Aquestive resubmits NDA for sublingual epinephrine film Anaphylm after FDA CRL

Aquestive Therapeutics has resubmitted its New Drug Application (NDA) to the FDA for Anaphylm (dibutepinephrine) sublingual film, a needle-free epinephrine product being developed for type I allergic reactions, including anaphylaxis. The resubmission follows a Complete Response Letter (CRL) the agency issued in January 2026, which centered on human factors and packaging concerns rather than the drug's underlying efficacy or safety data.¹

"This resubmission reflects the rigor of our response to the FDA's Complete Response Letter, and we believe it addresses the items identified by the FDA," said Daniel Barber, president and chief executive officer of Aquestive Therapeutics, in a statement announcing the filing. Barber noted that new human factors and pharmacokinetic (PK) testing reduced median pouch-opening time from 17 seconds to 3 seconds, changes intended to support correct self-administration during an emergency.

Regulatory history and resubmission basis

Aquestive originally submitted the Anaphylm NDA in March 2025 for patients weighing at least 30 kg. The FDA's CRL, dated January 30, 2026, did not raise concerns about chemistry, manufacturing, and controls or about the pharmacokinetic comparability data supporting the drug's efficacy claims. Instead, the agency flagged deficiencies in a human factors validation study, including instances of difficulty opening the product's pouch and incorrect film placement, along with labeling issues and a request for an additional supportive PK study.^1,2

Following a Type A meeting with the FDA, Aquestive modified the pouch design, instructions for use, and outer packaging labeling. The company then completed a new human factors study evaluating the revised packaging and a confirmatory PK study in healthy volunteers that compared self-administration and clinician administration of Anaphylm with manual intramuscular epinephrine. No protocol-defined use errors occurred in the self-administration arm of the PK study, according to the company. The FDA will determine the resubmission's review classification and timeline after its initial review.¹

Clinical context: epinephrine underuse and access barriers

Anaphylaxis incidence has risen among children and adolescents over the past two decades, yet epinephrine remains underused outside the hospital setting. Survey and cohort data indicate that a substantial proportion of caregivers do not administer an autoinjector during a reaction, often because they underestimate its severity or feel unprepared to use the device. The 2023 Joint Task Force on Practice Parameters update on anaphylaxis emphasizes prompt epinephrine administration as the only intervention proven to halt disease progression, while acknowledging that fear of needles and device complexity are recognized barriers to timely use.3

Drug and mechanism background

Anaphylm is a polymer matrix-based epinephrine prodrug delivered as a sublingual film roughly the size of a postage stamp that dissolves on contact without water or swallowing. Its primary packaging is designed to be thinner than a credit card, pocket-sized, and resistant to temperature and humidity excursions. David B.K. Golden, MDCM, lead author of the 2023 anaphylaxis practice parameter and a member of Aquestive's Scientific Advisory Board, said prior clinical studies showed Anaphylm produced rapid onset with heart rate and blood pressure increases comparable to or greater than those seen with auto-injectors and manual intramuscular epinephrine. Aquestive is developing Anaphylm through its AdrenaVerse platform, which includes more than 20 epinephrine prodrug candidates for allergy and dermatologic indications.⁴

References

1. Aquestive Therapeutics. Aquestive Therapeutics announces resubmission of New Drug Application to FDA for Anaphylm (dibutepinephrine) sublingual film. September 17, 2026. Accessed September 17, 2026. https://investors.aquestive.com/news-releases/news-release-details/aquestive-therapeutics-announces-resubmission-new-drug

2. Aquestive Therapeutics announces FDA issuance of complete response letter for Anaphylm. BioSpace. February 2, 2026. Accessed September 17, 2026. https://www.biospace.com/press-releases/aquestive-therapeutics-announces-fda-issuance-of-complete-response-letter-for-anaphylm

3. Glassberg B, et al. Factors affecting use and misuse of epinephrine autoinjectors in pediatric patients. Presented at: AAP National Conference & Exhibition; Nov. 2-6, 2018; Orlando, Fla.

4. Golden DBK, Wang J, Waserman S, et al. Anaphylaxis: a 2023 practice parameter update. Ann Allergy Asthma Immunol. 2023. doi:10.1016/j.anai.2023.09.015