Article In Brief
A new study provides a proof of concept that inhaled alprazolam could potentially be a useful tool for stopping seizures. The study authors and independent experts said, however, that the inhaled drug suppressed photoparoxysmal response but not necessarily epileptic activity.
A rescue “inhaler could potentially provide relief for people experiencing seizures in the same way that an inhaler benefits people who experience asthma attacks, the findings of a very small proof-of-concept study suggest.
The new study found inhaled alprazolam quickly suppressed epileptiform activity in five photosensitive epilepsy patients in a laboratory setting, in which participants were exposed to flashes of light.
It will take much more research to determine if the approach could actually stop seizures in real life, the researchers, led by Jacqueline A. French, MD, FAAN, professor of neurology at the NYU Comprehensive Epilepsy Center, said.
They are encouraged enough by the early results to begin testing the rescue inhaler in a hospital monitoring unit with a group of patients who experience long or repetitive seizures.
“We think of it as an asthma inhaler for epilepsy. When you feel a seizure coming on, you take it out of your pocket and take a breath,” Dr. French said. “I think it could make people feel more secure.”
When patients experience an aura or other symptoms that may precede seizure onset, they, or a family member or friend if necessary, could use the inhaler to deliver a dose of aerosolized alprazolam into the lungs.
The researchers reported in the July 3 online edition of Epilepsia that the drug rapidly got to the bloodstream and into the brain, as demonstrated by electroencephalography (EEG), which showed that the drug seemed able to suppress the brain's photoparoxysmal response (PPR).
“It is a very interesting study and it is the type of work we need in the field of epilepsy because we do not have sufficient options for rescue interventions,” said Sheryl R. Haut, MD, professor of neurology and director of adult epilepsy at Montefiore Einstein, who was not involved with the study.
Dr. Haut said photosensitivity provides a good model for testing epilepsy drugs because epileptic-like activity can be triggered in a lab by using light stimulation, as was done in the current study. But she cautioned, “You can't extrapolate that suppressing the photoparoxysmal response is the equivalent to suppressing seizures. It is a marker. The ability of the drug to suppress seizures has to be studied in a clinical trial that measures seizure as the outcome.”
“There is a need for acute treatment options for seizure clusters (defined as acute repetitive seizures), as well as other seizure emergencies,” the study authors wrote.
One such drug, diazepam gel (Diastat), is administered rectally with a syringe. The approach has downsides, the study authors noted, including that it “requires the aid of a caregiver, is inconvenient to administer outside of the home, and may be socially embarrassing for some participants.”
Another rescue option, a nasal spray that delivers midazolam (Nayzilam UCB), was approved by the US Food and Drug Administration in May.
Speed of action is key for rescue medicines for epilepsy since “significant seizure activity may occur in the first 10 minutes after seizure or cluster onset is recognized—for example, a cluster of myoclonus preceding a generalized tonic-clonic seizure, a prolonged focal aware seizure preceding impaired awareness of bilateral tonic seizure,” the paper noted. “The development of fast-onset treatment options that can easily be administered in the outpatient setting is vital.”
Alprazolam is a well-known and highly characterized benzodiazepine used for treating anxiety disorders. To see if an inhaled version of the drug could also be useful for epilepsy, Dr. French's team tested a delivery system called Staccato, which is being developed by Engage Therapeutics, a sponsor of the trial.
With the system, the patients use a small hand-held device to inhale aerosolized alprazolam into the lungs. The antiseizure properties of benzodiazepines are believed to exert their action on GABAa receptors in the brain.
The phase 2a double-blind, crossover, placebo-controlled trial enrolled five patients with an epilepsy diagnosis who had a history of photosensitivity, or PPR, on EEG. After a screening visit, participants returned five more times to receive, in random order, alprazolam at doses of 0.5, 1.0 and 2.0 mg, and an inhaled placebo.
Intermittent photic stimulation and clinical assessments were done at one pre-dose and seven post-dose timepoints. The researchers also drew blood to measure concentrations of the drug in the bloodstream.
The primary endpoint was the change in standardized photosensitivity range (SPR) in participants receiving each dose of inhaled alprazolam.
The researchers reported that all doses of inhaled alprazolam reduced SPR at two minutes, and the effect was sustained through four hours for the 0.5 mg dose and six hours for the 1.0 mg and 2 mg doses. On an individual basis, one patient only responded at 2 mg of the active drug while the others responded at all doses, Dr. French said. Patients experienced sleepiness and sedation, which was not unexpected, and the degree and duration of those symptoms were dose dependent.
“The results support further development of Staccato alprazolam as a rescue medication for the acute treatment of seizures,” the researchers concluded.
Dr. French said an eight-person open-label study has already been completed and the next step is a double-blind study with about 115 people with epilepsy.
Michael A. Rogawski, MD, PhD, professor of neurology and pharmacology at the School of Medicine at University of California, Davis, said, “The interesting thing about this study is that the inhaled drug acts more rapidly than other benzodiazepines administered by other routes...and when you are dealing with a seizure emergency that is critical.”
It's possible that such a drug could prevent a full-blown seizure and perhaps keep patients out of the emergency department, Dr. Rogawski said.
Dr. Rogawski noted that the photosensitivity model used in this small, early-stage study does not strictly assess antiseizure activity but rather “is intended to demonstrate that the molecule delivered by the delivery system can engage the target and produce a functional effect.”
He added, however, that “alprazolam is a benzodiazepine that acts similarly to several other such drugs that are known to be effective antiseizure agents. If the drug achieves the required levels in the brain it is expected that it will have the desired effect of terminating ongoing seizures and preventing seizure recurrence.”
Along with getting more data on safety and efficacy of the inhaled drug in treating acute repetitive seizures (seizure clusters), epileptologists will be especially interested to know whether the product would be useful for terminating ongoing seizures and how it would perform in a real-life scenario, Dr. Rogawski said. For example, he posed this challenge: “How easy would the system be to use when a patient was having a seizure and was not fully conscious?”
Barbara C. Jobst, MD, PhD, FAAN, the Louis and Ruth Frank professor of neurosciences at Geisel School of Medicine at Dartmouth, said: “The small study of the inhaled drug was definitely a step in the right direction, but we can't conclude that seizures would be reduced in the same way epileptiform activity was, though there is some correlation between the two.”
She said that having inhaled rescue medicine for epilepsy would no doubt be an improvement over the rectal drug, which “is a problem in public places and for the caregiver it's not the nicest thing to apply. We definitely need other improved drugs that are delivered in different ways.”
Even with rescue drugs, however, the biggest attention needs to be on keeping epilepsy under control, Dr. Jobst said.
Dr. French receives NYU salary support from the Epilepsy Foundation and for consulting work and/or attending scientific advisory boards on behalf of the Epilepsy Study Consortium for Acadia, Adamas, Addex, Aeonian, Alexza, Anavex, Arvelle therapeutics, Axcella Health, Axovant, Biogen, Biomotiv/Koutif, Blackfynn, Bloom Science, Bridge Valley Ventures, Cavion, Cerebral Therapeutics, Cerevel, Clinilabs, Concert Pharmaceuticals, Covance, Crossject, CuroNZ, Eisai, Empatica, Encoded, Engage Therapeutics, Epitel, GW Pharma, Idorsia, Impax, Ionis, J&J Pharmaceuticals, Marinus, MonosolRx, Neurelis, Novartis, Otsuka Pharmaceutical Development, Ovid Therapeutics Inc., Pfizer, Pfizer-Neusentis, Praxis, Redpin, Sage, Sancillio, Shire, SK Life Sciences, Springworks, Stoke, Sunovion, Supernus, Takeda, UCB Inc., Ultragenyx, Upsher Smith, Vyera, West Therapeutic Development, Xenon, Xeris, Zogenix, Zynerba. Dr. French has also received research grants from Biogen, Cavion, Engage, Neurelis, Ovid, SK Life Sciences, UCB, and Zogenix as well as grants from the Epilepsy Research Foundation, Epilepsy Study Consortium, and NINDS. She is on the editorial board of Lancet Neurology and Neurology Today. She is scientific officer for the Epilepsy Foundation for which NYU receives salary support. She has received travel reimbursement related to research, advisory meetings, or presentation of results at scientific meetings from the Epilepsy Study Consortium, the Epilepsy Foundation, Adamas, Axovant, Biogen, Blackfynn, CuroNz, Eisai, Engage, Idorsia, Neurelis, Novartis, Otsuka, Ovid, Pfizer, Redpin, Sage, SK Life Science, Sunovion, Takeda, UCB, Ultragenyx, and Zynerba. Drs. Jobst and Rogawski had no conflicts.