Epinephrine Nasal Sprays, Sublingual Film Making Headway

 Nearly half a century since the epinephrine autoinjector hit the market in 1987, several companies are working on needle-free versions of this medicine, which is vital for treating anaphylaxis yet dangerously underused.

For the second year in a row, data from these investigational epinephrine products — two intranasal and one sublingual — drew attention at the American Academy of Allergy, Asthma and Immunology (AAAAI) 2023 Annual Meeting. The nasal sprays are further along, with ARS Pharmaceuticals' neffy under review as Bryn Pharma prepares to submit a New Drug Application for Utuly. Later this year, Aquestive Therapeutics plans to start a pivotal trial of its postage stamp–sized film (AQST-109), which delivers an epinephrine prodrug when placed under the tongue.

"Needle-free epinephrine — that is easier to carry and easier to administer than currently available forms of epinephrine — is a huge unmet need in food allergy and anaphylaxis management," said Brian Schroer, MD, a pediatric allergist at Cleveland Clinic in Ohio.

At last year's AAAAI meeting, ARS Pharmaceuticals reported that its neffy 1 mg spray reached maximal epinephrine plasma concentration in healthy adult volunteers in 30 minutes — slower than EpiPen 0.3 mg (20 minutes) and faster than manual intramuscular (IM) 0.3 mg injection (45 minutes). Since then, the company has completed similar pharmacokinetic (PK) and pharmacodynamic (PD) comparisons of the two existing epinephrine options against neffy 2.0 mg — single and double dosing (two doses given 10 minutes apart). 

As reported on a February 24 poster at this year's AAAAI meeting in San Antonio, neffy 2.0 mg had a PK profile comparable to approved epinephrine injection products in the single-dose analysis and looked even better in the double-dose comparison. PD effects on blood pressure and heart rate looked similar for all epinephrine delivery modes, as did safety profiles.

In Bryn Pharma's PK/PD analyses, Utuly 13.2 mg, administered as two consecutive 6.6-mg doses, produced higher and more sustained epinephrine plasma levels than did EpiPen 0.3 mg and manual IM 0.5 mg.

"We deliver the drug as fast as an autoinjector but maintain the level a bit longer," CEO David Dworaczyk, PhD, told Medscape Medical News. Safety and PD profiles looked comparable for all epinephrine products.

One difference between the two intranasal formulations is the delivery approach. ARS Pharmaceuticals uses an absorption-enhancing technology (Intravail) that is used in nasal spray medications approved for treating seizures (Valtoco) and migraines (Tosymra), according to CEO Richard Lowenthal. Bryn Pharma's absorption enhancer is a generally recognized as safe (GRAS) compound that has been used in oral and topical drug delivery systems but never before in a nasal spray, said Dworaczyk.

For its part, Aquestive Therapeutics compared PK/PD profiles of epinephrine delivered by its sublingually absorbed film (AQST-109 12 mg) vs EpiPen 0.3 mg or manual IM 0.3 mg. The sublingual product produced peak plasma levels faster (12 minutes) than did the EpiPen (23 minutes) and manual IM (45 minutes) but resulted in a lower overall plasma concentration than did these traditional routes. Company researchers also showed that AQST-109 effects were sustained in real-world conditions, such as peanut butter lingering on the tongue after consumption of a sandwich.

Several aspects of the AQST-109 data raised questions. One issue was PD: Compared with the injected forms of epinephrine, the sublingual product led to larger increases in both systolic and diastolic blood pressure. "That's a little bit of a concern," especially given epinephrine's known effects on the heart, Schroer said.

Another issue was PK: After a fast rise to maximum levels, serum epinephrine also dropped quickly. Because epinephrine works in part by blocking continued release of histamine and other chemicals that trigger anaphylaxis, the impact of the sublingual product may not last as long as an epinephrine autoinjector, said Schroer. "One way to overcome that would be to administer it again — which, frankly, if you're sticking something under your tongue, is probably not that hard to do."

Based on available data, the intranasal products seem to do a better job "mirroring what happens when you use the self-injectable epinephrine," Schroer said.

Dworaczyk is CEO of Bryn Pharma. Lowenthal is CEO of ARS Pharmaceuticals. Schroer reports no relevant financial relationships.
American Academy of Allergy, Asthma, & Immunology (AAAAI) 2023 Annual Meeting. Presented February 24, 2023. Poster 014

American Academy of Allergy, Asthma, & Immunology (AAAAI) 2023 Annual Meeting. Presented February 24, 2023. Poster L01

American Academy of Allergy, Asthma, & Immunology (AAAAI) 2023 Annual Meeting. Presented February 24, 2023. Poster L13

American Academy of Allergy, Asthma, & Immunology (AAAAI) 2023 Annual Meeting: Poster 007

https://www.medscape.com/viewarticle/988817