ARS Pharmaceuticals, Inc. announced topline results from its clinical study comparing repeat doses of neffy (epinephrine nasal spray) to repeat doses of epinephrine intramuscular (IM) injection, as requested by the FDA with and without nasal allergen challenge (NAC) conditions. Based on the company?s analysis of the data, the company believed these results should support filing its response to the FDA?s CRL. The repeat dose study under NAC conditions was designed with the FDA to address the Agency?s outstanding questions regarding neffy as described in the Complete Response Letter (CRL) from September 2023.

FDA did not provide guidance on a prespecified set of endpoints, but the data are anticipated to be informative to labeling if a second dose of neffy is needed. ARS Pharma also completed the nitrosamine testing requested in the CRL per FDA?s draft guidance issued in August 2023, with no measurable levels of nitrosamines detected. Previously reported data with a single dose of neffy under NAC conditions showed accelerated absorption of neffy with exposures higher than IM injection during the early time period when clinical response to epinephrine is expected.

ARS Pharma intends to submit this repeat dose NAC study data to the FDA as part of its response to the CRL early in the second quarter of 2024. neffy Repeat Dosing Study Design: The randomized, crossover pharmacokinetic (PK) and pharmacodynamic (PD) study enrolled 43 patients with seasonal allergic rhinitis who tested positive with a Total Nasal Symptom Score (TNSS) of =5 out of 12 and a congestion score of =2 out of 3 during the screening NAC. NAC involves spraying purified antigen directly onto the nasal mucosa ?

a worst-case experimental condition in contrast to real-world nasal conditions such as upper respiratory tract infections or acute allergic rhinitis from natural causes. All patients were dosed with epinephrine within 15 minutes of induction of the NAC during the peak effect, without allowing time for nasal symptoms to subside. A second dose of epinephrine was given to patients 10 minutes after the first dose per FDA labeling of epinephrine products.

FDA explicitly requested that ARS Pharma include intramuscular (IM) epinephrine given via manual syringe as the comparator in this study, as IM is the reference-listed drug and historical basis for efficacy of all other epinephrine products. Meta-analyses (Patel et al, JACI 2021) analyzing over 30,000 anaphylaxis events demonstrate that about 90% of events respond to a single dose of epinephrine injection irrespective of the delivery device, despite significant differences in PK. PK/PD Study Results: Data from the company?s primary analysis of the completed study showed that responses on pharmacodynamic (PD) surrogate markers for efficacy in anaphylaxis, such as systolic blood pressure and heart rate, correlated well with pharmacokinetic (PK) exposures and were consistently higher for repeat doses of neffy, irrespective of dosing in the same nostril (R/R) or opposite nostrils (R/L), compared to repeat doses of IM injection.

Dosing in the same nostril (R/R) resulted in higher PD than injection at all time points measured, while dosing in the opposite nostril (R/L) was higher than injection until the 40 to 60 minute time points, after which PD was indistinguishable from injection. Consistent with prior studies, significant responses on these PD surrogate markers of efficacy with neffy were observed even at one minute after dosing. The PD responses demonstrate that the epinephrine exposures achieved with repeat doses of neffy (R/R or R/L) fully activate the receptors involved in reversing anaphylaxis symptoms. The clinical data also demonstrated that mean epinephrine concentrations following repeat doses of 2 mg neffy in the same nostril (R/R) were numerically higher than repeat doses of 0.3 mg injection at all time points through at least 240 minutes under NAC conditions.

Mean epinephrine concentrations of 2 mg neffy in the opposite nostril (R/L) were also numerically higher than repeat doses of 0.3 mg injection for approximately 30 minutes, which is longer than the time period when clinical response would be expected to be observed after dosing epinephrine (i.e., within 10 minutes). The PK profile of repeat doses of neffy during normal nasal conditions was shown in prior studies to be highly similar to repeat doses of EpiPen, which serves as the upper bracket for exposures established to be safe. In this study, the PK profile of repeat doses of neffy in the same nostril (R/R) during nasal allergen challenge was highly similar to repeat doses of neffy during normal nasal conditions, and therefore also in the range of exposures established to be safe.

Other ARS Pharma clinical studies have evaluated neffy PK/PD in people with the same TNSS and congestion severity scores as the experimental NAC studies, but with nasal symptoms due to real-world conditions such as upper respiratory tract infections or acute allergic rhinitis from natural causes. These other studies showed no meaningful difference on PK/PD compared to dosing neffy under normal nasal conditions. Repeat doses of neffy were considered safe and well-tolerated.

All adverse events were mild and continue to be consistent with those observed in prior studies of neffy across more than 700 subjects. There were no serious adverse events. Regulatory Status of neffy: Additional discussions with FDA subsequent to its issuance of the CRL confirmed that the new data are anticipated to be informative to labeling of administering a second dose of neffy.

In May 2023, the FDA Advisory Committee (PADAC), determined a favorable benefit-risk profile of neffy (16:6 for adults and 17:5 for children). No PADAC member requested a repeat dose study during allergen-induced allergic rhinitis. In addition, multiple PADAC members highlighted the favorable profile of neffy in the company's single dose NAC study.

ARS Pharma intends to file its response to the FDA?s CRL for neffy early in the second quarter of 2024, with an expected PDUFA action date six months from filing, followed by potential U.S. launch of neffy in the second half of 2024. ARS Pharma also intends to submit this repeat dose study data to the European Medicines Agency (EMA) to inform its Committee for Medicinal Products for Human Use (CHMP) Opinion decision expected by mid-2024.