Allergen-related symptoms resolve within 5 minutes with epinephrine sublingual film
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Key takeaways:
- Aquestive Therapeutics’ Anaphylm begins to dissolve on contact.
- Median time to complete symptom resolution with Anaphylm was 12 minutes.
- Symptoms resolved for some participants within 2 minutes.
Allergen-related symptoms resolved within 5 minutes after an oral allergen challenge with the Anaphylm sublingual epinephrine strip from Aquestive Therapeutics, according to a press release from the company.
These results mark the completion of Aquestive’s final adult supportive study for Anaphylm (AQST-109) before meeting with the FDA later this year.
An alternative to injections
People with allergies often do not carry epinephrine, Daniel Barber, MBA, CEO of Aquestive, told Healio.
“They know they have an issue. Their allergist assigns a rescue product for them to carry, and 50% of the time, they don’t even have the product filled,” Barber said. “Fifty percent of the time, once they’ve gotten it filled, they don’t have it with them.”
Alternatives to epinephrine autoinjectors are designed to be easier to carry, he continued, adding that they also aim to ease patient fears by eliminating the needle.
“Using a needle is something that can create a barrier for certain patients and removing that is a way to improve people’s use of the product as well,” Barber said.
“It’s one thing to say that a patient requires a certain therapy, but if they need it during an emergency situation, during a rescue opportunity, and they don’t have it on them, then it does no good,” Carl Kraus, MD, FACP, chief medical officer at Aquestive, told Healio. “Making sure that they’re carrying and overcoming that barrier of portability is really critical.”
Aquestive describes Anaphylm as a polymer matrix-based epinephrine prodrug product candidate. About the size of a postage stamp, the sublingual film weighs less than an ounce and begins dissolving on contact. Administration does not require any water or swallowing.
Anaphylm also comes in a package that is thinner and smaller than a credit card, so it can be carried in a pocket or wallet, while withstanding exposure to weather such as rain or sunlight.
“The problem with epinephrine is it’s a vasoconstrictor, so it tightens tissue up as soon as it comes into contact,” Barber said.
The prodrug in Anaphylm cloaks the epinephrine from the vasoconstriction so it allows absorption, he continued.
“Once it gets into the bloodstream, enzymatic cleavage turns it into epinephrine very quickly,” he said.
In previous studies, the company tested Anaphylm’s performance with pharmacokinetic (PK) results that were comparable with EpiPen (Pfizer) autoinjectors including rapid exposure over a 60-minute profile and maximum concentration.
“The FDA has developed a method to demonstrate efficacy and safety in these products by using pharmacokinetics,” Kraus said.
“Subsequent to that, the agency has asked us to evaluate other factors that might influence the absorption of Anaphylm, of epinephrine, into the oral cavity,” Kraus said.
Additional studies examined the impact of temperature, pH, eating, and self-administration on outcomes. The latest study was designed to assess whether physiologic changes induced by oral allergens in the oral cavity would have a material impact on the PK profile.
“When you go ahead and administer an oral allergen to people who are susceptible to those allergens and invoke the changes in their physiology, that does not have a statistical impact on the absorption of epinephrine,” Kraus said.
Study design, results
Part 1 of the study included 36 adults with confirmed oral allergy syndrome (OAS). The researchers classified 17% of the participants with severe OAS, 77% with moderate OAS and 6% with mild OAS.
“We wanted to make sure they actually had a robust response before we recruited them into the trial,” Kraus said.
The first arm involved Anaphylm with exposure to an allergen, with single doses for 18 participants and repeat doses for the other 18 participants. The second arm involved Anaphylm with no allergen exposure, with 15 participants receiving a single dose and 13 receiving multiple doses. In the third arm, 18 participants received a single dose and 17 received multiple doses of manual intramuscular epinephrine.
Part 2, which was optional, asked six subjects who received a single dose in part 1 to receive a repeat dose along with six subjects who received multiple doses in part 1 to receive a single dose. The participants who received Anaphylm were exposed to an allergen, but those who received the intramuscular epinephrine were not.
“Whatever patients said that they were allergic to, from an oral allergy perspective, is what they were then subsequently challenged with in the clinic,” Kraus said.
Allergen exposures included pineapple (n = 14), red apple (n = 7), kiwi (n = 7), and cherry (n = 3), with two exposures each for banana, avocado, fig, grapefruit, lychee and tangerine. There were also four exposures to other fruits.
“It was a varied set of potential allergens,” Kraus said.
Every participant developed oral symptoms, 36% also developed systemic symptoms, and 94% had moderate or severe reactions after exposure. Additionally, all the participants reported symptoms indicating an allergic response in their mucosa, with 81% reporting two or more symptoms and 25% reporting swelling.
“What’s really interesting is that a quarter had reported swelling symptoms,” Kraus said. “That’s really what we think about when we consider what might reflect angioedema.”
Percentages of doses with a specified symptom included 31.9% with lip swelling, 10.6% with throat swelling, 6.4% with tongue swelling, 4.3% with cheek swelling, 2.1% for nasal congestion, and 2.1% for sublingual swelling.
“They were quite symptomatic from the allergen challenge,” Kraus said.
The researchers classified 100% of the Anaphylm administrations as successful. Symptoms completely resolved in a median of 12 minutes after Anaphylm was administered.
“Fifty-one percent of those symptoms resolved within 5 minutes,” Kraus said. “Most importantly, from my perspective clinically, is that all the symptoms of swelling fully resolved within 5 minutes, and we started seeing that resolution begin within 2 minutes.”
When Anaphylm was not administered, symptoms resolved in a median of 74 minutes. Also, the researchers said, remaining symptoms resolved rapidly among participants who received Anaphylm with a repeat dose at 15 minutes.
The researchers further said that Anaphylm’s PK profile remained consistent with and without allergen exposure.
Specifically, maximum concentrations with single doses included 261.2 pg/mL for intramuscular injection (n = 24), 403.5 pg/mL for Anaphylm with allergen exposure (n = 23) and 372.8 for Anaphylm with no allergen exposure (n = 15).
Median times to maximum exposure included 50 minutes for intramuscular injection and 12 minutes for both Anaphylm with and without allergen exposure.
Maximum concentrations with multiple doses included 538.8 pg/mL for intramuscular injection (n = 22), 1,194 pg/mL for Anaphylm with allergen exposure (n = 23) and 585.5 pg/mL for Anaphylm with no allergen exposure (n = 13).
Median times to maximum concentration included 57.5 minutes for intramuscular injection and 25 minutes for both Anaphylm with and without allergen exposure.
Anaphylm also elicited desired pharmacodynamic responses including systolic blood pressure, diastolic blood pressure and pulse, the researchers continued, that were consistent regardless of allergen exposure with single and repeat doses alike.
Among the 24 patients who received a single dose of Anaphylm with allergen exposure, two experienced palpitations and one experienced nausea, which the researchers classified as mild. These treatment-emergent adverse events were transient and resolved without any medical interventions, and there were no serious adverse events.
Among participants who received repeat doses, 96.2% of the treatment-emergent adverse events were mild and transient, resolving with no medical intervention. There were no serious adverse events.
These treatment-emergent adverse events included four cases of palpitations, one case of vomiting and two cases of nausea among those who received repeat doses of Anaphylm with an allergen challenge (n = 24) and one case of vomiting among those who received Anaphylm with no allergen challenge (n = 16).
Next steps
Aquestive will include these data when it meets with the FDA in a pre-new drug application (NDA) meeting later this year.
“We’ve done all the work we believe is necessary. We’ve also done all the work they’ve asked us to do,” Kraus said.
“We believe we built the full package for going to the FDA,” Barber said. “We’ve already characterized all of the things necessary.”
Kraus called Anaphylm’s outcomes remarkable.
“This is the first time that I’m aware of where subjects were challenged, and we could demonstrate that epinephrine is working in a clinical setting,” Kraus said.
“We’ve created a really robust set of data,” Barber added.
Next, Aquestive expects to complete a single-dose study of Anaphylm among children who weigh more than 30 kg and then submit its NDA in the first quarter of 2025. If approved, Aquestive expects to launch Anaphylm in the first quarter of 2026.
“It’s a solid plan,” Kraus said.
Kraus also is optimistic about how patients will receive Anaphylm if it is approved.
“We have found in patients where we’ve done typical survey work that our product is preferred over the other epinephrine medical devices that are either in process or in the market,” he said.
Reference:
- Anaphylm (epinephrine) sublingual film oral allergy syndrome challenge study supplemental materials. https://investors.aquestive.com/static-files/46303091-5060-4893-bb80-7be00a833927. Published Oct. 24, 2024. Accessed Nov. 13, 2024.