FDA issues complete response letter for sublingual epinephrine film Anaphylm

The FDA has issued a Complete Response Letter (CRL) for Anaphylm (dibutepinephrine; Aquestive Therapeutics) Sublingual Film, a noninvasive epinephrine product candidate for the treatment of type I allergic reactions, including anaphylaxis. The letter, received on January 30, 2026, applies to the company’s New Drug Application (NDA) for use in patients weighing 30 kg or more.¹

According to the company, the CRL does not raise concerns related to chemistry, manufacturing, and controls (CMC) or to the comparability data submitted in the NDA. Instead, the FDA’s feedback centers on human factors (HF), labeling, and the need for a single supportive pharmacokinetics (PK) study following planned modifications.

“While it is unfortunate to have received a CRL, we believe that, with the clarity we now have from the FDA, we have made significant progress toward approval,” said Daniel Barber, president and CEO of Aquestive. “We are encouraged that the issues in the letter are limited to human factors and a supportive PK study, once human factors are addressed, and we noted several labeling comments that will inform the final label for Anaphylm, if approved by the FDA.”

Anaphylm is a polymer matrix–based epinephrine prodrug formulated as a sublingual film. The product is designed to dissolve upon contact without the need for water or swallowing and is packaged in a thin, portable pouch intended for rapid access during emergencies.

Suggested changes

In the CRL, the FDA cited deficiencies in the human factors validation study related to administration. Specifically, the agency noted instances of difficulty opening the pouch and incorrect placement of the sublingual film. The FDA indicated that these issues, if not adequately addressed, could pose safety risks in the setting of anaphylaxis, where timely and correct administration of epinephrine is critical.

To address these concerns, Aquestive reported that it has modified the pouch opening mechanism, instructions for use, and both pouch and carton labeling. The company plans to conduct a new HF validation study incorporating these changes. In addition, the company stated it will further evaluate potential tolerability considerations as part of its resubmission.

Due to the packaging and labeling modifications, the FDA also requested a single PK study to assess the impact of these changes. The agency indicated that the HF and PK studies may be conducted in parallel, and no additional clinical or nonclinical studies were requested in the CRL.

“We remain confident in the effectiveness and safety of Anaphylm and its potential as an easy-to-use, easy-to-carry, fast-acting epinephrine treatment,” Barber said. “We look forward to working with the FDA to achieve approval for Anaphylm. Our commitment to bringing this innovative therapy to the allergy community remains steadfast.”

Next steps

Based on its initial assessment of the FDA’s feedback, Aquestive plans to request a Type A meeting with the agency to discuss next steps and the most efficient path to resubmission. The company estimates a potential NDA resubmission in the third quarter of 2026, assuming timely completion of the HF and PK studies and standard FDA response timelines. The company also plans to request a rapid review.

“As a clinician and investigator for various allergy clinical trials, I am well versed in the nuances related to clinical development and regulatory approval,” said Jay Lieberman, MD, professor at the University of Tennessee Health Science Center and a practicing physician at LeBonheur Children’s Hospital. “FDA’s response is focused on patient experience issues and their potential impacts. I am confident in Aquestive’s ability to address the issues described above and remain optimistic in having Anaphylm available for my patients in the future.”

Lieberman also highlighted the broader clinical context. “Given the continued underuse of epinephrine in anaphylaxis, the availability of more treatment options remains a top priority for clinicians and the allergy community,” he said.

Beyond the United States, Aquestive reported ongoing regulatory engagement for Anaphylm in international markets. The company initiated discussions with regulators in Canada, Europe, and the United Kingdom in 2025. According to the company, the European Medicines Agency provided feedback indicating that no additional clinical trials would be required prior to submission. Marketing authorization applications in Europe and a New Drug Submission in Canada are expected in the second half of 2026, with feedback from the UK Medicines and Healthcare Products Regulatory Agency anticipated in the first quarter of 2026.

The company stated that the original NDA submission was supported by a clinical development program comprising 11 independent studies, with approximately 967 total administrations across 411 participants. These included both single-dose and repeat-dose exposures. The program also included an oral allergy syndrome study designed to evaluate performance in an allergen-induced setting. According to the company, the studies demonstrated a PK profile comparable to leading epinephrine auto-injectors and a safety profile consistent with epinephrine.²

References

1. Aquestive Therapeutics. Aquestive Therapeutics Announces FDA Issuance of Complete Response Letter for Anaphylm. Aquestive Therapeutics. February 2, 2026. Accessed February 2, 2026. https://investors.aquestive.com/news-releases/news-release-details/aquestive-therapeutics-announces-fda-issuance-complete-response
2. Aquestive Therapeutics. Aquestive Therapeutics Announces Regulatory Development for Anaphylm™ (dibutepinephrine) Sublingual Film and Provides Business Update. Aquestive Therapeutics. January 9, 2026. Accessed February 2, 2026. https://investors.aquestive.com/news-releases/news-release-details/aquestive-therapeutics-announces-regulatory-development