Neffy Generates Favorable PK/PD Data Under Nasal Allergen Challenge in Repeat Dosing Study Requested by FDA
neffy (epinephrine nasal spray) delivered a PK and PD profile greater than or similar to that of IM epinephrine after extreme nasal challenge, reports ARS Pharmaceuticals.
Repeat doses of the investigational epinephrine nasal spray neffy given after nasal allergen challenge (NAC) exhibited a pharmacokinetic (PK) profile that was greater or similar to that observed with intramuscular epinephrine injection and a pharmacodynamic (PD) profile showing numerically higher mean drug concentrations than seen with the injectable comparator.
The topline findings, announced in a news release by ARS Pharmaceuticals, come from a study that compared repeat doses of neffy to repeat doses of epinephrine intramuscular (IM) injections with and without NAC conditions, an investigation mounted to satisfy a request from the US Food and Drug Administration (FDA) in a Complete Response Letter sent to the company in September 2023.
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The topline findings, announced in a news release by ARS Pharmaceuticals, come from a study that compared repeat doses of neffy to repeat doses of epinephrine intramuscular (IM) injections with and without nasal allergen challenge (NAC) conditions, an investigation mounted to satisfy a request from the US Food and Drug Administration (FDA) in a Complete Response Letter sent to the company in September 2023.
Neffy is a potential needle-free option to treat type 1 allergic reactions, including anaphylaxis in adults and children weighing more than 66 lbs.
In the announcement ARS noted that repeat doses of neffy administered in the same nostril vs once in each provided greater exposure that was also greater than observed after epinephrine injection for PK exposure and PD response at all time points. These results “may help inform labeling and instructions for use. With these results, we are completing the necessary work to submit our response to FDA in the next couple of months,” Richard Lowenthal, ARS cofounder, president, and CEO, said in the company statement. “We look forward to working with the Agency in our efforts to make neffy available to patients as soon as possible.”
In the announcement ARS noted that repeat doses of neffy administered in the same nostril vs once in each provided greater exposure that was also greater than observed after epinephrine injection for PK exposure and PD response at all time points.
The PK and PD study used a randomized, crossover design and enrolled 43 individuals with seasonal allergic rhinitis (SAR) who had positive results on the Total Nasal Symptom Score (TNSS) of ≥5 out of 12 and a congestion score of ≥2 out of 3 during the screening NAC, according to ARS Pharma. NAC produces a “worst-case” experimental condition vs a real-world nasal scenario, ie, an upper respiratory infection or acute allergic rhinitis triggered by natural exposures, as explained in the ARS statement.
Within 15 minutes of the NAC induction, during the antigen’s peak effect, all patients were dosed with epinephrine without allowing time for nasal symptoms to subside. Ten minutes after the first dose, a second dose was given, based on FDA labeling of epinephrine products.
Since IM epinephrine delivered via manual syringe is the reference-listed drug and historical basis for efficacy of "all other epinephrine products," the federal agency "explicitly requested that ARS Pharma include IM epinephrine... as the comparator in this study," the company said.
Primary analysis of data from the completed study showed that PD surrogate marker responses for efficacy in anaphylaxis (systolic blood pressure and heart rate) correlated well with PK exposures and were consistently higher for repeat doses of neffy compared to IM injection, regardless of nostril dosing pattern (same [R/R] or opposite [R/L]), according to findings reported in the press announcement.
PD was higher following same-nostril dosing (R/R) vs injection at all time points measured. Dosing in the opposite nostrils demonstrated higher PD compared to injection until the 40- to 60-minute time points when the responses were comparable.
PD was higher following same-nostril dosing (R/R) vs injection at all time points measured. Dosing in the opposite nostrils demonstrated higher PD compared to injection until the 40- to 60-minute time points when the responses were comparable.
Importantly ARS notes that the current results are consistent with findings from previous studies, showing significant surrogate marker responses as early as 1 minute after initial dosing—a sign that repeat doses of neffy fully activate reversal of anaphylaxis symptoms. Findings from this study also showed no “meaningful differences on PK/PD” compared with dosing of neffy under naturally induced nasal conditions.
"[The] FDA asked what would happen if NAC conditions occurred during the 10% of anaphylaxis events that require a repeat dose of epinephrine. This study answers this question - exposures with repeat doses of neffy under NAC are at least as good as repeat doses of injection, and dosing in the same nostril is greater than injection," lead author Thomas Casale, MD, professor of added medicine and pediatrics and chief of translational research in allergy/immunology at the University of South Florida, said in an interview with Patient Care® partner website Contemporary Pediatrics.®
"I believe the robust pharmacodynamic effect observed with repeat dosing in the same nostril or opposite nostrils compared to injection during [NAC] shows that neffy will be at least as effective as injection in reversing anaphylaxis symptoms, even during infrequently observed rhinitis of note."
ARS Pharma plans to submit data from the repeat dose study of neffy to the FDA early in the second quarter of 2024, as part of its response to the agency’s CRL for the New Drug Application the company submitted in the first half of 2023.
The company expects a Prescription Drug User Fee Act date 6 months from filing, for potential approval and launch in the second half of 2024.
