First-in-class intranasal epinephrine spray for anaphylaxis: Dose finding clinical study

Abstract

Background: Anaphylaxis is a life-threatening clinical presentation of acute systemic allergic reactions. Timely administration of epinephrine, usually by intramuscular autoinjector, is a robust life-saving treatment. Despite the critical necessity, there are multiple deterrents to patients' proper use of epinephrine autoinjectors. FMXIN002 is a novel nasal dry powder formulation of epinephrine in a single-use device, offering first-in-class alternative treatment.

Objectives: We sought to measure epinephrine pharmacokinetics, pharmacodynamics, and safety following a single administration of FMXIN002 at doses of 3.6 and 4.0 mg epinephrine versus intramuscular (IM) autoinjector 0.3 mg, in healthy adults.

Methods: This was an open-label, single-dose, 3-treatment, crossover, randomized, comparative bioavailability study with 12 healthy adults, female and male. FMXIN002 stability was also tested.

Results: FMXIN002 4.0 mg was absorbed faster and in higher amounts by most of the subjects, compared to IM autoinjector: 91% of subjects achieved the clinical threshold of 100 pg/mL plasma epinephrine at 6 minutes after administration of FMXIN002 4.0 mg compared to 55% of subjects treated with IM autoinjector. The area under the curve for 0 to 4 minutes' period was significantly higher for FMXIN002 4.0 mg (geometric mean: 7.49 h ∙ pg/mL vs 2.06 h ∙ pg/mL, respectively; P = .0377). The pharmacodynamic response and safety were comparable among all treatments. No serious adverse events occurred, all events were mild and self-resolved. FMXIN002 was highly stable at all tested conditions including 5 years at 20 ± 5ºC.

Conclusions: FMXIN002 4.0 mg nasal spray enables faster and higher epinephrine plasma absorbance at the short therapeutic window required for the treatment of anaphylaxis, using a patient-friendly, needle-free, stable and safe device.

Keywords: Anaphylaxis; allergy; bioavailability; epinephrine; intranasal; powder; spray.

Fig 1

Study design. The subjects were randomly assigned to 1 of 2 sequences (arms 1 and 2), each of which consisted of 3 epinephrine administrations: 1 IM (treatment A, EpiPen 0.3 mg) and 2 escalating doses via intranasal route (treatment B, 3.6 mg; treatment C, 4.0 mg). The administrations were separated by 1 week of washout. Pharmacokinetics and vital signs were followed at each administration day from −1 hour before to 2 hours post dose administration. Safety was also followed by AEs, physical examination, 12-lead ECG, safety laboratory (hematology, chemistry, urinalysis) evaluations, nasal cavity examination, nasal and nonnasal symptoms questionnaire.

Fig 2

Mean measured plasma epinephrine concentration time profile at −1 to 2 hours. Inset shows mean measured plasma epinephrine concentration at 0 to 0.5 hours. (A) EpiPen 0.3 mg, (B) Nasus spray 3.6 mg, (C) Nasus spray 4.0 mg. Results are mean ± SE.

Fig. 3

Comparison of mean AUC (baseline-subtracted). ∗P = .037 by differences of LSM.

Fig 4

Median time (minutes) results: T_100pg/mL and T_max. T_max is the time to reach the maximum concentration of the drug observed in the plasma following administration. T_100pg/mLis the time when epinephrine concentration in plasma is 100 pg/mL (clinical threshold).

Fig 5

Proportion of subjects achieving clinical threshold of 100 pg/mL at 4 and 6 minutes.

Fig 6

Pharmacodynamic parameters at 0 to 120 minutes post dose. (A) Systolic blood pressure (BP), (B) diastolic BP, (C) heart rate (HR), (D) respiratory rate (RR). All results are presented as means. There were no significant differences compared to EpiPen. All results were within normal clinical ranges. (SE is not presented for graphical clarity.)

Fig 6

Pharmacodynamic parameters at 0 to 120 minutes post dose. (A) Systolic blood pressure (BP), (B) diastolic BP, (C) heart rate (HR), (D) respiratory rate (RR). All results are presented as means. There were no significant differences compared to EpiPen. All results were within normal clinical ranges. (SE is not presented for graphical clarity.)