Four companies are making progress on developing needle-free epinephrine auto-injectors to treat severe allergic reactions. The competition includes two nasal sprays, a nasal powder and a film that is placed under the tongue and dissolves in seconds.
First in line is a nasal epinephrine nebulizer from ARS Pharmaceuticals called neffy. On April 2, the company resubmitted its request for approval to the Food and Drug Administration. ARS Pharma applied for approval in 2023, but suffered a setback when the FDA refused to educate. Instead, the agency requested additional investigation.
This investigation is complete and forms part of the company’s resubmission. “We look forward to working with the FDA to make neffy available to allergy patients as soon as possible,” said Richard Lowenthal, president and CEO of ARS Pharma.
The FDA has until 2024 October 2 to make a decision whether to approve neffy epinephrine spray.
A second auto-injection alternative should also be ready for FDA approval in 2024. “Aquestive Therapeutics is a sublingual film,” says Daniel Barber, the company’s president and CEO.
There are at least two other auto-injector alternatives: an epinephrine nasal spray made by Bryn Pharma and an epinephrine powder made by the Swedish company Orexo. Epinephrine powder is a newer entrant into the field of potential needle-free epinephrine products.
Epinephrine sprays, film vs. Nozzles
Several studies have already been done with neffy and Bryn Pharma nasal sprays, as well as Aquestive film. Three product manufacturers recently shared new clinical trial results comparing their products to auto-injectors and syringe-injected epinephrine.
There are nuances between them. However, tests show that both the nasal spray and the film increase heart rate, blood pressure, and epinephrine levels in the blood, similar to using auto-injectors or epinephrine from a syringe.
These measurements show that epinephrine is absorbed and will help treat real anaphylaxis, says Dr. Jay Lieberman, an allergist-immunologist at the University of Tennessee Health Science Center. “Pharmacokinetic” and “pharmacodynamic” data are called studies that the FDA also reviews when considering approval.
“All of these products achieve what you want to see,” says Lieberman. “These companies have shown pharmacokinetic and pharmacodynamic data that are very promising and appear to be consistent with what the FDA wants them to be able to simulate.”
Overall, “the differences between all these products are very small,” he adds. Lieberman is chairman of the Food Allergy Committee of the American College of Allergy, Asthma and Immunology.
All Eyes on neffy epinephrine spray
ARS Pharma’s neffy epinephrine nebulizer was the first to be submitted for approval. in 2023 May. FDA’s independent expert advisory committee recommended approval of the spray. However, in 2023 in September, ARS Pharma suffered a setback when the FDA refused to approve a 2-milligram nebulizer for adults and children weighing 66 pounds or more.
ARS Pharma shared that the agency wanted to see a study of two doses of their nasal spray in people with nasal congestion due to allergic rhinitis. In announcing the resubmission to the FDA, Lowenthal notes that this study was “successfully completed.”
The FDA has six months from the date of submission to make a decision. According to Lieberman, other companies are watching closely.
“For these other companies, everything will depend on what the FDA does with the ARS product.” If the FDA continues to say no to ARS, it could complicate their path to approval, an allergist says. He has worked as a consultant for ARS and Bryn Pharma.
Meanwhile, other manufacturers of alternative epinephrine are continuing the necessary clinical trials. Here is the latest information on each.
Sublingual film of epinephrine
Aquestive Therapeutics’ sublingual film, called Anaphylm, would be the only oral medication to treat serious allergic reactions.
in 2024 March. a pivotal phase 3 study in 64 adults showed that the time to peak epinephrine blood concentrations averaged 12 minutes when the film dissolved. This was faster than the other methods tested – 20 minutes with the EpiPen, 30 minutes with the Auvi-Q, and 50 minutes with manual epinephrine.
“It’s faster than both auto-injectors and much faster than manual injection,” Barber told Allergic Living.
The company’s research also shows that the time to peak concentration with Anaphylm was broken down into 12 minutes. Intramuscular epinephrine varied more from patient to patient in how long it took to peak.
A study in adults using a repeated dose of the film showed that it took 10 minutes for the second dose to reach its peak. Barber says that the rapid peak increase may be especially important because people who need a second dose often have worsening symptoms. (One analysis of studies found that about 8 percent of people treated with epinephrine need a second dose to relieve anaphylaxis.)
He calls the short time to peak “ideal for those patients because they’re going to get a very quick burst of epinephrine” to treat symptoms.
In discussions with the FDA, it was determined that the instruction label would not require an ingestion warning. When placed under the tongue, the film dissolves in seconds. Swallowing is fine, Barber says.
Anafil will be packaged with a foil that can be placed in a pocket, purse or even a cell phone case. The instructions simply tell you to take the film out of the foil packet and place it under your tongue.
Anafilm: OAS and next steps
Because Anaphylm is taken by mouth, the FDA requested a repeat dosing study in people who had a reaction due to oral allergy syndrome, says Dr. Carl Kraus, Chief Medical Officer, Aquestive. People with oral allergen syndrome (OAS) develop local symptoms such as itching, burning, and swelling of the mouth after eating raw fruits and vegetables.
Patients with OAS will be included in the study. The researchers will then “create a local response in the oral cavity and assess whether that affects the absorption of the drug,” says Kraus. The study protocol will be submitted to the FDA shortly.
Barber says the company plans to approve their 12 mg dose for adults and children weighing 66 pounds and more by 2024. the end
He says it’s not known whether the FDA will ask the company to appear before an FDA advisory committee before approving it, as it did with neffy. The members of these committees are physicians and other experts who provide independent advice to the FDA.
“There are certain benefits to having an advisory committee. We can talk about our data in a public forum with a committee of doctors,” says Barber. “We don’t know if the FDA will require it, but we’ll certainly be ready if they do.”
Bryn Pharma Nasal Epinephrine
A second nasal spray is also making progress: Bryn Pharma’s epinephrine spray, called the NDS1C in the study. This is a 13.2 mg dose given in two consecutive sprays. (For comparison, one dose of neffy is one spray.)
Two recent studies combined data from four studies involving more than 460 people. Studies have shown that the nebulizer’s effect on epinephrine levels in the blood is similar to that of a 0.3 mg auto-injector. Participants received a total of 13.2 mg of NDS1C: either two sprays in the same nostril or two sprays in opposite nostrils. In comparison, a third group had a single 0.3 mg auto-injector.
Time to peak epinephrine blood concentration was 25 minutes for the contralateral nasal spray, 20 minutes for the same nostril, and 20 minutes for the autoinjector. Changes in blood pressure and heart rate were similar for all three methods.
In a repeat-dose study in 36 healthy adults, epinephrine absorption increased by 50% after the second dose. Two doses of the Bryn Epinephrine Nebulizer are four puffs. Side effects were mostly mild and included upper abdominal pain, nasal discomfort, headache and nausea in some participants. There were no serious adverse events.
Bryn’s data was introduced in 2024. February. At the American Academy of Allergy, Asthma and Immunology meeting in Washington, a Bryn spokesperson said by email, “The company is working to complete clinical development and looks forward to cooperating with the FDA. the ability to bring to market needle-free as soon as possible.
Fourth contender: epinephrine powder
A fourth contender, Orexo Nasal Epinephrine Powder, also shared a clinical trial at the Allergists’ Meeting.
In the study, 40 healthy volunteers received four 1 mg powder forms of epinephrine. Results were compared with a 0.3 mg EpiPen, with a 24-hour interval between all doses. The purpose of the study was to determine the optimal formulation for future clinical trials, says Martin Jonnson, clinical pharmacologist at Orex.
The study found that epinephrine levels in the blood tended to peak when the EpiPen was used. However, 6 to 10 minutes after administration, blood levels of epinephrine administered via an auto-injector and powder were approximately the same. Epinephrine powder increased heart rate and blood pressure more than the EpiPen.
The powder dissolves quickly when it comes into contact with the moisture inside the nose, Jonnson says.
The study also showed that the powder remains stable when stored at high temperatures. After 12 months of storage at 104 degrees Fahrenheit, epinephrine powder is virtually non-degradable. By comparison, the EpiPen lost about 45 percent of its active drug in hot temperatures.
in 2023 In November, the FDA approved Orexo’s new drug application using powder technology and naloxone to treat opioid overdoses.
The next steps for their epinephrine powder is to test it in people with nasal congestion due to allergic rhinitis. Jonsson did not have a date for when that investigation would begin.
He admits his company’s research isn’t as advanced as others. “Of course, it’s good to be first,” Jonnson says. “But we think we can add something extra with our stability data.”
Is there a race to be the first alternative?
Lowenthal says neffy could hit drugstores within eight weeks of FDA approval. Reimbursement from commercial insurers can take longer, from six months to a year.
From a marketing perspective, Barber of Aquestive says that all pharmaceutical companies would like to be the first to approve a new epinephrine product. But “it’s not really a race.”
“The reality is that once these products are available to patients, patients will be the end-to-end solution and will be for many years,” he says.
Cost, availability, and patient preferences can influence those decisions.
Needle-free products: different doses
Each of the auto-injector alternatives delivers a different dose of epinephrine. Neffy is a 2 mg pen. ARS Pharma is also developing a 1 mg nebulizer for children weighing 30 to 66 pounds. Anaphylm is a 12 mg dose and Bryn nebulizer is a 13.2 mg dose.
In contrast, EpiPen and Auvi-Q come in 0.3 mg doses.
Why the differences? This has to do with how epinephrine is absorbed in different ways, Lieberman explains.
The most important thing is absorption and its effect on the body. This is exactly what the pharmacokinetic and pharmacodynamic research data show.
Each company’s goal is to find a dose that matches the heart rate and blood pressure levels of the epinephrine products already on the market — the auto-injectors and the hand-held syringe — epinephrine.
Tags: Epi Auto Injector Alternatives Making Progress Seeking Approval
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