FDA Flags Administration Concerns for Aquestive's Noninvasive Epinephrine Film

Aquestive Therapeutics announced it received a Complete Response Letter (CRL) from the FDA regarding its New Drug Application (NDA) for Anaphylm (dibutepinephrine) Sublingual Film, a noninvasive epinephrine therapy for the treatment of type I allergic reactions, including anaphylaxis, in patients weighing at least 30 kg (approximately 66 pounds).¹

The CRL, dated January 30, 2026, does not raise concerns about dibutepinephrine’s safety, efficacy, or manufacturing quality. Instead, the FDA’s feedback focuses on human factors and labeling issues related to product administration. The agency did not identify any chemistry, manufacturing, and controls (CMC) deficiencies, and no additional efficacy studies were requested.

Dibutepinephrine is being developed as a fast-acting, easy-to-carry alternative to injectable epinephrine auto-injectors, with the goal of improving access and use during life-threatening allergic reactions. The drug is positioned to compete with ARS Pharmaceuticals’ needle-free nasal spray Neffy.²

Human Factors Concerns

According to the CRL, the FDA identified deficiencies in the dibutepinephrine human factors (HF) validation study, including instances in which users experienced difficulty opening the pouch or incorrectly placing the sublingual film.¹ The agency indicated that these issues could pose significant safety risks during anaphylaxis, when timely and correct administration is critical.

To address the FDA’s concerns, Aquestive has modified the pouch opening mechanism, instructions for use, and both pouch and carton labeling. The company plans to rapidly conduct a new HF validation study incorporating these changes and will also further evaluate potential tolerability issues as part of its resubmission. Comparability data included in the NDA, such as bracketing, repeat-dose, and sustainability data, were not questioned in the CRL.

Additional PK Study Requested

In connection with the HF modifications, the FDA’s clinical pharmacology review requested a single pharmacokinetics (PK) study to assess the impact of packaging and labeling changes. The agency indicated that the HF and PK studies may be conducted in parallel. No other clinical or nonclinical studies were requested.

Based on its initial review of the CRL, Aquestive estimates it will be able to resubmit the NDA in the third quarter of 2026, assuming timely completion of the HF and PK studies and standard FDA response timelines. The company plans to request a Type A meeting with the FDA to discuss the most efficient path forward and intends to seek rapid review of the resubmission.

“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. 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,” Daniel Barber, president and CEO of Aquestive, said in the statement.

Clinical and Global Outlook

Jay Lieberman, MD, professor at the University of Tennessee Health Science Center and a practicing physician at LeBonheur Children’s Hospital, said the FDA’s response centers on patient experience rather than clinical performance. He noted that expanding treatment options remains critical, given the continued underuse of epinephrine in anaphylaxis.

Despite the US regulatory setback, Aquestive plans to continue advancing dibutepinephrine internationally. The company initiated regulatory engagements in Canada, Europe, and the United Kingdom in 2025 and reported receiving positive feedback from the European Medicines Agency (EMA), which indicated that no additional clinical trials would be required prior to submission. Aquestive expects to submit a marketing authorization application in Europe and a New Drug Submission in Canada in the second half of 2026 and to receive feedback from the UK’s Medicines and Healthcare Products Regulatory Agency in the first quarter of 2026.

References

1. Aquestive Therapeutics announces FDA issuance of Complete Response Letter for Anaphylm. News release. Aquestive Therapeutics. February 2, 2026. Accessed February 2, 2026. https://www.globenewswire.com/news-release/2026/02/02/3230115/0/en/Aquestive-Therapeutics-Announces-FDA-Issuance-of-Complete-Response-Letter-for-Anaphylm.html

2. Ananthan P. US FDA declines to approve Aquestive’s oral drug for allergic reactions. Reuters. February 2, 2026. Accessed February 2, 2026. https://www.reuters.com/business/healthcare-pharmaceuticals/us-fda-declines-approve-aquestives-oral-drug-allergic-reactions-2026-02-02/