Anaphylm Resubmission: Procedural CRL Cleared, But Prodrug PK Adequacy Remains the Unverified Pivot

Aquestive Resubmits Anaphylm NDA After Addressing CRL

Aquestive Therapeutics has resubmitted its New Drug Application (NDA) for Anaphylm (dibutepinephrine) sublingual film to the U.S. Food and Drug Administration (FDA) for the treatment of Type I allergic reactions, including anaphylaxis. This resubmission addresses the Complete Response Letter (CRL) issued on January 30, 2026, which requested additional human factors and confirmatory pharmacokinetic (PK) studies. The company successfully completed these studies, generating positive data that supports the revised packaging design and instructions for use, including a significant reduction in pouch-opening time. Aquestive's CEO expressed strong conviction in Anaphylm's potential as a rapid, needle-free treatment option.

• Aquestive Therapeutics' resubmission directly addresses the FDA's January 30, 2026, Complete Response Letter (CRL). The CRL had specifically requested a human factors study concerning packaging and administration, and a confirmatory pharmacokinetic (PK) study. The company conducted a Type A meeting with the FDA to align on the approach, subsequently completing both requested studies to support the revised NDA.
• The completed human factors study evaluated revised packaging, leading to significant improvements, including a reduction in median pouch-opening time from 17 seconds to 3 seconds. Furthermore, the confirmatory PK study in healthy volunteers, which included self-administration and clinician administration arms, observed no protocol-defined use errors in the self-administration arm, demonstrating improved usability and safety of the revised product.
• Anaphylm (dibutepinephrine) sublingual film is highlighted as a small, highly portable, and needle-free epinephrine prodrug investigational product. Clinical studies have previously shown that Anaphylm provides a rapid onset and robust increases in heart rate and blood pressure, comparable to or greater than those observed with auto-injectors and manual intramuscular epinephrine. This profile suggests Anaphylm could offer a meaningful advancement for patients needing rapid, convenient treatment for severe allergic reactions.

The Pivotal Studies Supporting Anaphylm's NDA Resubmission

Several trials have examined interventions for Type I allergic reactions, spanning epicutaneous and oral immunotherapy approaches as well as cofactor effects on reaction severity. The studies below represent key designs and endpoints across this landscape.

Addressing Critical Gaps in Anaphylaxis Treatment

Despite advances in acute management protocols, significant gaps persist in the treatment of Type I allergic reactions and anaphylaxis — spanning epinephrine delivery, long-term prevention, and equitable access to emerging therapies.

• Delayed and insufficient epinephrine administration: Intramuscular adrenaline remains the primary treatment for anaphylaxis, yet its administration is often delayed or insufficiently used. Undercarriage and underuse of epinephrine autoinjectors (EAIs) are common, and delayed epinephrine use is associated with increased morbidity and mortality. Availability and usage rates of adrenaline autoinjectors differ widely across countries.

• Limitations of current epinephrine delivery platforms: Patients, caregivers, and healthcare professionals have expressed a strong desire for small, needle-free devices offering improved carriage, ease of use, and less invasive routes of administration. Injection fears, needle-based safety risks, and other barriers contribute to lack of or delayed use of current EAI formats.

• Rising incidence and preventable deaths: The global incidence of anaphylaxis is on the rise, and preventable deaths persist — driven largely by delayed epinephrine administration and inadequate long-term follow-up. Drug-induced anaphylaxis, often the main cause of anaphylaxis-related deaths worldwide, is increasing due to the growing use of chemotherapies and biologic agents.

• Biphasic and refractory phenotypes: Contributing factors to persistent morbidity include the emergence of biphasic and refractory anaphylaxis phenotypes, which complicate acute management and underscore the inadequacy of single-intervention protocols.

• Inadequate response to first- and second-line therapies in CSU: In chronic spontaneous urticaria — a Type I hypersensitivity-related condition — H1-antihistamine treatment leads to absence of symptoms in fewer than 50% of patients. Updosing of second-generation H1-antihistamines (up to fourfold) can improve response, but many patients remain symptomatic. Definitions of response are often subjective, and a consensus is needed regarding appropriate treatment targets.

• Unmet need for biomarkers and access equity: There is an unmet need for biomarkers to assess severity and activity and to predict treatment response. Gaps in access, awareness, and supporting evidence — particularly for children and older adults — underscore the need for additional research and health system investment. Validated predictive biomarkers and equitable device access remain critical unresolved priorities.

Anaphylm's Differentiated Profile in the Anaphylaxis Landscape

Epinephrine remains the first-line treatment for acute anaphylaxis, with current clinical care pathways specifying intramuscular (IM) or intranasal (IN) administration every 5–15 minutes for persistent reactions. IM and IN routes are considered equally efficacious based on pharmacokinetic data, with an intravenous epinephrine infusion indicated for patients with persistent anaphylaxis after two doses of IM/IN epinephrine. Antihistamines and systemic corticosteroids serve as adjunctive agents to relieve symptoms, while supportive measures — including supplemental oxygen, positive-pressure ventilation, and intravenous fluid resuscitation — address airway, breathing, and circulatory derangements. Intranasal epinephrine delivery via neffy has been evaluated as an additional option, with preclinical data in a beagle dog model of anaphylaxis demonstrating that mean maximum epinephrine concentration was higher during anaphylaxis than under normal conditions (2,670 ± 2,150 pg/mL vs. 1,330 ± 739 pg/mL; P < .05), and overall exposure (AUC₀₋₄₅) was similarly elevated (54,400 ± 18,100 vs. 34,300 ± 21,500 min × pg/mL; P < .05), attributed to increased vascular permeability during severe allergic reactions.

Beyond acute rescue therapy, allergen-specific immunotherapy represents the primary disease-modifying approach for Type I allergic conditions. Subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) have been compared in head-to-head randomized controlled trials: low-grade evidence supports greater effectiveness of SCIT than SLIT for asthma symptom reduction, and moderate-grade evidence supports greater effectiveness of SCIT for nasal and/or eye symptom reduction in allergic rhinoconjunctivitis. Oral immunotherapy (OIT) is the more effective immunotherapy route in food allergy, though it carries the risk of adverse reactions including anaphylaxis. For lipid transfer protein (LTP) syndrome — a food allergy phenotype associated with frequent systemic reactions and anaphylaxis — sublingual immunotherapy with LTPs is described as a promising therapy, while specific immunotherapy with pollen is not indicated for pollen-food syndrome.

Anti-IgE therapy with omalizumab has emerged as a clinically significant investigational and now approved alternative or adjunct to standard-of-care approaches across multiple Type I allergic conditions. Omalizumab, a humanized monoclonal anti-IgE antibody administered by subcutaneous injection every 2–4 weeks based on weight and serum IgE levels, reduces the body's sensitivity to allergen exposure by binding and neutralizing serum IgE antibodies. It is currently indicated for severe allergic asthma not controlled by conventional treatment, and has received FDA approval to reduce the risk of allergic reaction associated with IgE-mediated food allergy — the first such approval for multiple food allergies. The OUtMATCH trial, the largest trial to date, demonstrated that omalizumab significantly increases the threshold dose for experiencing an adverse allergic reaction among subjects with allergies to multiple foods including peanuts, cashew, milk, egg, walnut, wheat, or hazelnut. When used as an adjunct to OIT, omalizumab has been shown to facilitate the speed of desensitization and reduce the risk of adverse allergic reactions compared with OIT alone, with particular benefit suggested in patients with high risk of fatal anaphylaxis. Placebo-controlled trial data also support omalizumab's efficacy in anaphylaxis prevention and in conditions previously considered unrelated to IgE — including idiopathic urticaria and intrinsic asthma — and its use has been shown to prevent systemic reactions that preclude allergen immunotherapy, particularly for Hymenoptera venom.

Redefining Emergency Epinephrine: Anaphylm's Sublingual Promise

The recent resubmission of Anaphylm's New Drug Application for anaphylaxis treatment marks a pivotal moment for emergency allergy care. This sublingual epinephrine film represents a significant departure from the traditional intramuscular injection, offering a needle-free alternative that could profoundly impact patient experience and outcomes. Clinical data highlight its rapid onset, with a time to maximum concentration (Tmax) of just 12 minutes, outperforming several existing autoinjectors. Crucially, its pharmacokinetic and pharmacodynamic profile remains robust even in the presence of oral symptoms, ensuring reliable absorption when it matters most. The company's successful resolution of prior regulatory concerns, particularly around human factors and the significant reduction in pouch-opening time, underscores a commitment to user-centric design, which is vital for an emergency medication.

Should Anaphylm gain approval, its strategic implications are considerable. It stands to disrupt a market long dominated by injectable devices, appealing to a broad segment of patients, including those with needle phobia, who may currently avoid carrying or administering epinephrine. This could lead to improved patient adherence and more timely interventions during life-threatening allergic reactions. However, the path forward is not without its challenges. The prior Complete Response Letter signals continued regulatory scrutiny, and market adoption will necessitate extensive education for both healthcare providers and patients to ensure proper use and build confidence in this novel delivery system. Furthermore, while its PK/PD profile is promising, establishing clear real-world clinical superiority or non-inferiority against deeply entrenched autoinjector brands will be key to widespread acceptance. Ultimately, Anaphylm has the potential to redefine emergency epinephrine administration, offering a more accessible and less daunting option that could save lives.