EPIPHAST

25 evidence topics · 7 sources

Objective

Comparison of sublingual film with intramuscular epinephrine and selection of the final configuration

“The EPIPHAST study is a randomized, open-label, three-part adaptive design, crossover study intended to compare the pharmacokinetics and pharmacodynamics of epinephrine following administration of AQST-109 and epinephrine administered as intramuscular injection in healthy adult subjects. This study will be used to determine the final product configuration that will be used to manufacture registration batches and conduct pivotal studies planned for the second half of 2022.” (opens the source at this quote in a new tab)

Purpose of Part 3

“The purpose of Part 3 was to continue to study the administration of the film under a variety of conditions to further characterize its pharmacokinetics, pharmacodynamics, and safety.” (opens the source at this quote in a new tab)

Location and study date

Conducted in Canada under Health Canada clearance from late 2021

“In addition, Health Canada has provided clearance for Aquestive’s crossover study, known as the EPIPHAST study, of AQST-109. Patient recruitment has begun and the Company expects the first dosing to occur before the end of the year.” (opens the source at this quote in a new tab)

Part-by-part reporting through 2022

“WARREN, N.J., Feb. 25, 2022 (GLOBE NEWSWIRE) -- Aquestive Therapeutics, Inc. (NASDAQ: AQST), a pharmaceutical company advancing medicines to solve patients’ problems with current standards of care and provide transformative products to improve their lives, today announced positive topline results from Part 1 of the EPIPHAST study for its AQST-109 epinephrine oral film.” (opens the source at this quote in a new tab)

Study design

Three-part adaptive crossover design

“EPIPHAST is a randomized, open-label, three-part adaptive design, crossover study in healthy adult subjects comparing the pharmacokinetics and pharmacodynamics of epinephrine delivered via Aquestive’s AQST-109 oral film compared to intramuscular injection of epinephrine. The study is being conducted pursuant to clearance from Health Canada.” (opens the source at this quote in a new tab)

Part 2 replicate crossover design

“Part 2 of the EPIPHAST study was a replicate design crossover study in twenty-four (24) healthy subjects comparing the pharmacokinetic and pharmacodynamic measures of AQST-109 12 mg and epinephrine intramuscular injection 0.3 mg.” (opens the source at this quote in a new tab)

Five administration-condition arms in Part 3

“The first three arms were designed to assess the impact of holding the film under the tongue and limiting swallowing for different periods of time. These time periods were (1) the target holding time of 4 minutes, (2) a 50% reduction in hold time to 2 minutes and (3) no hold time, or 0 minutes. The remaining two arms of the study for which data are not yet available include (4) dosing the film 2 minutes after eating a peanut butter sandwich and (5) swallowing the film immediately with 240 mL of water.” (opens the source at this quote in a new tab)

Eligibility criteria

Healthy adult volunteers

“EPIPHAST was a randomized, open-label, three-part adaptive design, crossover study in healthy adult subjects comparing the pharmacokinetics and pharmacodynamics of epinephrine delivered via Aquestive’s AQST-109 oral film compared to intramuscular injection of epinephrine.” (opens the source at this quote in a new tab)

Treatment

Multiple formulations and dose strengths evaluated in Part 1

“In Part 1 of the EPIPHAST study, multiple oral film formulations and dosage strengths of AQST-109 were evaluated.” (opens the source at this quote in a new tab)

Intramuscular comparators used in Part 1

“the healthy volunteers were also exposed to a 0.5mg intramuscular injection (IM) of epinephrine, allowing for a comparison with the pharmacokinetics, safety, and tolerability of the higher end of the approved dosage range of epinephrine, consistent with guidance received from the U.S. Food and Drug Administration (FDA) in a written response to the company’s pre-Investigational New Drug (pre-IND) submission.” (opens the source at this quote in a new tab)

AQST-109 12 mg versus epinephrine 0.3 mg intramuscular injection in Part 2

“Part 2 is a randomized, crossover design comparing AQST-109 12mg to epinephrine IM 0.3mg.” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using time to maximum epinephrine concentration as the primary endpoint

Time to a concentration associated with hemodynamic effect

“The median time to reach 100 pg/mL, which has been suggested to be the threshold for the onset of hemodynamic effects, was 8 minutes for AQST-109 and 10 minutes for the 0.3mg IM injection.” (opens the source at this quote in a new tab)

Partial area under the curve within clinically relevant windows

“The Area Under the Curve (AUC) within the clinically relevant periods of 10 minutes, 20 minutes, and 30 minutes, were comparable for both AQST-109 and the 0.3mg IM injection.” (opens the source at this quote in a new tab)

Pharmacodynamic parameters assessed

“In addition to positive pharmacokinetic results, AQST-109 demonstrated favorable pharmacodynamic effects on systolic blood pressure, diastolic blood pressure, and heart rate.” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

Participants and doses in Part 2 and Part 3

“Part 2 of the EPIPHAST study was a replicate design crossover study in twenty-four (24) healthy subjects comparing the pharmacokinetic and pharmacodynamic measures of AQST-109 12 mg and epinephrine intramuscular injection 0.3 mg.” (opens the source at this quote in a new tab)

Description of analysis sets

No evidence found.

Results

Participant disposition

No evidence found.

Baseline characteristics

No evidence found.

Efficacy results

Part 1 pharmacokinetics of two film configurations

“As shown in the figure below, the lead formulation of AQST-109 rapidly reached clinically meaningful blood concentrations when delivered in two different physical configurations, with a median Tmax of 13.5 minutes and 22.5 minutes, respectively. Part 1 also demonstrated arithmetic mean maximum concentrations (Cmax) of 771 pg/mL and 580 pg/mL for the two configurations, or geometric mean Cmax values of 258pg/mL and 268pg/mL for the two configurations, respectively.” (opens the source at this quote in a new tab)

Part 2 pharmacokinetics of AQST-109 12 mg versus intramuscular epinephrine

Study result	AQST-109 12 mg (N=48 doses)	Epinephrine IM injection 0.3 mg (N=48 doses)
Arithmetic mean Cmax (pg/mL)	“426.1”	“396.7”
Geometric mean Cmax (pg/mL)	“274.3”	“350.6”
AUC 0-10 minutes (hr*pg/mL)	“7.9”	“9.4”
AUC 0-20 minutes (hr*pg/mL)	“33.1”	“23.0”
AUC 0-30 minutes (hr*pg/mL)	“56.7”	“47.5”

Part 2 time to maximum concentration

“The median time to maximum concentration (Tmax) was observed to be 15 minutes for AQST-109, compared to 50 minutes for the epinephrine 0.3mg intra-muscular (IM) injection.” (opens the source at this quote in a new tab)

Part 3 effect of tongue hold time

“The median time to maximum concentration (Tmax) was observed to be 12 minutes for AQST-109 compared to 50 minutes for the epinephrine 0.3mg intra-muscular (IM) injection from Part 2 of the EPIPHAST study.” (opens the source at this quote in a new tab)

Part 3 effect of recent food intake

“The data showed that administering the film sublingually two minutes after consuming a peanut butter sandwich had no statistical impact on the resulting pharmacokinetics when compared to previous data from the initial Part 3 dataset. The medium time to maximum concentration (Tmax) and partial area under the curve (AUC) results were comparable and the time to reach Tmax remained 12 minutes when sublingually administered after consumption of a peanut butter sandwich. The geometric mean maximum concentration, or Cmax of 286 pg/mL was also comparable to previous data from Part 3.” (opens the source at this quote in a new tab)

Part 3 effect of swallowing the film whole with water

“The data also showed that swallowing the film whole immediately with water unexpectedly resulted in significant absorption of epinephrine. This finding has the potential of further de-risking the development program by lowering the risks associated with patient non-compliance to the administration instructions in a real-world setting. The Cmax was 313 pg/mL and the Tmax, while slower than the sublingual administration was significantly faster than the epinephrine 0.3mg IM injection from Parts 1 and 2 of the EPIPHAST study.” (opens the source at this quote in a new tab)

Integrated phase 1 pharmacokinetic comparison with injectable products

“AQST-109 yielded comparable epinephrine PK and exposure to both manual intramuscular injections and epinephrine autoinjectors. The median time to maximum concentration (Tmax) for AQST-109 was 15 minutes, compared with EpiPen (10 minutes), generic EpiPen (15 minutes), Auvi-Q (30 minutes), and manual intramuscular injection (50 minutes). There was also an early, rapid, and consistent increase in systolic blood pressure, diastolic blood pressure, and heart rate after the administration of AQST-109.” (opens the source at this quote in a new tab)

Health-related quality of life and patient-reported outcomes

No evidence found.

Safety results

Tolerability in Part 1 and Part 2

“Part 1 showed that key pharmacokinetic measures were aligned with previous favorable results for AQST-109 and that the product was well tolerated with no serious adverse events.” (opens the source at this quote in a new tab)

Tolerability reported for Part 2

“The results were aligned with previous positive results reported for AQST-109, and the product candidate was well tolerated with no serious adverse events.” (opens the source at this quote in a new tab)

Study limitations

Summary: study limitations

EPIPHAST was an open-label adaptive crossover study in healthy adult volunteers conducted in Canada, and its parts used small numbers of doses, for example 48 doses per treatment in Part 2 and 21 to 23 doses per arm in the Part 3 hold-time comparison. Comparisons between Part 3 arms and the intramuscular injection were made against data generated in Part 2 rather than within the same treatment period, and formulations and configurations changed between parts, so results are not uniform across the study. No registry record for the study was located, and the numeric results are reported in company announcements rather than a full study publication.