Epinephrine auto-injectors are essential, lifesaving medications for people with allergies to food, medication or insect stings at risk of anaphylaxis.
But auto-injectors have drawbacks. The bigger pen-style devices can be inconvenient to carry. They need to be stored at room temperature because heat can render epinephrine less effective. A big issue is that many people are reluctant to use auto-injectors, even when symptoms call for it. Surveys show reasons for that include: needle fear, panic when an anaphylactic reaction occurs, and preferring to head to the hospital for treatment, despite the fact that delay in getting epinephrine leads to worse reactions.
“What’s currently available is very effective, but we know it’s also underutilized,” says Dr. Jennifer Dantzer, a pediatric allergist and immunologist at Johns Hopkins School of Medicine in Baltimore.
Alternatives to the auto-injector may be on the way. Three pharmaceutical companies are developing new epinephrine delivery methods that are needle-free and potentially less cumbersome to carry.
This may encourage allergic patients to both carry epinephrine – and use it in a reaction. Two of the products in development are nasal sprays, the third is an epinephrine film that dissolves under the tongue.
Fast-Track for Needle-Free Epinephrine
The U.S. Food and Drug Administration has granted all three products fast-track status, which is intended to speed up the approval process. At least one of them, the sublingual film made by Aquestive Therapeutics in Warren, New Jersey, is expecting to wrap up studies and apply for FDA approval in late 2023.
Dr. Harold Kim, an associate professor at Western University in Ontario, Canada, who isn’t involved with the drug development, says auto-injector alternatives would be a welcome addition to the anaphylaxis arsenal.
But he cautions that before allergists would recommend that patients rely on anything other than auto-injectors, they would need to feel confident that a nasal spray or oral film works as fast and effectively. Auto-injectors have a long track record of delivering a dose of epinephrine, that’s quickly absorbed, in amounts that halt most serious allergic reactions.
“If those different methods of delivery are shown to be effective, it will be very popular. There is a need because many patients are reluctant to use auto-injectors,” says Kim, who is past-president of the Canadian Society of Allergy and Clinical Immunology. “But those products will have to be shown to lead to blood serum levels that are adequate to treat anaphylaxis.”
What the FDA Needs to See
Both the nasal sprays and the oral film use epinephrine, an existing, approved drug. That means the companies developing the needle-free products need to show the FDA that their alternative is comparable to current methods of administering epinephrine. That’s through intramuscular injection, either manually with a syringe, or using an auto-injector.
Specifically, the companies need to demonstrate that their products are similar to an injection on two key measurements: peak concentration of epinephrine in blood plasma, and how fast that peak is reached.
Studies have found it takes approximately five to 10 minutes to reach initial peak epinephrine concentration in the blood when using an auto-injector, says Kim, who recently co-authored a review of auto-injector findings. The studies show that a second maximum epinephrine level is then reached from 30 to 50 minutes after an auto-injection.
Along with showing their products are safe, the companies are conducting “human factor” studies. These assess the products in conditions that mimic a severe allergic reaction.
Dosing for Auto-Injector Alternatives
Another aspect of product development will be dosing, Dantzer says. The epinephrine dose contained in a nasal spray or sublingual film will likely need to be higher than what’s in an auto-injector to reach a similar concentration in the blood, she says.
Injecting epinephrine into the thigh muscle with a needle enables the medication to be absorbed and distributed quickly and efficiently throughout the body, she says. To absorb a sufficient amount through the blood vessels in the nose or the mucosal membrane under the tongue, you’d probably need a higher dose.
Here’s more on the development of each product, and what allergists say they want to see before prescribing them.
Under-the-Tongue Epinephrine Film
Aquestive Therapeutics’ sublingual, or under-the-tongue, epinephrine film is about the size of a postage stamp. The film quickly dissolves in saliva, delivering epinephrine in a reliable, predictable dose, says Dan Barber, CEO and president of Aquestive.
“The three gaps in the market we see are portability, correct technique and willingness to use auto-injectors,” Barber says. “Those are the three gaps that are leading people to not have their rescue medication when they need it, or not to use it.”
Early results are promising. A Phase 1 study in 24 healthy adults showed that it took an average of 15 minutes for a 12 milligram (mg) dose of sublingual epinephrine film to reach maximum concentration in the blood plasma. By comparison, the company’s research showed it took longer, about 50 minutes for an 0.3mg syringe injection to reach maximum concentration.
Epinephrine absorption also leads to a faster heart rate and higher blood pressure. Aquestive’s research found that changes in blood pressure and heart rate of participants given the oral film were similar to those given epinephrine by a syringe.
Aquestive already has other oral film medications on the market. These include buprenorphine and naloxone (brand name: Suboxone), a treatment for opioid addiction, and clobazam (brand: Sympazan), approved for a type of epileptic seizure in patients 2 years of age and older.
The sublingual film comes in a foil packet about the size of a business card, so it’s small and easy to carry, Barber says. The foil also helps protect the film from sunlight.
In testing, “we are seeing how far we can push the boundaries for cold and hot” temperature exposures, he says. Aquestive expects that, if approved, their labeling would allow a wider range of temperatures acceptable for storing the medication than auto-injectors.
The company is enrolling volunteers for a Phase 2 study that will compare the film to an EpiPen. That study should be complete by the end of the 2022 summer. The last step before seeking FDA approval will be a larger study, including 80 to 100 healthy volunteers, slated for the end of 2022.
Neffy Nasal Spray
There are two epinephrine nasal sprays in development: Neffy by ARS Pharmaceuticals of San Diego, and another by Bryn Pharma of Raleigh, North Carolina. Both nasal sprays reach maximum epinephrine concentration in the blood in about 20 minutes.
ARS is developing Neffy in a 2 mg dose for adults and kids over 66 pounds as well as a 1 mg dose for children 33 to 66 pounds. The company released some key study data at the 2022 American Academy of Allergy, Asthma and Immunology (AAAAI) meeting, and its data is now at a review stage with regulators.
One analysis, involving 171 participants, compared the 1 mg nasal spray for pediatric use to a 0.3 mg syringe thigh injection and the EpiPen 0.3 mg. ARS Pharma’s research found that EpiPen reached a higher maximum plasma concentration than the Neffy or syringe. The time to reach the peak was also fastest with the EpiPen, with an average of 12 minutes, while Neffy averaged 20 minutes, and syringe administration maximized at 45 minutes.
Kim says research suggests the force of some auto-injectors may help the epinephrine to be absorbed more quickly into the body as compared to a syringe, which has been the gold standard at hospitals for decades.
ARS’s human factor studies showed that just shy of 100 percent of participants were able to administer the Neffy spray to themselves or another participant safely and effectively during a simulated emergency, just by reading the package instructions. The single-shot sprayer used in the Neffy device is already used in other FDA-approved drugs, including Tosymra (sumatriptan) for migraines.
“Given that Neffy is easier to carry, easier to use, and does not pose the safety risks associated with the needle in auto-injectors, we are confident that patients and caregivers will use Neffy more reliably and quickly in an emergency allergic reaction leading to better outcomes,” the company told Allergic Living.
Bryn Pharma Nasal Spray
Bryn Pharma’s epinephrine nasal spray device can deliver two doses of epinephrine, designed to be the equivalent of carrying two auto-injectors.
The company’s 2021 clinical trial in 25 healthy adults compared their nasal spray at various dosages with a 0.3 mg auto-injector. They found that their 6.6 mg spray resulted in a peak plasma concentration that was comparable to the 0.3 mg auto-injector. The company’s CEO said in a press release that “a single spray from our bi-dose nasal spray device delivered epinephrine at levels equaling or exceeding those administered with a single 0.3 mg epinephrine auto-injector.”
About 44 percent of participants who received the 6.6 mg nasal spray reported mild adverse reactions, such as tremors, nausea, headache, palpitations or stomach pain, that went away within a few minutes to a few hours. About 28 percent in the auto-injector group reported those symptoms.
At the 2022 AAAAI meeting, Bryn presented data showing its sprayer was used as easily by patients as by trained professionals.
Allergists on Needle-Free Epinephrine
Even if the FDA approves the needle-free epinephrine alternatives, it may take time for allergists to put their trust in them, Kim says. The trials for the new medications are being done in healthy volunteers. For safety and ethical reasons, these are not conducted in people who are actually having a severe allergic reaction.
This means that the real-world test of how a nasal spray or sublingual film works during actual allergic reactions will come later, when doctors and patients are using them.
“It will take some time for us to flip over to using those delivery methods, until we get comfortable with it,” Kim says. He adds that this process is not unexpected. For the same reasons, epinephrine and auto-injectors have also never been subjected to rigorous randomized, placebo-controlled trials (the gold standard of medical research) during actual allergic reactions.
Dantzer agreed that she’d like to see more data showing a nasal spray or oral film will work well during emergencies. “To me there would still be a question if it would definitely work the same in healthy individuals as it would during an allergic reaction,” she says.
The food allergy community is closely watching the progress of the needle-free epinephrine options. But the Baltimore allergist reminds that, meantime, we still need better education on using the good tools we have. She stresses the importance of carrying two auto-injectors at all times, and “to know how and when to use epinephrine.”
Related Reading:
Anaphylaxis and Lack of Epinephrine Use in Young Kids
All About Epinephrine, with ER Dr. Julie Brown
At 30,000 Feet, Why We Can’t Count on Epinephrine Vials on an Airplane
Calm, Cool and Ready to Epi During an Allergic Reaction
