The FDA has requested an additional study. ARS Pharmaceuticals plans to appeal the decision.
The FDA has issued a complete response letter (CRL) for ARS Pharmaceuticals’ new drug application (NDA) for neffy (epinephrine nasal spray) to treat patients with allergic reactions that could lead to anaphylaxis. ARS officials said in a press release they plan to appeal.
“We are very surprised by this action and the late requirement at this time to change the repeat-dose study from a postmarketing requirement,” Richard Lowenthal, co-founder, president and CEO of ARS Pharma, said in a press release. “We stand by the totality of the neffy data package generated in a comprehensive registration program that was aligned upon with FDA and believe strongly in the value neffy can provide for patients, families and caregivers living daily with severe allergic reactions.”
The FDA has requested a pharmacokinetic/pharmacodynamic (PK/PD) study assessing repeat doses of neffy compared with repeat doses of an epinephrine injection under allergic rhinitis conditions.
PK/PD studies provide information about the drug within the body. Pharmacokinetics assesses what the body does to the drug (adsorption, distribution, metabolism and excretion), and pharmacodynamics assess what the drug does to the body (how the body reponds).
This request comes after the recommendation of an FDA advisory committee in May 2023 to approve neffy without the need for additional studies to demonstrate its efficacy or safety. Previously, the FDA and ARS Pharma had agreed on the labeling and a postmarketing requirement to conduct this study.
Lowenthal pointed out that advisory committee members highlighted the favorable profile of neffy in the company’s single-dose nasal allergy challenge study. In May, the Pulmonary-Allergy Drug Advisory Committee (PADAC) voted to support approval of neffy to treat severe allergic reaction including anaphylaxis in a vote of 16 to 6 in favor for adults and 17 to 5 in favor for children.
Those who voted no had concerns about translating the PK/PD data from healthy subjects to patients with anaphylaxis, the lack of clinical outcomes data, and inconsistent data in the first 10 minutes of administration compared with EpiPen. Those who voted yes said the pharmacodynamic data demonstrated favorable risk benefit.
ARS Pharma had submitted PK/PD data that compared neffy with approved epinephrine injection products. Regulators, however, expressed uncertainty about translating data from an intranasal drug in healthy subjects to patients with anaphylaxis where nasal mucosal changes may impact absorption.
Regulators noted in a briefing document that there is limited PK/PD data on epinephrine injection products. Epinephrine was in use before 1938 when regulations required demonstration of safety. Epinephrine was not included in the Drug Efficacy Study Implementation determinations to evaluate effectiveness of products approved from 1938 to 1962. Recent epinephrine products have been based on chemistry and manufacturing data and PK/PK data were not required.
“There is no regulatory precedent for approval of a noninjectable epinephrine product for treatment of anaphylaxis,” regulators said in the briefing document. “Given that ARS-1 [neffy] is proposed for emergency treatment and that clinical efficacy data are not available, we expect the available comparative PK/PD data to be robust to support approval, and that residual uncertainties regarding efficacy and safety are minimized.”