Drugs

FDA Reviewers Question ARS-1 Development Program

Members of the FDA Pulmonary-Allergy Drug Advisory Committee will discuss 5/11 whether the ARS Pharmaceutical development program for its ARS-1 (intranasal epinephrine) is sufficient to support a favorable benefit/risk assessment for an indication for emergency treatment of allergic reactions (Type 1) including anaphylaxis in some adults and children. An agency briefing document released before the meeting questions whether the applicant’s use of pharmacokinetic/pharmacodynamic (PK/PD) data comparing ARS-1 to approved epinephrine injection products and human factor (HF) studies is sufficient to establish a benefit/risk assessment without clinical trials.

“The use of epinephrine injection for the treatment of anaphylaxis is based on historical and anecdotal use,” the document says. “Adequate and well-controlled clinical trials have not been conducted. Given feasibility constraints of conducting clinical efficacy trials for the anaphylaxis indication, the ARS-1 development program consists of PK/PD and HF studies. Support for the efficacy of ARS-1 is based on PK/PD similarity of ARS-1 to approved epinephrine injection products. Establishing efficacy based on PK/PD similarity to approved epinephrine injection products is challenging due to the paucity and variability of PK/PD data for epinephrine injection and uncertainties in translating PK/PD results of a topically administered drug from healthy subjects to patients with anaphylaxis where nasal mucosal changes may impact absorption.

“Based on the severity of the indication and the availability of approved safe and effective products, we need to have confidence that efficacy and safety of epinephrine administered by this novel route of administration have been established; residual uncertainties should be minimized. A high level of confidence in both PK and PD results and confidence in bridging the PK/PD findings to clinical efficacy in the setting of anaphylaxis are expected to support a favorable benefit-risk assessment.”

The briefing document acknowledges that the ARS-1 development program involved discussions between the company and the agency. “Throughout the interactions with ARS,” FDA says, “the division noted areas of uncertainty with a PK/PD approach that would need discussion with an FDA advisory committee.”

FDA says it is asking the committee members to consider the PK/PD and safety data and give an opinion on whether they are robust enough to support a favorable benefit/risk analysis for the emergency treatment of anaphylaxis and if they are not robust enough, to identify the additional data that would be needed.

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