A novel epinephrine film starts to ease symptoms of an oral allergy syndrome (OAS) reaction in as soon as two minutes, new research finds. The film, which dissolves under the tongue, provided complete symptom relief in around 12 minutes on average.
Aquestive Therapeutics is developing the product – called Anaphylm – to treat anaphylaxis, a severe allergic reaction that can be triggered by food, sting or drug allergies. Aquestive’s CEO and President Daniel Barber said the Food and Drug Administration requested the study in OAS patients.
The intent was to see whether oral swelling would affect the absorption of the Anaphylm dose. The researchers measured how long it took for epinephrine to reach its maximum concentration in the blood, both with and without exposure to fruit allergens. There was no significant difference and they concluded that mouth swelling does not impact absorption rates.
“We were ecstatic,” Barber told Allergic Living. “What we really like about these results is they show the symptoms of edema [swelling] rapidly go away with our product.”
People with oral allergy syndrome experience itching and swelling in their mouths when eating certain raw fruits or vegetables. However, unlike anaphylaxis, which is a full-body response, OAS is typically localized to the mouth and throat. (For safety and ethical reasons, epinephrine studies are not done in patients with food allergies known to trigger anaphylaxis.)
Dr. Jay Lieberman, a pediatric allergist-immunologist at Le Bonheur Children’s Hospital in Memphis, said the study provides strong evidence that the dissolving film works in patients experiencing real-world allergy symptoms.
“I am reassured by the speed of symptom relief seen in the OAS study and by the continued and consistent rapid absorption profile of Anaphylm,” Lieberman says.
Next Steps for Anaphylm
Aquestive plans to conduct an additional, single-dose study in teens and older children before submitting Anaphylm for FDA approval. That study will be conducted in the next few months, with a meeting planned with the FDA in the fourth quarter of 2024. The company aims to submit their New Drug Application in early 2025. Then the FDA will have up to 10 months to review it.
If approved, Anaphylm, which has a 12-milligram dose of epinephrine, would be for adults and children weighing 66 pounds and more. Aquestive is also developing a lower dosage film for smaller children weighing 30 to 66 pounds. But Barber says the studies for this will come later.
Anaphylm & OAS: Quick Resolution
The Anaphylm OAS study involved 36 adults with allergies to foods such as pineapple, apple, kiwi, cherry, banana or avocado.
In OAS, the allergic reaction relates to tree or other pollen allergies. The immune system “sees” the proteins in fruits or vegetables as similar to those allergenic pollens. In response, it mounts an allergic reaction.
Participants in the OAS study chewed their allergenic fruit then spat it out to trigger a reaction. About 77 percent experienced moderate symptoms and 17 percent experienced severe symptoms. Reactions included swelling of the lips, throat, tongue and cheek, and nasal congestion.
When symptoms peaked, participants were given Anaphylm. Symptoms started to go away in as a little as two minutes, with about 50 percent of symptoms gone within five minutes. Participants had complete resolution in 12 minutes on average – compared to 74 minutes without treatment.
“That’s a really nice sign the drug is doing exactly what you’d hope it would do,” says Steve Wargacki, PhD, Aquestive’s chief science officer.
For comparison, the study also tested Anaphylm in participants when they hadn’t been exposed to their allergen. Results showed similar absorption in both scenarios, with 12 minutes to reach maximum epinephrine concentration in the blood. That compared to 50 minutes to reach maximum concentration when epinephrine was given using a syringe and no allergen exposure.
Researchers also did a repeat dosing study. Fifteen minutes after one dose of Anaphylm, the study found about 20 percent of oral allergy symptoms remained on average. After a second dose, all remaining symptoms resolved within five to 10 minutes.
Side effects were mild. After the second dose, four of 24 patients said they felt heart palpitations, and two felt nauseated. There were no complaints about the taste, Barber says.
Solving Puzzle of Oral Epinephrine
Researchers have tried for years to deliver epinephrine by mouth. But getting enough absorption proved difficult because epinephrine causes blood vessels to constrict, also called vasoconstriction, Wargacki says.
In anaphylaxis, blood vessel constriction is a good thing because it helps counteract a drop in blood pressure. But if the blood vessels in the mucus membranes of the mouth constrict before the epinephrine gets into the bloodstream, it hinders absorption.
“You want the vasoconstriction to happen in the body, but not at the site of absorption,” Wargacki says. “It’s the thing you want, but you don’t want it just yet.”
To overcome that, Aquestive scientists modified the epinephrine molecules for their film to allow them to slip unnoticed through the mouth’s mucosal membrane. As soon as the epinephrine hits the bloodstream, enzymes detect it and trigger the blood vessel constriction. “It happens really fast,” Barber says.
Other Trials: Swallowing, Eating PB
The OAS study is the latest in several studies Aquestive has conducted on the epinephrine film in preparation to apply for FDA approval.
In March 2024, a pivotal, Phase 3 trial involving 64 adults found that Anaphylm’s time to reach peak concentration of epinephrine in the blood averaged 12 minutes. By comparison, the EpiPen took 20 minutes. The Auvi-Q auto-injector took 30 minutes and epinephrine given by syringe averaged 50 minutes to hit the peak.
The company has also conducted studies at the FDA’s request to test Anaphylm during different scenarios simulating the real world. These included after drinking a hot liquid or cold liquid, when the mouth has a high or low pH level, and after eating a peanut butter sandwich (not in those with an allergy). “They wanted to see if a sticky substance would change the absorption,” Wargacki says.
Across all studies, “the amount of epinephrine you get in your bloodstream is comparable,” Barber says.
Another trial looked at what happens if the sublingual film is accidentally swallowed. This may be unlikely to occur, since the film adheres to the mouth when it comes into contact with saliva and dissolves in seconds.
However, if swallowed, “you are still going to get epinephrine,” Wargacki says. The study showed it just takes longer – 25 minutes to reach maximum concentration instead of 12 minutes.
Anaphylm: Fits on a Phone
If approved, the company hopes to launch Anaphylm in early 2026. Barber believes patients and families will welcome it as a convenient auto-injector alternative.
Anaphylm is about the size of postage stamp, and comes in a foil packet. The packet can be slipped into a pocket, wallet or the back of a mobile phone, making it easier to carry than an auto-injector. Anaphylm can also be frozen, and can withstand high temperatures if left in a car.
“The biggest, No. 1 issue is people don’t carry their [epinephrine] product. It’s a problem that has been around forever,” Barber says.
“We believe the more alternative products in this space, the more patient choice there is … the better it is for patients. We think our product does that very nicely, and if approved by the FDA, ours will be the first and only oral product.”
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