Effect of oral allergen challenge on absorption

“To compare AQST-109's PK and PD in adults with oral allergy syndrome undergoing oral allergen challenge (OAC) to elicit symptoms.” (opens the source at this quote in a new tab)

Comparison of single and repeat doses with and without allergen challenge

“A 2-part open-label study to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of epinephrine administered as single and repeat doses of DESF in healthy adults with oral allergy syndrome (OAS).” (opens the source at this quote in a new tab)

Single United States site and study dates

Field	Quoted record
Location	“Secaucus, New Jersey, United States, 07094”
Facility	“Frontage Clinical Services, Inc.”
Study start (actual)	“2024-07-17”
Primary completion (actual)	“2024-10-10”
Study completion (actual)	“2024-10-13”

Two-part fixed-sequence stratified crossover design

“This was a phase 2, 2-part, open-label, randomized, fixed-sequence, stratified, crossover study to evaluate the PK and PD of single (12 mg) and repeat doses (12 mg × 2) of AQST-109 in adults with screening-confirmed oral allergy syndrome administered with and without OAC, and of single (0.3 mg) and repeat doses (0.3 mg × 2) of manual intramuscular epinephrine injection given without OAC.” (opens the source at this quote in a new tab)

Oromucosal allergen challenge procedure

“Allergen Challenge: The oromucosal allergen challenge begins approximately 20 minutes before the expected administration of DESF. Subjects have a single food allergen known to trigger an allergic reaction in the subject placed on their tongue for up to 15 minutes after initial exposure to upper and lower lips and gums. Subjects keep the allergen in place for up to 15 minutes until symptoms are reported. The subjects are monitored from the start of the allergen challenge to determine severity of symptoms. The allergen is then removed from the mouth and within 5 minutes subjects rate their symptoms and DESF is administered.” (opens the source at this quote in a new tab)

Treatment periods in Part 1 and Part 2

“In Part 1, there are three treatment periods evaluating single and repeat doses of study drug, DESF after an allergen challenge (Treatment Period 1), intramuscular (IM) injection without allergen challenge (Treatment Period 2), and DESF without allergen challenge (Treatment Period 3). In Part 2, there are two treatment periods evaluating single and repeat doses of study drug, DESF after an allergen challenge (Treatment Period 1) and intramuscular (IM) injection without allergen challenge (Treatment Period 2).” (opens the source at this quote in a new tab)

Key inclusion criteria

“Healthy males and females 18 through 55 years of age.” (opens the source at this quote in a new tab)
“Known history of oral allergy syndrome in response to exposure to any of the allergens (e.g., apple, cherry, mango, melon, kiwi, celery, banana and/or carrot).” (opens the source at this quote in a new tab)
“Subject has not had exposure to antihistamines within 3 days prior to the Screening visit.” (opens the source at this quote in a new tab)

Key exclusion criteria relating to the oral mucosa

“Known history or presence of any disorder of the sublingual mucosa or any disease or condition which affects the normal production of saliva (e.g., xerostomia, Ehlers-Danlos syndrome, or Sjögren's syndrome) which, in the opinion of the investigator, would jeopardize the safety of the subject or impact the validity of the study results.” (opens the source at this quote in a new tab)

Single-dose cohort

“Single dose of DESF (12 mg) administered after allergen challenge (Treatment Period 1), followed by a single dose of intramuscular (IM) manual injection (0.3 mg) without allergen challenge after a 24-hour washout period (Treatment Period 2), followed by a single dose of DESF (12 mg) without allergen challenge after a 14-day washout period from Treatment Period 1.” (opens the source at this quote in a new tab)

Repeat-dose cohort

“Repeat dose of DESF (24 mg [12 mg x 2]) administered after allergen challenge (Treatment Period 1), followed by a repeat dose of IM manual injection (0.6 mg [0.3 mg x 2]) without allergen challenge after a 24-hour washout period (Treatment Period 2), followed by a repeat dose of DESF (24 mg [12 mg x 2]) without allergen challenge after a 14-day washout period from Treatment Period 1.” (opens the source at this quote in a new tab)

Sublingual administration and intramuscular comparator

“DESF administered in the sublingual space.” (opens the source at this quote in a new tab)
“Epinephrine manual injection administered intramuscularly according to the approved prescribing information.” (opens the source at this quote in a new tab)

Registered primary outcome measures

Outcome measure	Quoted description	Quoted time frame
Cmax	“Baseline Corrected Maximum Epinephrine Plasma Concentration occurring at Tmax (Time to reach maximum concentration)”	“0 to 240 minutes post-dose”
AUC0-10	“Baseline Corrected Plasma Epinephrine Concentration-Time Curve from Time Zero to 10 minutes”	“0 to 10 minutes”
AUC0-20	“Baseline Corrected Plasma Epinephrine Concentration-Time Curve from Time Zero to 20 minutes”	“0 to 20 minutes”
AUC0-30	“Baseline Corrected Plasma Epinephrine Concentration-Time Curve from Time Zero to 30 minutes”	“0 to 30 minutes”
AUC0-45	“Baseline Corrected Plasma Epinephrine Concentration-Time Curve from Time Zero to 45 minutes”	“0 to 45 minutes”

Rationale for testing absorption under allergen-induced oral change

“AQST-109 is an investigational epinephrine prodrug sublingual film for anaphylaxis treatment, with well-characterized pharmacokinetics (PK) and pharmacodynamics (PD) in healthy adults. It is unclear how oral symptoms during allergic reactions may affect its absorption and these parameters.” (opens the source at this quote in a new tab)

Regulatory request that prompted the allergen challenge design

“Regarding mouth conditions, the FDA recommended administering Anaphylm after oral exposure to a known allergen and assessing PK performance thereunder. The Company will execute this study in the second quarter of 2024. This study will replace the Company’s previously planned angioedema study.” (opens the source at this quote in a new tab)

Planned and actual enrollment

Field	Quoted record
Planned enrollment, Part 1	“Up to 36 subjects will be enrolled in Part 1.”
Planned continuation into Part 2	“Up to 12 subjects who have completed Part 1 (6 from each cohort) may continue to Part 2.”
Enrollment (actual)	“36”

Pharmacokinetic, pharmacodynamic, and safety subsets

“Geometric means for PK and PD parameters were analyzed for the PK, PD, and safety subsets.” (opens the source at this quote in a new tab)

Participants per arm in Part 1 and crossover in Part 2

“Part 1 of the study enrolled subjects with confirmed OAS into a three-period study with the following arms: (1) Anaphylm with allergen exposure (n=18 single dose; n=18 repeat dose); (2) Anaphylm without allergen exposure (n=15 single dose; n=13 repeat dose); and (3) Adrenalin intramuscular (IM) injection without allergen exposure (n=18 single dose; n=17 repeat dose). Part 2 was an optional follow-on study to Part 1. Six subjects who received single dose in Part 1 received repeat dose; and six subjects who received repeat dose in Part 1 received single dose.” (opens the source at this quote in a new tab)

Severity of allergen-induced oral symptoms at screening

“During screening with OAC, 94.4% of the 36 patients experienced moderate or severe oral symptoms.” (opens the source at this quote in a new tab)

Distribution of symptoms after allergen exposure

“Following allergen exposure, all subjects reported symptoms consistent with those experienced with their known allergies. Approximately twenty-five percent of subjects reported swelling of their tongues, lips, cheeks, and/or throat. Additional mucosal allergic symptoms included tingling, pain, and nasal congestion. Ninety-four percent of subjects were categorized as having moderate or severe symptoms according to the pre-defined oral severity score.” (opens the source at this quote in a new tab)

Pharmacokinetics and pharmacodynamics with and without allergen challenge

“Pharmacodynamics were not impacted by OAC after single- and repeat-dose administration of AQST-109 vs without OAC. AQST-109 PK values were similar with or without OAC. Single- and repeat-dosing PD parameters were higher with AQST-109 after OAC vs intramuscular epinephrine injection without OAC, and were nonsignificantly higher for AQST-109 with vs without OAC.” (opens the source at this quote in a new tab)

Endpoints met and time to maximum concentration

“Both primary and secondary endpoints of the OAS challenge study were successfully met with no significant differences found between Anaphylm PK results in subjects with and without allergen exposure. Anaphylm PK results in subjects with allergen exposure remained similar to previous profiles from the Company’s pivotal study in healthy subjects. The time to maximum plasma concentration, or Tmax, remained at twelve minutes in subjects with and without allergen exposure following a single dose of Anaphylm.” (opens the source at this quote in a new tab)

Time to resolution of allergen-induced oral symptoms

“The median time for complete symptom resolution for subjects in the study following administration of Anaphylm was twelve minutes. This is faster than the median time to complete symptom resolution at screening, which was seventy-four minutes. After Anaphylm administration, symptoms began resolving as early as two minutes in some subjects and fifty percent of all symptoms across all subjects were resolved by five minutes. Importantly, all instances of symptomatic swelling were completely resolved by five minutes after administration of Anaphylm.” (opens the source at this quote in a new tab)

Conclusion on absorption during oral allergic symptoms

“AQST-109 PK and PD are not diminished with oral symptoms and changes, supporting reliable absorption in allergic reactions in such contexts.” (opens the source at this quote in a new tab)

Participant-rated oral symptoms after allergen exposure

“During allergen exposure arms in Parts 1 and 2, subjects were exposed to a fruit they were known to be allergic to, and the resulting symptoms were documented for location, severity, and duration. There were no reports of difficulty administering Anaphylm to subjects in the study.” (opens the source at this quote in a new tab)

Treatment-emergent adverse events

“Almost all patients experienced a related mild treatment-emergent adverse event; 4 were considered moderate in severity, and no new safety signals were identified compared with previous studies.” (opens the source at this quote in a new tab)

Tolerability reported with topline data

“In addition, Anaphylm was safe and well-tolerated with all adverse events categorized as mild or moderate and resolving without medical intervention.” (opens the source at this quote in a new tab)

Summary: study limitations

The study enrolled 36 adults with oral allergy syndrome at a single site and used a fruit allergen challenge to produce oral symptoms, a model of localized oral change rather than of systemic anaphylaxis. The design was open label and fixed sequence, the intramuscular comparator was given without allergen challenge, and Part 2 involved only 12 participants who crossed between single and repeat dosing. Symptom resolution was recorded after epinephrine administration without a placebo or no-treatment control, so the contribution of spontaneous resolution cannot be separated from the treatment effect.