Motohiro Ebisawa, MD, PhD
A phase 3 open-label study has demonstrated that neffy, a recently approved epinephrine nasal spray, successfully treated anaphylaxis symptoms induced by an oral food challenge (OFC).1
“The present study is the first prospective study conducted to assess both the efficacy of an epinephrine product during anaphylaxis, as well as to characterize the clinical course of anaphylaxis before and after administration of epinephrine,” wrote investigators, led by Motohiro Ebisawa, MD, PhD, from the clinical research center for allergy and rheumatology at NHO Sagamihara National Hospital in Japan.
Despite extensive safety and efficacy data, many people remain hesitant to use epinephrine, the only approved first-line treatment for severe allergic reactions, largely due to fear of injection. The US Food and Drug Administration (FDA) approved neffy, a needle-free epinephrine option, on August 9, 2024, eliminating patients’ top-cited fear.2
In this phase 3 single-period, single-dose, open-label study, investigators assessed neffy’s efficacy for treating OFC-induced anaphylaxis symptoms in 15 Japanese children aged 6 – 17 years with food allergies.1 Patients received neffy following moderate (grade 2) anaphylaxis symptoms in the gastrointestinal, respiratory, or cardiovascular systems. Triggers included egg (n = 5), milk (n = 4), peanut (n = 4), wheat (n = 1), and walnut (n = 1).
Patients < 30 kg received neffy 1 mg (n = 6; 1 male and 5 female), and those ≥ 30 kg received 2 mg (n = 9; 6 male and 3 female). The median age and weight were 7 vs 12 years and 18 vs 40 kg for the 1 mg and 2 mg groups, respectively.
The primary endpoint was the change from baseline in main symptoms at 15 minutes or before alternative treatment. Secondary endpoints included the proportion of patients not requiring additional treatment, symptom grading by organ system at each time point, and time to resolution. Safety measures included vital signs, adverse events, and nasal assessments.
No patients needed a second epinephrine dose to treat their initial reaction. However, 1 patient developed a biphasic reaction 2 hours and 45 minutes later and received intramuscular epinephrine. On average, symptoms resolved in 16 minutes.
“In the present study, the mean symptom Grades started improving within 5 minutes (the first timepoint), followed by continuous improvement,” investigators wrote, mirroring what clinicians often observe in practice.
However, several patients received alternative medication after neffy. One child with grade 2 respiratory symptoms received procaterol hydrochloride 8 minutes after neffy for dyspnea. Other post-neffy treatments included antihistamines, a nebulized B2 agonist, cromoglicate sodium, hydrocortisone sodium succinate, oxygen for decreased oxygen saturation, and cooling as adjunctive treatment for skin itching.
Some adverse events were unrelated to the OFC, including tremor (n = 3) and nasal mucosal erythema (n = 2). Other mild to moderate adverse events included headache, cough, intranasal hypoesthesia, nasal crusting, nasal discomfort, oropharyngeal pain, pharyngeal hypoesthesia, rhinalgia, abdominal pain, oral hypoesthesia, chills, pain, and tachycardia.
Erythema appeared in 4 patients at 15 minutes post-dose, 5 patients in 20 minutes, 6 patients at 30 minutes, 4 patients at 60 and 120 minutes, and 3 patients at discharge. One patient had nasal crusting at 120 minutes. No patients had hemorrhage, inflammation/erosion, or abnormal oxygen saturation or ECG findings.
Following neffy administration, an overall increase in systolic blood pressure and heart rate was observed. A transient decrease in systolic blood pressure occurred shortly after dosing, coinciding with reductions in diastolic blood pressure across all dose groups. A brief decline in heart rate was also noted at 10 minutes post-dose, and the diastolic blood pressure decrease persisted for approximately 20 minutes following administration.
“These data provide a bridge between neffy’s extensive PK and PD data which demonstrate activation of adrenergic receptors and the clinically measurable therapeutic effects of neffy,” investigators wrote. “In addition, the exploration of the PD response to epinephrine provides insights into the mechanism of action for the treatment of severe allergic reactions.”
References
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Ebisawa M, Takahashi K, Takahashi K, et al. Epinephrine Nasal Spray Improves Allergic Symptoms in Patients Undergoing Oral Food Challenge, Phase 3 Trial. J Allergy Clin Immunol Pract. Published online July 8, 2025. doi:10.1016/j.jaip.2025.06.038
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Smith, T. FDA Approves Epinephrine Nasal Spray for Emergency Treatment of Allergic Reactions. HCPLive. August 9, 2024. https://www.hcplive.com/view/fda-approves-epinephrine-nasal-spray-for-emergency-treatment-of-allergic-reactions. Accessed July 16, 2025.