An ARS Pharmaceuticals nasal spray expected to become the first approved non-injectable version of epinephrine for treating severe allergic reactions has been turned down by the FDA, a decision that bucks an affirmative advisory committee vote earlier this year.

San Diego-based ARS Pharma characterized the rejection as a surprise. In addition to the advisory committee support, the company’s discussions with the FDA had gotten as far as physician labeling and post-marketing requirements—steps that are indications a product is on its way to an approval. In its late-Tuesday announcement of the negative regulatory decision, ARS Pharma said the agency is now asking for more data from another study. The company said it will appeal.

Epinephrine administered via intramuscular injection has been available since the 1987 FDA approval of EpiPen for treating type 1 allergic reactions, which are immediate reactions prompted by antigens from food, medication, or insect bites. Such reactions include anaphylaxis, which can be life-threatening. Self-injection pens provide a way to immediately counteract these allergic reactions. ARS Pharma developed its intranasal product, dubbed Neffy, as another way to provide a quick response.

ARS Pharma’s product candidate consists of an aqueous formulation of epinephrine along with Intravail, an ingredient that improves how much of a drug is available to provide its effect when it is administered intranasally. Intravail is already a component of other FDA-approved intranasal products. The device that administers the ARS Pharma product is also part of FDA-approved intranasal products, perhaps most notably the naloxone nasal spray Narcan.

ARS Pharma’s FDA submission included data from “human factor” studies, which are tests to ensure that how people interact with a drug/device combination product supports the safety and efficacy of its intended use. According to FDA documents, ARS Pharma included two human factor studies as part of its submission. In these studies, participants were placed in a simulated emergency scenario of responding to a severe allergic reaction to themselves or someone else.

The data from the human factor studies were sufficient to support the product’s new drug application. According to the company, its subsequent discussions with FDA led to alignment on a post-marketing study that would test repeat doses of the product under allergen-induced allergic rhinitis conditions. Complete response letters are not public documents, but ARS Pharma said the FDA is now requiring that this repeat-dose study be part of the application. That requirement comes despite the FDA advisory committee’s recommendation for approval without any additional tests to show safety or efficacy.

“We are very surprised by this action and the late requirement at this time to change the repeat-dose study from a post-marketing requirement, which we had previously aligned on with FDA, to a pre-approval requirement, particularly given the positive advisory committee vote,” ARS Pharma President and CEO Richard Lowenthal said in a prepared statement. “In fact, multiple committee members highlighted the favorable profile of Neffy in our completed single-dose nasal allergy challenge study and that any decline in exposure 20 minutes after dosing, after the expected response period, is of no concern.”

Though the advisory committee supported approval, the vote was not unanimous. Some of those who voted “no” expressed misgivings about supporting the nasal spray without any clinical data.

In a note sent to investors on Wednesday, William Blair analyst Tim Lugo wrote that the FDA decision was a surprise, given the positive advisory committee vote and the company’s interactions with the regulator. The additional required study adds both execution and clinical risk, complicating what has already been a long development process, he added. In Lugo’s view, the FDA is holding the ARS Pharma nasal spray to a higher standard than comparable products.

“It does raise questions of whether the agency really wants to approve the therapy, as the pathway has already far exceeded epinephrine products such as EpiPen,” Lugo said.

ARS Pharma is prepared to conduct the additional study because it had already agreed to it as part of the post-marketing requirements. The company said it expects to resubmit Neffy’s application in the first half of next year, potentially receiving an FDA decision in the second half of 2024. But investors showed their own negative reaction to the developments, and ARS Pharma’s stock price tumbled more than 56% to $2.88 on Tuesday. The company, which has no revenue from any FDA-approved products, had a cash position of $117.9 million as of the end of June, according to its most recent financial report.

The ARS Pharma drug is still under review by the European Medicines Agency. The company plans submissions next year in other markets as well.

Photo: Getty Images, Sarah Silbiger