The president and CEO of Engage Therapeutics, along with the company’s executive VP and COO, discussed its investigational Staccato alprazolam product in the abortive treatment of seizures.
Gregory T. Mayes
Recently, data from the phase 2 StATES study (NCT03478982) showed that use of Staccato alprazolam resulted in a meaningful proportion of responders who achieved cessation of seizure activity
within 2 minutes of administration without recurrence within a 2-hour window.
The study of the Engage Therapeutics agent included 116 patients who were assigned to either 1 mg (n = 38) or 2 mg (n = 38) Staccato alprazolam or placebo (n = 40). Of the overall active treatment cohort, 65.8% (n = 50) achieved the primary end point (P
= .0158). Likewise, 65.8% (n = 25) of patients in each of 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 the cessation of seizure activity was approximately 30 seconds, on average.
spoke with Gregory T. Mayes, president, CEO, and founder, Engage Therapeutics, and Mark Theeuwes, executive vice president and chief operating officer, to learn more about the study and the unique treatment as it makes its way through the regulatory pipeline.
NeurologyLive: Were there any identifiable differences—patient demographics, age, weight—which might be plausible explanations for the efficacy of the lower dose?
One of the things that we found is—and this is just speculation which we've got to dig into a bit more—we saw early seizure termination that was similar between both doses. It's theorized that [the medication] needs to get to a certain level in the bloodstream, and both doses achieved that minimum dose level, if you will, to be able to terminate an early seizure. One of the things that we do start to see, which is a little bit different with 2 mg and 1 mg, is that [after time] the level stays a little bit higher on the 2-mg dose than it does with the 1 mg dose.
So, one of the exploratory end points that we had was the average number of seizures 0 to 4, 0 to 6, and 0 to 12 hours. There, the 2-mg dose has statistical significance from placebo in the prevention of recurrent seizures—or the number of occurrences that end up happening after a dose is given—but the 1 mg dose didn't. The thought process, early on, is that both doses probably achieve a therapeutic dose level—although we don't really know what the therapeutic level is, as we didn’t determine that in this study. But, the 2 mg dose remains at a much higher level, almost twice the level of 1 mg, as one would expect. That then keeps the patient seizure-free.
The other piece that I would point to is that both doses performed the same in the primary endpoint, and both doses have a similar side effect profile. That's the other side of it - that you don't really see any dramatic differences between side effect profiles when you go from one dose to the other.
What makes this product unique in its termination of seizures?
The key to the current products in this space is that they're approved for acute repetitive seizures. When you start to think about it, medications for acute repetitive seizures or ARS, really work on the second seizure or on the third seizure. The reason for that is even with Nayzilam (midazolam) the fastest Tmax
that you'll see is 17 minutes. So, even if you assume an onset of action of 10 minutes, that's still not stopping the current seizure. It's really only going to help the patient for a second or third or fourth seizure.
When we start thinking about this product, Staccato alprazolam, what makes this exciting is that this is really the first time that a clinical study was done to show dosing at the onset of a seizure. What we were trying to prove is seizure termination for the active seizure that is happening now, and can we terminate that within 2 minutes and prevent any recurrence down the line within 2 hours? That is what makes this really different. You're talking about seizure termination within 2 minutes. The average time to seizure termination that we saw was 30 seconds.
Whenever somebody thinks about epileptic seizure rescue, they think about ARS products. But, it's kind of a misnomer, because you're not really rescuing somebody from the current seizure, you're rescuing somebody from follow on seizures. Unless somebody has a half-hour long seizure—then obviously, those could work. But there are enough people that have a tendency for prolonged seizures—anything lasting more than 2 minutes or less than 5—and this allows them to abort those seizures early on. That's what we're trying to prove and that's what this study showed, that Staccato alprazolam was statistically significant from placebo in doing that.
In terms of potential use for Staccato alprazolam, would it be for those who are well-controlled and may experience breakthrough seizures or who are prone to seizure clusters and may escalate to status epilepticus?
Gregory T. Mayes:
The answer is yes. Obviously, the company is excited to take this data to the FDA as part of an End of Phase 2 meeting and, hopefully, agree on plans for Phase 3 that we would start later this year. That next step in the Phase 3 study is trying to mimic as closely as possible what we just accomplished in the outpatient setting—that rapid termination that Mark was speaking to. We do believe that this has the potential to be sort of an Epi-pen®- like solution for patients with epilepsy. Now, it could be for people that have an uncontrolled breakthrough seizure once every 6 weeks. It could be for people that have one once every 6 months.
From my perspective, my son is relatively well-controlled now, but he's in college. If this type of product was on the market, would I encourage him to keep this in his dorm room or in his backpack as he goes to classes? I think he does know when he's at a high risk of seizures and feeling unwell. This would be a great security blanket, that if he wasn't feeling well, or is starting to have an aura, this would be a perfect product to quickly knock that seizing activity out, and most importantly, all the brain damage that comes with the seizure.
Obviously, the most natural population, or the sort of the target population, will be people with a method of predicting their seizures, and their seizures are long. This is the perfect product that can stop that seizure just as it's starting. We can stop an active seizure episode. The other products called themselves ARS products. We are calling ourselves a REST product, which stands for Rapid Epileptic Seizure Termination, because that's what we offer and why it is different.
We're still a long way away from any sort of pricing decisions or anything like that, but Mark and I are very much committed to seeing this program move forward. Also, making sure that once this does go forward, and is ultimately, hopefully, approved, it can be available on a reasonable basis, so that even if a patient doesn’t have insurance, it could be bought on a cash basis. We're very passionate about making sure this is affordable and something that people can have access to.
Today, in many of these seizure types, people (who have a seizure) ride the storm off. In many cases, even if they feel like they’re about to have a tonic-clonic seizure—and maybe it's only 1 out of 4 times that they go into a generalized convulsion—today, people play roulette. It’s because they don't want to shove a bunch of medicine down their throats because if they do that, and it just happens to not generalize, now they've knocked themselves out for the rest of the day. Having something is key—especially if it's cost-effective and they don't have to make a decision based on it affecting the rest of their day.
The idea is that there are 3.4 million people with epilepsy in the US, and right now, currently available seizure rescue medications are only indicated for less than 200,000, and all of them have orphan indications. The intention for Staccato alprazolam is really to try to address the other 3.2 million people with epilepsy who it might be appropriate for, so they have something that they could use as well.
Transcript edited for clarity
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