Potential of Epinephrine Sublingual Film for Anaphylaxis, With David Golden, MD

On February 2, 2026, Aquestive Therapuetics announced that the US Food & Drug Administration (FDA) had issued a Complete Response Letter (CRL) to the New Drug Application (NDA) for dibutepinephrine (Anaphylm), an orally dissolving epinephrine sublingual film, to treat Type 1 allergic reactions.1,2

Despite dibutepinephrine having strong data across > 10 studies with nearly 1,000 administrations across adult and pediatric populations, the FDA cited usability concerns. The agency noted difficulty opening the pouch and incorrect film placement.

To address these concerns, Aquestive plans on modifying the packaging, instructions for use, and labeling, as well as conducting a new human factors validation study and a pharmacokinetics study. The company anticipates resubmission in the third quarter of 2026.

Although it may be awhile before epinephrine sublingual film becomes available to the public as another fast-acting, needle-free option, HCPLive spoke with trial investigator David Golden, MD, an associate professor from Johns Hopkins, on what this treatment could mean for anaphylaxis management.3 In this Q&A, Golden shared how epinephrine sublingual film (Anaphym) differs from autoinjectors, its rapid symptom reduction, and the role it plays in improving real-world readiness for anaphylaxis.

HCPLive: How does sublingual epinephrine delivery compare with autoinjectors in terms of onset, absorption, and usability?

Golden: We like the fact that Anaphylm works very rapidly, as fast as the auto injector. As far as how it builds up to its peak level in the system, it's very comparable to auto-injectors.

Many doctors in a hospital and clinic… [still] give epinephrine… [with] a syringe and needle. They don't use an auto-injector. That's actually not nearly as fast as Anaphylm or auto injectors.

[Epinephrine sublingual film is] not only easy to carry but easy use because it’s so small. It’s something you can just pop under your tongue in a moment. This is not something that needs training. Usability is a very high level…even in an emergency… which is one of the problems with some existing products. In… panic or emergency…everything gets harder to use. This is quite easy to use.

Absorption is part of what allows it to build up quickly. The problem with every type of epinephrine is getting it into the system…one of the problems with epinephrine is that…it constricts blood vessels. Now, that's great for helping your blood pressure go up when you have anaphylaxis, but it means that wherever you put it, it fights its own absorption.

Whether you inject it in the muscle, it actually is a little bit of a problem there. If you just sprayed epinephrine in your nose or in your mouth, would it get absorbed? Hardly at all, because it would block itself off. So, each of these products has to have something in it that helps absorption.

Anaphylm is a really engineered platform for delivering epinephrine into the system, dissolving under the tongue and releasing it into the system. One of the key features is that the end of [the] film is a pro-drug. It's a form of epinephrine that doesn't cause that local problem with absorption. It can easily be absorbed, and after it gets into the system, [that] is when it gets broken down into epinephrine.

HCPLive: How should clinicians interpret the rapid symptom resolution observed in the pivotal studies?

Golden: The mean time to complete resolution of symptoms was 15 minutes after giving the Anaphylm under the tongue.

[In the trial], the idea [was] to let the reaction build up until [participants] can't stand it anymore…and then they [could] take the food out and take the Anaphylm. [This is] mainly to see how it's absorbed, but also to see what happens to the symptoms. When they did that, the symptoms completely went away after 15 minutes, initially in the study, before there was an initial oral food challenge…to confirm that we had the right patients, that they were going to get this kind of reaction in the mouth.

They're not dangerous reactions. Usually, when [people] get those reactions, [they] don't necessarily take medication, but when they didn't take medication in that initial phase of the study, the mean time to resolution [was] 74 minutes.

HCPLive: What should clinicians understand about the strength of the evidence supporting this product as they digest the FDA’s decision?

Golden: We have to keep in mind that there have been… at least 10 or 11 clinical studies with probably close to 1000 administrations in hundreds of subjects, including single dose and repeated dose. That's a lot of experience with the Anaphylm product for the company to be able to provide information to clinicians as to how it performs, how it gets into the system, what kind of effects it has, the desirable effects, which are really good…as far as it being able to counteract anaphylaxis and the pretty good side effect profile.

HCPLive: What role do you see epinephrine sublingual film playing in improving real-world readiness and response to anaphylaxis?

Golden: Anaphylm will really be a big step in improving [the] readiness of people to deal with anaphylaxis, for themselves, as caregivers, and even as innocent bystanders. It's just so easy to carry, use, and be available.

Right now, we're so concerned…that most people don't use epinephrine when they should. Just delaying or not using epinephrine… leads to more problems with more severe reactions in hospitalizations and intensive care. I think, in the real world, we're going to see more people using epinephrine before deciding even whether they need to go to the emergency department.

HCPLive: What remaining questions about non-injectable epinephrine do you think future studies will need to address?

Golden: Future studies absolutely need to address the confidence that everyone wants to have in an epinephrine product. The prescribers, the patients, and caregivers want to know that this has been tried and tested and worked as good as you expect epinephrine to work. You expect it to work fast and get rid of your reaction. So, do we know that? Not really.

We haven't seen published evidence that [sublingual epinephrine film] … works in all kinds of anaphylactic reactions. We need to see that, but these studies are very hard to do. It's hard to be there when someone goes into anaphylaxis in a restaurant…but there are ways to do this, and we're looking forward to getting more of that.

Right now, we can say that we expect it to work, and the evidence…is based on the way that…it does get into the system. We know that in the system, these [epinephrine] products do give the results you expect…like the blood pressure goes up. So, if it does that the same way that an auto injector does, of course, it's going to work. That's the reason that [Neffy was] approved…But until there are actually 1000 reactions that have been treated, we can't say that there have been 1000 reactions treated, and it worked 80 or 90 or 100% of the time.

References

1. Brooks A. FDA Issues CRL to Dibutepinephrine (Anaphylm) Sublingual Film for Type 1 Allergic Reactions. HCPLive. February 2, 2026. https://www.hcplive.com/view/fda-issues-crl-to-dibutepinephrine-anaphylm-sublingual-film-for-type-1-allergic-reactions. Accessed February 3, 2026.

2. Aquestive Therapeutics. Aquestive Therapeutics Announces FDA Issuance of Complete Response Letter for Anaphylm™. February 2, 2026. Accessed February 2, 2026. https://investors.aquestive.com/news-releases/news-release-details/aquestive-therapeutics-announces-fda-issuance-complete-response

3. Golden G. Anaphylm Remains Promising for Anaphylaxis Despite FDA CRL, With David Golden, MD. HCPLive. Published on February 3, 2026. Accessed on February 6, 2026. https://www.hcplive.com/view/anaphylm-remains-promising-anaphylaxis-despite-fda-crl-david-golden-md