FDA Issues Complete Response Letter to Dibutepinephrine (Anaphylm) Sublingual Film for Anaphylaxis

The US Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) for the New Drug Application (NDA) seeking approval of dibutepinephrine (Anaphylm) sublingual film for the treatment of type I allergic reactions, including anaphylaxis, in patients weighing at least 30 kg, according to an announcement from the manufacturer. The CRL, dated January 30, 2026, identifies deficiencies related primarily to human factors and a requested supportive pharmacokinetic (PK) study, rather than to chemistry, manufacturing, or core clinical efficacy data.

For clinicians, the decision underscores ongoing regulatory scrutiny around usability and administration of novel epinephrine delivery systems—an issue of particular importance in anaphylaxis, where treatment delays or user error can have life-threatening consequences. Although intramuscular epinephrine delivered by auto-injector remains the standard of care, real-world data consistently show underuse and misuse of epinephrine in emergency allergic reactions, motivating development of alternative delivery platforms.¹,²

Regulatory Overview and FDA Concerns

According to the company, the FDA’s CRL focused on deficiencies identified in the Anaphylm human factors (HF) validation study. Specifically, the agency cited instances in which users experienced difficulty opening the pouch and errors in film placement. The FDA concluded that these issues, if not adequately addressed, could pose significant safety risks in the context of anaphylaxis, where rapid and correct administration is essential.

To address these concerns, the sponsor has modified the pouch design, instructions for use, and outer labeling, and plans to conduct a new HF validation study incorporating these changes. In addition, the FDA’s clinical pharmacology reviewers requested a single PK study to assess whether the packaging and labeling modifications affect drug exposure. The agency indicated that the HF and PK studies may be conducted in parallel. No additional efficacy trials were requested, and the CRL did not identify concerns related to chemistry, manufacturing, and controls (CMC).

The company has stated its intent to request a Type A meeting with the FDA to clarify expectations for resubmission and estimates a potential resubmission in the third quarter of 2026, contingent on completion of the requested studies.

Clinical Context: Anaphylaxis and Epinephrine Use

Anaphylaxis is an acute, potentially fatal systemic allergic reaction that requires prompt recognition and treatment. Epinephrine administered intramuscularly is the recommended first-line therapy across major guidelines, including those from the World Allergy Organization and the American Academy of Allergy, Asthma & Immunology.³,⁴ Despite clear guidance, multiple observational studies have demonstrated that epinephrine is underused in both community and emergency care settings, with barriers including fear of injection, device complexity, and delayed recognition of symptoms.¹,²

Currently approved epinephrine products for out-of-hospital use in the US are injectable, most commonly auto-injectors. While effective when used correctly, auto-injectors are associated with user errors, needle-related anxiety, and cost concerns, all of which have driven interest in non-injectable alternatives.

Drug Background and Development Program

Anaphylm is a sublingual film formulation of epinephrine designed for oral mucosal absorption. The NDA submission was supported by a clinical development program comprising 11 studies, including pharmacokinetic, tolerability, and human factors evaluations, with approximately 967 total administrations in 411 participants. According to the sponsor, these studies demonstrated that Anaphylm achieved PK profiles comparable to those of approved epinephrine auto-injectors, a regulatory benchmark for alternative epinephrine delivery systems.⁵

The development program also included an oral allergy syndrome (OAS) study intended to assess performance in an allergen-induced setting. Peer-reviewed publications detailing these studies remain limited, and most publicly available data derive from regulatory disclosures and company communications, which constrains independent assessment of efficacy beyond PK comparability.

Interpretation and Next Steps

From a regulatory standpoint, the CRL suggests that the FDA’s concerns are procedural and usability-related rather than reflective of fundamental doubts about epinephrine’s effectiveness or systemic safety. However, in the context of anaphylaxis, human factors considerations are clinically consequential. Even modest rates of administration error may translate into meaningful risk when patients or caregivers are under stress.

Whether Anaphylm, if approved, would meaningfully improve real-world epinephrine use remains an open question. Evidence that non-invasive delivery improves timely administration or adherence compared with auto-injectors is not yet established. Postmarketing data would be essential to determine whether such a formulation reduces treatment delays or improves outcomes.

The company has also indicated plans to pursue regulatory approvals outside the US, including in Europe, Canada, and the United Kingdom, with submissions anticipated in the second half of 2026. Regulatory feedback from the European Medicines Agency reportedly did not require additional clinical trials prior to submission, though review outcomes and labeling decisions may differ by region.

Limitations

At present, publicly available evidence is limited by the absence of head-to-head clinical outcome trials comparing sublingual epinephrine with injectable products. Additionally, human factors performance in simulated or controlled studies may not fully predict real-world use during severe allergic reactions. These limitations highlight the need for cautious interpretation of preapproval data.

References

1. Simons FE, et al. World Allergy Organization anaphylaxis guidelines: summary. J Allergy Clin Immunol. 2011;127(3):587-593.e22.
2. Prince BT, et al. Underuse of epinephrine for the treatment of anaphylaxis: missed opportunities. J Asthma Allergy. 2018;11:143-151.
3. Shaker MS, et al. Anaphylaxis—A 2020 practice parameter update. J Allergy Clin Immunol. 2020;145(4):1082-1123.
4. Muraro A, et al. EAACI guidelines: anaphylaxis (2021 update). Allergy. 2022;77(2):357-377.
5. Sicherer SH, Simons FE; Section on Allergy and Immunology. Epinephrine for first-aid management of anaphylaxis. Pediatrics. 2017;139(3):e20164006.