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March 02, 2022
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Sublingually administered epinephrine meets therapeutic thresholds

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PHOENIX — Epinephrine can reach therapeutic plasma concentrations via sublingual administration, according to a study presented at the American Academy of Allergy, Asthma & Immunology Annual Meeting.

“Anaphylaxis is a disease state that has faced a lack of innovation for decades,” John Oppenheimer, MD, clinical professor of medicine at UMDNJ Rutgers University School of Medicine and allergist at Pulmonary and Allergy Associates NJ, told Healio.

AQST-109 achieved maximum drug concentration in 15 minutes, while the EpiPen required 22 minutes.
Data were derived from Oppenheimer J, et al. Abstract L37. Presented at: AAAAI Annual Meeting; Feb. 25-28, 2022, Phoenix (hybrid meeting).

“Epinephrine has been in use for more than a century, yet epinephrine auto-injectors are often underutilized due to various factors, including needle phobia, delayed administration and failure to carry,” he said.

An alternative to injections

Many at-risk patients refuse to fill their prescriptions for injectable forms of epinephrine such as the EpiPen (Viatris/Mylan Inc.), Oppenheimer continued, whereas many of those who do get their prescription filled do not carry the device.

John Oppenheimer

“Hence, a different treatment modality could address a significant unmet medical need resulting from deficiencies of auto-injectors and improve patient access, usage and therapeutic response,” Oppenheimer said.

Yet alternative delivery routes have not produced the speed and observed plasma levels (Cmax) that the standard of care produces, Oppenheimer said. Aquestive Therapeutics then developed a sublingual, polymer matrix-based film containing AQST-109, which is a prodrug of epinephrine, using the company’s PharmFilm technology.

About the size of a postage stamp, the film dissolves on contact and is designed to be used in place of epinephrine injections during the emergency treatment of Type 1 allergic reactions including anaphylaxis.

“Medical devices such as EpiPen are often bulky, have temperature-storage limitations and require the patient or caregiver to be comfortable with an injection,” Oppenheimer said.

Aquestive Therapeutics used feedback from patients who are at risk for anaphylaxis and from their caregivers and doctors indicating that needle-based epinephrine auto-injectors are not optimal for administration.

“One of the product’s most appealing attributes to patients and parents of pediatric patients is that the drug is kept in a foil sachet that is similar in size and thickness to a business card. In addition, as a clinician, I strongly believe that a significant difference is the oral application of the product,” Oppenheimer said.

“Given the small size, portability and needleless delivery of the product, AQST-109 has the ability to significantly improve how patients and caregivers manage anaphylaxis,” he continued.

The study’s results

The phase 1 study was designed to provide first-in-human data for the film. It involved 12 healthy male volunteers who were randomly assigned to receive formulation one (F1) or two (F2) of AQST-109.

The researchers measured the volunteers’ systolic and diastolic blood pressure and heart rate before dosing and up to 6 hours afterward. Adverse events and local tolerability were monitored as well.

The F1 and F2 doses of AQST-109 were absorbed and rapidly converted to epinephrine with an observed median time to reach maximum drug concentration (Tmax) of 15 minutes. In previous studies, EpiPen dosing has had a median Tmax of 22 minutes.

“In the study, AQST-109 sublingual film demonstrated consistent Tmax values in a tighter range than reported for injectable epinephrine,” Oppenheimer said. “Its range was narrower compared to the range of injectable epinephrine both from our historical data and the published literature.”

Also, the 12 mg F1 dose resulted in a geometric mean Cmax of 552 pg/mL, and the 12 mg F2 dose resulted in a geometric mean Cmax of 762 pg/mL. EpiPen dosing has a geometric mean Cmax of 341 pg/mL, according to previous studies.

“This is the first time it has been demonstrated that epinephrine could achieve therapeutic plasma concentrations following sublingual administration,” Oppenheimer said.

AQST-109 produced results comparable to previous studies of Auvi-Q (kaelo, Inc.) as well, the researchers added.

Additionally, it resulted in meaningful changes in blood pressure and heart rate that were comparable to epinephrine auto-injectors.

Doses across all formulations and levels were generally well-tolerated with no serious adverse effects, significant medical events or treatment-related severe adverse events as well.

Noting that AQST-109 produced pharmacokinetic (PK) and pharmacodynamic (PD) responses within the expected therapeutic range, the researchers concluded that AQST-109 shows promise as a viable alternative for treating anaphylaxis.

Aquestive Therapeutics is now awaiting data from its three-part EPIPHAST pilot study, which will examine the PK and PD values of AQST-109 compared with epinephrine injections.

“EPIPHAST is designed to demonstrate important safety, tolerability and PK information regarding AQST-109 that will define the eventual dose and the final formulation for a future bioequivalence study with epinephrine [intramuscular] injection,” Oppenheimer said.

Aquestive Therapeutics aims to complete Part 2 of the EPIPHAST study in the first half of 2022.

“I am looking forward to seeing the data and continuing the discussion on this exciting program,” Oppenheimer said.

Reference:

  • Oppenheimer J, et al. Abstract L37. Presented at: AAAAI Annual Meeting; Feb. 25-28, 2022; Phoenix (hybrid meeting).