Abortive Seizure Agent Staccato Alprazolam Meets Primary End Point in Phase 2

Jaqueline French, MD, professor of neurology, and co-director, epilepsy research and epilepsy clinical trials, NYU Langone Health Comprehensive Epilepsy Center, and founder/director, Epilepsy Study Consortium

Jaqueline French, MD

Engage Therapeutics has announced that its investigational abortive seizure treatment Staccato alprazolam has met its primary end point in the phase 2 StATES study (NCT03478982), with a meaningful proportion of responders achieving cessation of seizure activity within 2 minutes of administration without recurrence within a 2-hour window.

The study included 116 patients randomly assigned to either 1 mg (n = 38) or 2 mg Staccato alprazolam (n = 38) or placebo (n = 40). Notably, 65.8% (n = 50) of the total patients in the active groups achieved the primary end point (P = .0158). Data from the trial is expected to be presented at the American Academy of Neurology (AAN) Annual Meeting in April in Toronto.

“With statistically significant and clinically meaningful phase 2 results in this randomized, placebo-controlled trial, Staccato alprazolam has demonstrated the ability to rapidly terminate seizures in patients with epilepsy in 2 minutes or less and prevent recurrence of seizure within 2 hours,” said principal investigator Jaqueline French, MD, in a statement. “We are now 1 step closer to bringing to patients an EpiPen®-like rescue treatment that works fast enough to terminate an active seizure episode.”

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In total, 65.8% (n = 25) of patients in the 1-mg and 2-mg groups were deemed responders compared to 42.5% (n = 17) for placebo (P = .0392 for both). The onset of action for ceasing seizure activity was approximately 30 seconds, on average.

French, who is professor of neurology and co-director, epilepsy research and epilepsy clinical trials at NYU Langone Health’s Comprehensive Epilepsy Center, and founder/director of the Epilepsy Study Consortium, told NeurologyLive that the time to action of Staccato alprazolam is particularly of note compared to other therapies that are currently available or pending approval.

“For most of the rescue therapies that cross the mucous membrane—for example, the nasal therapies that have recently been approved and certainly the oral therapies, the rectal therapies—you're talking about an average of 10 minutes, and in an oral form 20 minutes,” she explained. “There is a huge difference between 2 minutes or even less than 2 minutes, in many people's cases, versus 10 minutes. In the lifetime of a seizure, that's an eternity.”

Mark Theeuwes, senior vice president and chief operating officer, Engage Therapeutics, told NeurologyLive that while the 2 doses evaluated were nearly identical in their responses in the StATES study, the tail remains higher for the 2-mg dose. While the precise therapeutic dose threshold has not been identified, he explained that it appears that both 1 mg and 2 mg reach this threshold.

“One of the exploratory end points that we had was the average number of seizures over 0 to 2, 0 to 4, 0 to 6, and 0 to 12 hours. The 2 mg dose has statistical significance from placebo, in the prevention of recurrent seizures—or the number of recurrent seizures that end up happening—but the 1 mg didn't,” he said. “The 2 mg remains at a much higher level—almost twice the level of one milligram—and that then keeps you seizure-free.”

Additionally, the agent was generally well-tolerated in both treatment arms, with most adverse events (AEs) mild in nature and no treatment-related serious AEs observed. The most common AE was somnolence, reported by 14.5% (n = 11) of the 76 patients in the treatment arms, and cough, which also occurred in 14.5%. Other AEs included dysgeusia (13.2%), dizziness (5.3%), sedation (2.6%), and throat irritation (2.6%).

“As a parent, I have personally experienced the need for a product that can work fast enough to terminate an active seizure when it occurs,” Gregory T. Mayes, founder and CEO, Engage Therapeutics, said in a statement. “We believe these data from the StATES study show what we hoped could be done — can be done. As we move the clinical development forward, we want to see Staccato alprazolam become a tool that patients with epilepsy can use to rapidly stop a seizure.”

REFERENCE

Engage Therapeutics Announces Phase 2b StATES Study of Staccato® Alprazolam for Seizure Cessation Meets Primary Endpoint [press release]. Summit, NJ: Engage Therapeutics; Published March 12, 2020. Accessed March 12, 2020. globenewswire.com/news-release/2020/03/12/1999155/0/en/Engage-Therapeutics-Announces-Phase-2b-StATES-Study-of-Staccato-Alprazolam-for-Seizure-Cessation-Meets-Primary-Endpoint.html.