A needle-free anaphylaxis treatment runs into an FDA roadblock

ARS Pharma had high hopes that the FDA on Tuesday would approve its flagship product, a needle-free treatment for adults and children with severe allergic reactions. But instead, the drugmaker was set back with the agency requesting an additional study.

Neffy, as the product is called, is a nasal spray that delivers the same drug, epinephrine, as the auto-injectors currently used to treat anaphylaxis.

“We are very surprised by this action and the late requirement at this time,” Richard Lowenthal, president and CEO of ARS Pharma, said in a news release. The company is being asked to conduct a repeat-dose study of neffy — something Lowenthal said was originally a post-marketing requirement. 

While an advisory committee recommended the FDA approve neffy, some raised questions about whether ARS provided sufficient data on the drug’s efficacy compared to available epinephrine products. Viatris, the maker of the EpiPen, also filed a petition asking for more data, Endpoints reported. 

As of May, there were still questions about whether neffy worked as well as auto-injector epinephrine, since much of ARS’ data was from people who were healthy or only had mild allergies (not anaphylaxis), there was limited safety data, no formal clinical efficacy trial, and results varied across trials. The review process is based on surrogate measures of efficacy, such as how well neffy raises a person’s blood pressure (a necessary step for calming an allergic reaction). Epinephrine has been widely used since before the FDA existed, so its approval process is different from that of newer drugs. 

The study now required for neffy’s approval will compare repeat doses of neffy to repeat doses of an epinephrine injection in people with allergen-induced allergic rhinitis. ARS plans to file a dispute resolution request with the FDA, and resubmit neffy in the first half of 2024, with hopes of getting the product approved by the end of next year.

ARS presents neffy as a smaller and more easily administered rival to auto-injectors like the EpiPen, which for decades have been the only quick treatment option for people with severe allergies. Epinephrine, which is the same thing as adrenaline, has been used for a century to treat anaphylaxis.

But existing treatments have run into several problems that the makers of neffy hope to resolve: supply, cost, and design. 

Since 2017, there have been shortages of the EpiPen, and other auto-injectors have been pulled from the market over quality control problems. Lowenthal said supply won’t be an issue; it’s the complicated design of the pens that has been a problem. Epinephrine itself is available, and neffy will be using a simple spray device, the same one used for overdose reversal medication Narcan and several other products on the market. Neffy’s nasal spray containers are about the size of a tea bag, and deliver a single dose into the nose with a one-handed pump. 

Cost is another frequent barrier for users. In 2007, a pack of two EpiPens retailed for about $100 in the U.S. But when Mylan (now Viatris, with Pfizer’s Upjohn division) bought the product, it raised prices. By 2016, a two-pack cost over $600, despite manufacturing costs being a fraction of that per pen. In response, Mylan made a generic epipen, which sold for about $300. 

FDA approval of competing products, including a generic from Teva Pharmaceuticals, and Kaleo’s voice-guided Auvi-Q pen, also drove down prices. But a pack of two generic epinephrine auto-injectors still retails at anywhere from $110 to nearly $500 depending on the pharmacy. 

Lack of access to epinephrine — because of cost or supply, or insurance coverage — can put people with severe allergic reactions in very risky situations, said Ruchi Gupta, a pediatrician and founding director of the Center for Food Allergy & Asthma Research at Northwestern University’s Feinberg School of Medicine and Lurie Children’s Hospital of Chicago. While deaths from anaphylaxis are rare, delaying treatment means the allergic reaction will worsen and require hospitalization, and could leave psychological scarring.

She said her patients “really do need options” for epinephrine, and she hopes a nasal spray and sublingual option will both become available. 

Access issues widen health disparities. Already, data suggest there are significant differences in food allergy prevalence by socioeconomic status. And Black, Hispanic, and Asian children have higher rates of severe allergic reactions, allergies to multiple foods, and related emergency visits, Gupta found in her research. (The top nine allergens are peanuts, tree nuts, shellfish, finned fish, milk, eggs, soy, wheat, and sesame.)

When it comes to anaphylaxis treatment, cost is one of the top issues, Gupta said. “Sometimes it’s really hard to get our patients the one they want because certain insurances will only cover certain types,” she said.

Lowenthal said a pair of neffy would not cost more than $199, even for people who are uninsured or have high-deductible health insurance plans. For most people with commercial insurance, ARS plans to use coupons to drive copays down to $25 per two-pack.

A third key issue is design. Beyond a fear of needles that might make users hesitate in an emergency, auto-injectors can be large and inconvenient to carry around, or tricky to use, leaving some unprepared when they go into anaphylactic shock. 

Chris Lauletti, 30, is well aware of traditional auto-injectors’ shortcomings. He’s had a severe allergy to sesame and certain tree nuts since he was a child. After his first episode of anaphylaxis at age 5 — the inside of his mouth felt super-hot after eating a piece of halva — he was armed with an EpiPen. But he didn’t often carry it once the scare wore off. 

“I was really bad about it, and that’s because it was just so awkward and big to carry. It’s huge. Who has the pockets for this thing? I’m not gonna wear a fanny pack, dude,” he said. 

The second time he went into anaphylaxis was Thanksgiving when he was about 16. His Italian family had served up a big spread of food, including novel dips Lauletti’s aunt made. He asked if he could try one, and she said yes. It turned out to have tahini in it. About 10 minutes after eating the dip, Lauletti developed a strange stomachache and then his whole body swelled up. 

His parents were rushing him to the hospital and while in the backseat of the car, Lauletti’s mom went to use the auto-injector for the first time and used it upside down, jabbing herself in the finger instead. By the time they arrived at the emergency room, the younger Lauletti needed two shots of epinephrine to tamp down his allergic reaction. And his mom was in the hospital bed next to him, getting her finger treated, since a misdirected shot of epinephrine can lead to tissue damage and even amputation. “It was such a mess. It just feels like such old tech for something that so many people have,” said Lauletti, a senior marketing manager in New York City.

Despite the chaos of that Thanksgiving, his third anaphylaxis hospitalization was even worse. Since allergies are stored in the body’s immune memory, each subsequent exposure can lead to an even more aggressive reaction. In 2017, Lauletti went out with friends the day before New Year’s Eve and stayed over at one of their houses. A late-night craving led him to his friend’s pantry, and to chocolate chip cookies. But as soon as he ate one, within a couple of seconds, he felt his throat closing up. The cookies had tahini in them. 

Lauletti didn’t have an EpiPen on him, so his friend called an ambulance. Lauletti said he blacked out on his way to the hospital — his throat closed so much he had to be intubated — and was in a medically induced coma for 48 hours. “I woke up the day after New Year’s and it was the next year. And I didn’t even know what happened,” he said.

In the back of his mind, Lauletti knows another reaction to sesame might kill him if he doesn’t have anaphylaxis treatment on him. He says a version of epinephrine that’s smaller and easier to carry (and less costly) would be a game-changer for him. “If that was real and I could have it, I would never not carry that. End of story.”

ARS’ research suggests children as young as 12 years old can use neffy by themselves (the drugmaker chose the name to be kid-friendly). “It doesn’t matter if you dose it upside down, right side up, at an angle — doesn’t matter. It fires exactly the same way in every direction,” Lowenthal said. And ARS has designed a clip-on carrying case reminiscent of an AirPods case to keep the doses in. 

Another bonus: neffy could be stored at up to 122 degrees Fahrenheit for up to three months, meaning users don’t need to worry about the drug going bad if they leave it in a hot car for an afternoon, Lowenthal said. That pushes the temperature stability further than auto-injectors, he said. 

The 2-milligram dose of neffy was proposed for anaphylaxis in adults and children who weigh more than 66 pounds. Lowenthal said ARS is ready to have neffy at pharmacies within eight weeks of approval, once the FDA issues its final labeling. “We have product ready to launch,” he said. 

An epinephrine nasal spray has been difficult to develop because the drug is not well-absorbed through the nose, said Lowenthal, a 25-year veteran in drug development who started his career as a new drug reviewer at the FDA. But Lowenthal had connections. His clinical research group got Narcan nasal spray approved, and helped get a diazepam nasal spray approved for the treatment of epilepsy. Through that work, he learned of a compound that could open up tight junctions in the mucous membrane of the nose. He negotiated a licensing deal to use the compound, Intravail, to improve nasal absorption of epinephrine.

If neffy is approved, ARS will look to expand the patient pool to children of lower weights. The drugmaker also said it is conducting trials to see if neffy can work for people with chronic hives or persistent asthma. 

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