzilam in clinical trials

A randomized, placebo-controlled, double-blind Phase 3 clinical trial (NCT01999777) called ARTEMIS-EMU, assessed the efficacy, safety, and tolerability of Nayzilam compared to a placebo.

A total of 62 patients with epilepsy were randomized to receive either 5 mg of Nayzilam or a placebo if the participant experienced two or more seizures within six hours.

The study showed that 54.8% of the participants who received Nayzilam were seizure-free for six hours following treatment, compared to 38.7% of the patients who received placebo.

The difference in effectiveness was, however, not statistically significant between patients receiving Nayzilam and those receiving placebo.

Another larger randomized Phase 3 trial (NCT01390220, ARTEMIS1) included 262 epilepsy patients who had a history of seizure clusters that last for 10 minutes or longer.

A total of 201 participants received either 5 mg of Nayzilam or a placebo once they experienced a seizure cluster. The treatment was defined as successful when the seizures stopped within 10 minutes following treatment and did not recur for at least six hours.

The treatment was successful in 53.7% of the participants receiving Nayzilam and in 34.4% of the participants receiving the placebo.

In the Nayzilam receiving group the seizure recurrence between 10 minutes and four hours after dosing was lower, and the time until the next seizure was longer compared to the placebo-receiving group. The difference in all three parameters measured was statistically significant.


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