Anaphylm Remains Promising for Anaphylaxis Despite FDA CRL, With David Golden, MD

A sublingual epinephrine film could still represent a meaningful advance in anaphylaxis preparedness, despite a recent regulatory setback, according to investigator David Golden, MD, an associate professor from Johns Hopkins.

“This product really meets the needs of a lot of patients and fits beautifully into what we as allergists and as physicians want to be able to recommend to patients that they could easily carry,” Golden told HCPLive. “People should be aware of the different options that they have and make sure that they choose some kind of epinephrine. More than anything else, I don't care what kind [of epinephrine they] choose, as long as they choose something they will carry and will use.”

Dibutepinephrine (Anaphylm), an orally dissolving epinephrine film designed for rapid use outside medical settings, received a Complete Response Letter (CRL) from the US Food and Drug Administration (FDA) on February 2, 2026, citing human factors deficiencies rather than concerns about pharmacology or manufacturing.

The FDA’s decision focused on usability issues identified in validation studies, including difficulty opening the pouch and incorrect film placement. The FDA believes these factors could pose safety risks during an acute anaphylactic event. The CRL did not raise concerns about clinical pharmacology, chemistry, manufacturing, or comparability data, nor did it question the underlying epinephrine exposure or physiologic effects demonstrated across the development program.

The product is intended to address persistent gaps in anaphylaxis care: delayed or absent epinephrine use. Despite longstanding guideline recommendations, epinephrine remains underused in real-world settings, often because patients are reluctant to carry or administer injectable devices. A sublingual film, which is small, needle-free, and rapidly administered, could reduce hesitation and enable earlier treatment, which is consistently associated with improved outcomes and fewer hospitalizations.

Dibutepinephrine is supported by an extensive clinical program, encompassing > 10 studies and nearly 1,000 administrations across adult and pediatric populations. These studies demonstrated predictable epinephrine absorption, expected cardiovascular responses such as increased blood pressure, and a safety profile consistent with epinephrine exposure. Pediatric pharmacokinetic data showed epinephrine concentrations comparable to adult trials (280 pg/mL vs 330 pg/mL mean baseline-adjusted epinephrine concentrations 10 minutes after the administration of dibutepinephrine 12 mg), with no serious adverse events reported.

Aquestive Therapeutics has indicated it will modify packaging, instructions for use, and labeling, and will conduct a new human factors validation study alongside a supportive pharmacokinetics study. The company anticipates resubmission in the third quarter of 2026.

“The company is absolutely prepared to rapidly address any concerns that the FDA may have, any regulatory concerns, understand that it's been a long process and that there have been many discussions and many questions from the FDA and responses from Aquestive, so that there's been a very comfortable understanding all along of what they are looking for and what Aquestive can do to meet those requirements,” Golden said. “It's a little puzzling right now as to what these questions are that have been raised.”

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