FDA Briefing Document

NDA/BLA# 214697

Drug name: ARS-1 (intranasal epinephrine)

Applicant: ARS Pharmaceuticals

Pulmonary-Allergy Drug Advisory Committee Meeting

May 11, 2023

Division of Pulmonology, Allergy, and Critical Care

Office of Immunology and Inflammation

Office of New Drugs

Center for Drug Evaluation and Research

DISCLAIMER STATEMENT

Red circle with number represents inclusion of correction from FDA’s Errata to Briefing Document

Table of Contents

Table of Tables

Table of Figures

Glossary

1   Executive Summary/Draft Points for Consideration by the Advisory Committee

1.1   Purpose/Objective of the AC Meeting

1.2   Context for Issues to Be Discussed at the AC

1.3   Brief Description of Issues for Discussion at the AC

1.3.1    Key Aspects of Development Program of ARS-1

1.3.2    Key Results

1.4   Summary and Draft Points for Consideration

2   Introduction and Background

2.1   Background of the Condition/Standard of Clinical Care

2.1.1    Analysis of the Condition

2.1.2    Barriers to Use of Epinephrine Injection Products

2.1.3    Pharmacology of Epinephrine from the Literature

2.2   Pertinent Drug Development and Regulatory History

2.2.1    Epinephrine Regulatory History

2.2.2    ARS Regulatory History

3   Summary of Issues for the AC

3.1   Efficacy Issues

3.1.1    Sources of Data for Efficacy

3.1.2    Clinical Pharmacology Summary

3.1.3    ARS-1 Pediatric Development

3.1.4    Summary of Efficacy Issues

3.2   Safety Issues

4   Benefit-Risk Framework

5   References

6   Appendix

6.1   Nonclinical Supportive Data

6.1.1    Nasal Mucosal Damage

6.1.2    PK and Cardiovascular Assessment Under Anaphylaxis Condition in Dog

6.2   Human Factors

6.2.1    Human Factors Overview

6.2.2    HFVS Conducted for NDA 214697

6.2.3    Human Factors Discussion and Conclusion

1   Executive Summary/Draft Points for Consideration by the Advisory Committee

1.1  Purpose/Objective of the AC Meeting

The FDA is convening this Advisory Committee (AC) meeting to discuss whether the available data for ARS-1, intranasal (IN) epinephrine, support a favorable benefit-risk assessment “for the emergency treatment of allergic reactions (Type I) including anaphylaxis in adults and children ≥30 kg.” The development program is based upon pharmacokinetic (PK)/pharmacodynamic (PD) data comparing ARS-1 to approved epinephrine injection products, as well as human factors (HF) studies. Since there are no clinical efficacy data for anaphylaxis treatment in the ARS-1 development program, there are several key issues for discussion:

1.  Whether PK/PD data for IN epinephrine, compared to epinephrine injection, are sufficient to establish the efficacy and safety of IN epinephrine; and

2.  whether the available PK/PD data for ARS-1 are sufficiently similar to epinephrine injection to establish efficacy of ARS-1 for the proposed indication; and

3.  whether the data from the ARS-1 development program supports a favorable benefit-risk assessment for the proposed indication.

1.2  Context for Issues to Be Discussed at the AC

Anaphylaxis is a severe, potentially fatal, systemic allergic reaction that occurs suddenly after contact with an allergy-causing substance (Sampson et al. 2006). Symptoms and signs develop rapidly, usually in minutes, and include hives, swelling, vomiting, difficulty breathing, and hypotension. Epinephrine injection is considered first-line standard of care by national and international guidelines and is the only life-saving treatment for anaphylaxis. Administration of epinephrine injection may be delayed or underused in the setting of anaphylaxis for a variety of reasons, including not recognizing anaphylaxis, lack of access (e.g. procurement challenges or not carrying), fear of using a needle containing device, and lack of knowledge as to how to administer the device (Prince et al. 2018). Development of alternative, non-injectable routes for epinephrine administration may improve compliance with treatment recommendations and address an unmet need.

ARS Pharmaceuticals submitted a new drug application (NDA) for IN epinephrine (ARS-1) for the emergency treatment of allergic reactions (Type I) including anaphylaxis in adults and children ≥30 kg. ARS-1 is a single-dose (2 mg), IN epinephrine spray that has a permeant to enhance absorption of epinephrine. The solution is packaged into a nasal spray device; the device used is the same nasal spray device used for IN naloxone for the treatment of opioid overdose, as well as other approved nasal sprays. The proposed dose is 2 mg administered as one spray (100 µL) into one nostril for children and adults weighing ≥30 kg; if symptoms progress after 10 min or any error occurs in administering ARS-1, the Applicant recommends administration of a second dose with a new device. In the remainder of this document, we refer to the 2 mg IN epinephrine product as ARS-1, unless otherwise specified.

The use of epinephrine injection for the treatment of anaphylaxis is based on historical and anecdotal use; adequate and well-controlled clinicals trials have not been conducted. Given feasibility constraints of conducting clinical efficacy trials for the anaphylaxis indication, the ARS-1 development program consists of PK/PD and HF studies. Support for the efficacy of ARS-1 is based on PK/PD similarity of ARS-1

to approved epinephrine injection products. Establishing efficacy based on PK/PD similarity to approved epinephrine injection products is challenging due to the paucity and variability of PK/PD data for epinephrine injection and uncertainties in translating PK/PD results of a topically administered drug from healthy subjects to patients with anaphylaxis where nasal mucosal changes may impact absorption.

ARS Comment 1:

In Section 1.3.1, FDA comments that “ultimately, the Applicant and FDA designed a clinical pharmacology program that may provide scientific bridging/justification to establish efficacy and safety for ARS-1 for emergency treatment of allergic reactions (type I) including anaphylaxis.”

This jointly developed program is described in Table 2: ARS-1 Clinical Pharmacology Development Program below in that same Section 1.3.1. Here FDA states that “Given the variability in PK profiles across epinephrine injection products, the Applicant and FDA agreed to a bracketed approach in which the PK profile for ARS-1 would be bracketed between two different approved epinephrine injection products with different delivery systems (i.e., needle-syringe and autoinjector).”

FDA commented below on the need for a “a high level of confidence in both PK and PD results.”

Based on the severity of the indication and the availability of approved safe and effective products, we need to have confidence that efficacy and safety of epinephrine administered by this novel route of administration have been established; residual uncertainties should be minimized. A high level of confidence in both PK and PD results and confidence in bridging the PK/PD findings to clinical efficacy in the setting of anaphylaxis are expected to support a favorable benefit-risk assessment. Throughout this briefing document, areas of uncertainty in the data will be highlighted for consideration by the AC.

1.3  Brief Description of Issues for Discussion at the AC

1.3.1   Key Aspects of Development Program of ARS-1

Table 1. Intranasal Epinephrine PK/PD Development Program

Table 2. ARS-1 Clinical Pharmacology Development Plan

PK/PD/Safety Trial

Second dose (EPI 15)

Nasal allergen challenge (EPI 16)

PK/PD/Safety Trial

Source: Clinical and clinical pharmacology reviewers

Abbreviations: PD, pharmacodynamics; PK, pharmacokinetics

The available data (or lack thereof) for epinephrine injection products introduces complexities to interpretation and design of clinical pharmacology studies to establish efficacy and safety for noninjectable routes of administration for epinephrine. Some of the issues are outlined below:

•   Limited Data on Approved Epinephrine Injection Products

Epinephrine injection was in use prior to passage of the Federal Food, Drug, and Cosmetic Act of 1938, which required demonstration of safety, and was not included in the Drug Efficacy Study Implementation determinations to evaluate effectiveness of products approved from 1938 to 1962. Data from PK and randomized controlled trials were not required for approval of epinephrine injection products. In addition, more recent epinephrine injection product approvals have been based on chemistry and manufacturing data; PK/PD data were not required.

As a result, there is a paucity of PK data for epinephrine injection products, PK endpoints critical to establish efficacy have not been determined (see Section 2.2.1 for further details), and the approved doses of epinephrine have not been validated by dedicated clinical efficacy trials. Whether there is a safe and effective dose above or below the accepted 0.01 mg/kg is unknown.

ARS Comment 2:

There are numerous approved epinephrine products, which were approved without PK data, as listed in Table 3. As FDA comments later in Section 1.3.1, it is therefore important in cases where there is uncertainty about PK to consider “PD data as supportive” information in evaluating the efficacy of ARS-1.

•   PK Variability and Comparators Selection

The PK data generated from the ARS-1 development program demonstrates that there is substantial variability in PK profiles with epinephrine injection products, despite being administered via the same route. This variability raises questions about which approved epinephrine injection product(s) should be used as the comparator(s) and which PK endpoints (e.g., maximum plasma concentration (C_max), time to maximum plasma concentration (T_max), area under the concentration-time curve [AUC]) are most critical to ensure efficacy. Given the variability in PK profiles across epinephrine injection products, the Applicant and FDA agreed to a bracketed approach in which the PK profile for ARS-1 would be bracketed between two different approved epinephrine injection products with

different delivery systems (i.e., needle-syringe and autoinjector).

•   Dose Selection

ARS conducted an initial dose ranging program, using a crossover design, which was complicated (as described in Section 2.2.2) by the discovery of a carryover effect with IN epinephrine; the carryover effect refers to increased absorption of IN epinephrine following an initial dose, possibly related to mucosal changes from the initial dose. Because of the carryover effect, the Applicant repeated ARS-1 dose exploration. In the pivotal dose ranging study (EPI 11b), doses up to 2 mg were studied. ARS selected the 2 mg dose and FDA agreed to this dose, but we note that higher doses were not studied.

•   PK/PD Discrepancy

During development, a discrepancy between PK and PD (i.e., systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate [PR]) was noted that raised questions as to how to weigh PD versus PK in assessment of efficacy. The PD data generated from the ARS-1 development program demonstrated that there was not a consistent correlation between PK and PD at the individual level and that the PK/PD relationship is generally weak at the population level. In addition, different trends of PK and PD comparison results were observed between ARS-1 and EpiPen without a clear mechanism to explain this discrepancy. Taking this into account, along with high inter-subject variabilities of PD and concerns with translatability of the PD response from healthy subjects to patients with anaphylaxis, using PD to support bridging of ARS-1 to the approved injection products became uncertain and adds another complexity to the development program. Because of this, we focused on the PK data and viewed the PD data as supportive.

ARS Comment 3:

FDA comments on a perceived discrepancy between PK and PD in this Briefing Document.

FDA clarifies in its Addendum to the Briefing Document that they “acknowledge that in the literature and in general, epinephrine PK and PD are generally aligned (i.e. when epinephrine PK is higher, the PD response (systolic blood pressure (SBP) and pulse rate (PR) is higher as well), especially following the intravenous infusion route. We also acknowledge that for ARS-1 this same general alignment was demonstrated, especially under normal nasal condition.”

FDA elaborates in the Addendum to the Briefing Document that “When we refer to PK/PD discrepancy in the FDA Briefing Document, we refer to the differences in the PK/PD relationship between epinephrine products. The degree of PK and PD correlation varies. For example, the PK/PD relationship observed for ARS-1 is different from that of epinephrine injection products. ARS-1 generally has a lower epinephrine PK profile than EpiPen, but with a generally higher/more sustained PD (SBP/PR) response under normal nasal conditions.”

FDA comments in Section 2.1.1 that “epinephrine causes vasoconstriction, relaxation of airway smooth muscle, and increased rate of force of cardiac contractions, leading to decreased mucosal edema, bronchodilation, and increased cardiac output.” Therefore, in situations when it is not known whether PK thresholds have been met at certain time points, PD ought to be highly relevant and supportive in the assessment of efficacy, which FDA notes is “generally higher/more sustained PD (SBP/PR) response under normal nasal conditions.” In Section 3.1.2.25 PK/PD Summary in Healthy Volunteers, FDA states that “in general the PD comparison results support the PK bracketing.” approach for the ARS-1 drug development program.”

The positive PK/PD relationships noted by FDA can be graphically demonstrated when FDA’s Figure 1 and Figure 7 in this briefing document are viewed side by side, where even without the support of statistical analysis, SBP and HR for ARS-1 in the first 30 min postdose increase linearly with concentration, and are more robust than the injection products.

For clarity, below is the first 30 minutes post dose of epinephrine concentration from Figure 1 in Section 1.3.2.1 and SBP change from baseline values in Figure 7 in Section 3.1.2.2.2. Please note that ARS-1 is the red line, Adrenalin is the blue line and EpiPen is the green line.

ARS Comment 3 (continued):

Source: Clinical Pharmacology Reviewer. Based on adxd.xpt of Study EPI 15.

One subject each from the Adrenalin and EpiPen arms was excluded due to an insufficient number of postdose samples (N<3) within 30 min.

Subjects who were included in the PK analysis were included in the PD analysis.

Error bars represent 25% and 75% percentile of the PD values.

In Section 2.1.3 FDA observes that “Epinephrine exerts a concentration-dependent effect on PD (vital signs) responses following continuous IV infusion” and “there was an approximate linear relationship between real-time epinephrine concentrations and change from baseline values for SBP (increase), DBP (decrease), and HR (increase).”

FDA itself concluded on Page 5 of a 2012 clinical pharmacology review for epinephrine injection that “systemic vascular resistance and diastolic blood pressure [DBP] are shown to decrease due to action of epinephrine on ß2-receptors causing peripheral vasodilation.”

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205029Orig1s000ClinPharmR.pdf

Therefore, DBP is observed to decline with injection. FDA comments in Section 3.1.2.2.2 that “a more stable DBP time profile was observed following ARS-1 when compared to apparent declination profiles from both injection products.” As a result, there is a weak correlation for DBP and epinephrine concentrations with respect to ARS-1.

The mechanism for this different PK/PD relationship with respect to DBP for ARS-1 vs. injection products is described in a April 2023 peer-reviewed publication and in the ARS-1 NDA (www.annallergy.org/article/S1081-1206(22)01904-4/fulltext), where intranasal administration of “bypasses the ß2-mediated vasodilatation in the skeletal muscle” that results in a DBP drop, as observed with injection into the skeletal muscle of the thigh with EpiPen and Adrenalin. This DBP drop suppresses SBP, and is not observed with ARS-1, which is why ARS-1 has a higher and more robust SBP response than injection products.

•  Impact of IN Epinephrine on Absorption

Topical administration of epinephrine causes constriction of local blood vessels, which has the potential to change the absorption of epinephrine in the nasal mucosa and impact systemic plasma concentrations. This may be particularly important to consider when a second dose of epinephrine is needed. Therefore, FDA requested the Applicant evaluate the epinephrine PK/PD profiles following a second dose in a repeat-dose study.

•  Impact of Anaphylaxis on IN Absorption

Rhinitis and nasal congestion can be features of anaphylaxis; alterations of the nasal mucosa (e.g., vasodilation) may affect the local absorption of epinephrine. FDA and the Applicant agreed that nasal allergen challenge of subjects with allergic rhinitis with known allergen sensitization may reasonably mimic the findings that could occur in anaphylaxis. Therefore, FDA requested the Applicant to evaluate epinephrine PK/PD profiles of IN epinephrine under nasal allergen challenge conditions.

•  Pediatric Considerations

IN administration in younger children introduces anatomical/ontogeny challenges as the size, depth, and surface area of the nasal cavity in this pediatric population are noticeably different from the adults (Likus et al. 2014) and may affect the absorption of IN epinephrine, regardless of body weight-adjustment. Therefore, FDA requested that the Applicant conduct pediatric PK/PD studies to determine appropriate doses for children of different ages and body weights.

1.3.2  Key Results

The design and conduct of the clinical pharmacology studies are described in the body of this briefing document. Key results from the development program are described below. Detailed results are provided in Section 3.1.2.

1.3.2.1  Epinephrine PK/PD Results in Healthy Volunteers

•  The PK profile following a single dose of ARS-1 is reasonably bracketed by Adrenalin 0.3 mg and EpiPen 0.3 mg intramuscular (IM) injection starting 10 min postdose; however, plasma epinephrine concentration in the first 10 min postdose are lower than both epinephrine injection comparators (Figure 1), likely due to an initial slower absorption rate.

Figure 1. Epinephrine Geometric Mean (±Standard Error) Concentration-Time Profile Following a Single Dose of ARS-1 (2 mg) vs. a Single Dose of Intramuscular Injection Using Adrenalin 0.3 mg or EpiPen 0.3 mg in Healthy Subjects

Source: Clinical Pharmacology Reviewer. Based on adpc.xpt of Study EPI 15.

One subject each from the Adrenalin and EpiPen arms was excluded due to an insufficient number of postdose samples (N<3) within 30 min.

ARS Comment 4:

In Figure 1, which is based on EPI-15 in healthy adult subjects, FDA shows one of the many relevant studies ARS has conducted. FDA comments above that “the PK profile following a single dose of ARS-1 is reasonably bracketed by Adrenalin 0.3 mg and EpiPen 0.3 mg intramuscular (IM) injection…” FDA further comments that “plasma epinephrine concentration in the first 10 min postdose are lower than both epinephrine injection comparators (Figure 1), likely due to an initial slower absorption rate.”

However, FDA clarifies in its Addendum to the Briefing Document that in the other two primary studies ARS conducted in type I allergy adults subjects that “for completeness, ARS-1 under normal conditions was also compared to Adrenalin in EPI 16 and EPI 17. In EPI 16, the trend for the concentration of epinephrine in the first 10 minutes following ARS-1 in subjects without nasal allergen challenge is not distinctly different compared to Adrenalin 0.3 mg as shown in Figure B and (Figure 11 in the FDA Briefing document).”

Figure B. Epinephrine Geometric Mean (±Standard Error) Plasma Concentration-Time Profiles in Subjects With Allergic Rhinitis (EPI 16)

Source: Clinical Pharmacology Reviewer. Based on adpc.xpt of Study EPI 16.

Three subjects each in the Adrenalin 0.3 mg and Adrenalin 0.5 mg arms and one subject in ARS-1 with nasal challenge arm had insufficient number of quantifiable postdose samples (n<3) within 30 min. Two subjects each in the Adrenalin 0.3 mg, Adrenalin 0.5 mg arm, and the ARS-1 with nasal challenge arm did not have pharmacokinetic data.

ARS Comment 4 (continued):

In FDA’s Addendum to the Briefing Document, FDA also “acknowledges that results from Study EPI17, the self-administration study” in type I allergy patients, “show a different trend – the exposure of ARS-1 is higher than Adrenalin in the first 10 minutes, as shown in Figure 15 to the FDA Briefing Document (and shown below in Figure C). We included the ARS-1 treatment arm from Study EPI 15 for comparison.”

Figure C. Epinephrine Geometric Mean (±Standard Error) Plasma Concentration-Time Profiles Following a Single Dose of ARS-1 (Self-Administered), Adrenalin 0.3 mg (Staff-Administered) and Single Dose of ARS-1 (Staff-Administered from EPI 15)

    Source: Clinical Pharmacology Reviewer. Based on adpc.xpt of Study EPI 17 and EPI 15.

FDA also states in the Addendum to the Briefing Document that “The difference in trends is likely due to the variability that is seen with Adrenalin across trials. Figure D below shows a cross-study comparison of Adrenalin from various studies versus ARS-1 from EPI 15 and EPI 17.”

Figure D. Cross-study Comparison of ARS-1 2 mg and Adrenalin Geometric Mean Concentration-Time Profiles

ARS Comment 4 (continued):

In FDA’s Addendum to the Briefing Document, FDA states that “As shown in Figure D, the ARS-1 curves from EPI 15 and EPI 17 are similar, but the PK curve of Adrenalin in EPI 15 is higher than the PK curve of Adrenalin in EPI 17. FDA acknowledges that the differences seen in the first 10 minutes between EPI 15 and EPI 17 is mostly due to Adrenalin PK variability.”

Indeed, FDA’s Figure D above shows that the ARS-1 PK curve from EPI 15 and EPI 17 is generally higher during the first 10 minutes for the Adrenalin PK curves from four of five studies that ARS has conducted using the same analytical methods and study protocols.

Statistical analysis of the absolute geometric mean concentrations in the first 10 minutes within each individual study demonstrates that ARS-1’s PK is:

i)   Significantly higher than Adrenalin from timepoints 2, 4 and 6 minutes in EPI-17 type I allergy patients, no different than Adrenalin at timepoints 8 to 12.5 minutes (and significantly higher than Adrenalin after 15 minutes)

ii)  No different from Adrenalin at all time points in first 10 minutes in EPI-16 type I allergic rhinitis patients (and significantly higher than Adrenalin after 15 minutes)

iii)   No different from Adrenalin except for time points 4 and 6 minutes in EPI-15 healthy subjects (and significantly higher than Adrenalin after 12.5 minutes)

In addition, with respect to bracketing, the geometric mean partial AUC(0-10) values are greater or not statistically different from Adrenalin even respect to the EPI-15 study. In fact, all three studies (EPI-15, EPI-16 and EPI-17) are bracketed based on statistical analysis, wherein minimum early exposures are greater than or not statistically different from Adrenalin, and maximum early exposures are less than EpiPen, and overall exposure AUC(0-t) are less than 0.5 mg IM.

●  The PK profile of epinephrine following repeat doses (two doses administered 10 min apart) of ARS-1 is similar to the PK profile following repeat doses of EpiPen, starting 20 min postdose (Figure 8); however, in the first 20 min postdose, plasma epinephrine concentrations are lower for ARS-1, compared to EpiPen. This further implicates a slower initial absorption rate compared to that of EpiPen.

ARS Comment 5:

FDA’s comment highlighted above supports that ARS-1 is bracketed by EpiPen as the upper bracket agreed with FDA during the development program. As FDA explains in its Addendum to the Briefing Document during a pre-NDA meeting, “ARS showed PK results from doses of ARS-1 ranging from 1 to 2 mg. Based upon these results, the FDA did caution ARS about safety concerns with higher doses given that the AUC0-t with the 2 mg dose of ARS-1 was higher than EpiPen.” We note that ARS-1 exposures are not expected to be higher than EpiPen during the first 20 min post dose.

Figure 15 referenced in ARS Comment 5 shows that ARS-1 2 mg PK levels are higher than Adrenalin 0.3 mg at all time points” including the first 10 minutes. Figure 8 shown below from Section 3.1.2.3 Repeat-Dose PK Results of the FDA briefing book also shows that a repeat dose of ARS-1 2 mg gives an even higher exposure than those observed in Figure 15, as expected.

Figure 8. Epinephrine Geometric Mean (±Standard Error) Concentration-Time Profile Following Two Doses of ARS-1 Given in Same Naris (R/R) or Opposite Naris (L/R) vs. Two Doses of Intramuscular Injection Using EpiPen 0.3 mg in Healthy Subjects

Source: Clinical Pharmacology Reviewer. Based on adpc.xpt of Study EPI 15. One subject each in the ARS-1 (R/R) and ARS-1 (L/R) from EPI15 Part 2 were excluded due to insufficient number of postdose samples (n<3) within 30 min. Three subjects each in the ARS-1 (R/R) and ARS-1 (L/R) arms discontinued early and did not have PK data.

Abbreviations: L, left; PK, pharmacokinetics; R, right; RD, repeat doses

Higher PD responses (median SBP and PR change from baseline) are observed with both single-dose and repeat-dose ARS-1, in comparison to both Adrenalin and EpiPen, despite the ARS-1 PK profile being lower than that of EpiPen (see Sections 3.1.2.2.2 and 3.1.2.2.4 for more details).

ARS Comment 6:

ARS Pharma agrees with this statement. To the extent that FDA notes in one study that “plasma epinephrine concentration in the first 10 min postdose are lower than both epinephrine injection comparators,” the PD response is higher than Adrenalin 0.3 mg at all time points, including the first 10 minutes. See ARS Comment 3 for the mechanistic explanation.

Related to Figure 7 from Section 3.1.2.2.2 Single-Dose PD Results in this briefing document, FDA states that the “magnitudes of SBP and PR responses are generally higher for ARS-1 compared to both injection products” and a “more stable DBP time profile was observed following ARS-1.” The PD response of (SBP, PR and DBP) ARS-1 2 mg (red line) are above Adrenalin 0.3 mg (blue line), including in the first 10 minutes.

Figure 7. Median PD Responses (SBP, PR, and DBP Change from Baseline) Following a Single Dose of ARS-1, Adrenalin 0.3 mg, or EpiPen 0.3 mg in Healthy Subjects

Source: Clinical Pharmacology Reviewer. Based on adxd.xpt of Study EPI 15. Subjects who were included in the PK analysis were included in the PD analysis.

Error bars represent 25% and 75% percentile of the PD values.

Abbreviations: DBP, diastolic blood pressure; PD, pharmacodynamics; PK, pharmacokinetics; PR, pulse rate; SBP, systolic blood pressure

•   Pediatric subjects who weighed greater than 30 kg and were treated with ARS-1 had similar epinephrine PK profiles compared to that of adults treated with the same dose for the first 15

minutes; after 15 minutes the PK curve in pediatric subjects was higher. Conversely, the pediatric PD responses (SBP and PR change from baseline) were slightly lower compared to adults (see Section 3.1.3 for more details).

1.3.2.2 Epinephrine PK/PD Results in Adults with Allergen-Induced Nasal Congestion

•  Under nasal allergen challenge conditions, the ARS-1 epinephrine plasma concentration-time profile was characterized with an initial faster absorption, followed by a faster decline, resulting in a lack of PK sustainability starting about 10 min postdose compared to ARS-1 PK under normal nasal conditions (Figure 2) and 20 min postdose compared to epinephrine injection.

ARS Comment 7:

FDA comments that there is “a lack of PK sustainability starting about 10 min postdose compared to ARS-1 PK under normal nasal conditions and 20 min postdose compared to epinephrine injection.” FDA comments later in Section 2.2.1.2. Approved Epinephrine Dosing, that with respect to epinephrine injection, “dosing can be repeated with severe persistent anaphylaxis, with national and international guidelines recommending dosing every 5 to 15 mins” if clinical response is not observed.

Therefore, ARS-1 during nasal challenge is sustaining PK greater than that of epinephrine injection during the first 20 min post dose (covering the time period when clinical response is observed), as observed in Figure 2 below.

Figure 2. Epinephrine Geometric Mean (±Standard Error) Plasma Concentration-Time Profiles in Subjects With Allergic Rhinitis

Source: Clinical Pharmacology Reviewer. Based on adpc.xpt of Study EPI16.

Three subjects in the adrenalin 0.3 mg arm and one subject in the ARS-1 with nasal challenge arm had an insufficient number of postdose samples (n<3) within 30 min. Two subjects in the adrenalin 0.3 mg arm, five subjects in the adrenalin 0.5 mg arm, and two subjects in the ARS-1 with nasal challenge arm did not have PK data.

Abbreviation: PK, pharmacokinetics

•  Under nasal allergen challenge conditions, the trend of PD responses was similar to PK responses. Faster PD responses (SBP and PR change from baseline) were followed by a rapid reduction starting 5 to 15 min postdose compared to responses under normal nasal conditions (see Section 3.1.2.3.2 for more details). The lack of epinephrine PK/PD sustainability under nasal allergen challenge conditions raises concerns for durability of effect, and the need for a repeat dose, in patients with anaphylaxis who experience nasal edema. Since repeat dose studies have not been performed under nasal allergen challenge conditions, and proposed labeling includes repeating a dose if symptoms persist, there is residual uncertainty in the PK/PD response following a repeat dose. Additional data may be needed to assess this decrease in exposure; options include a repeat dose nasal allergen challenge PK/PD study and/or exploration of a higher dose.

ARS Comment 8:

FDA comments above based on Figure 12 from Section 3.1.2.3.2 PD Data in Allergen-Induced Nasal Congestion, which is copy and pasted below. However, Figure 12 also shows that the median SBP change from baseline and median PR change from baseline for ARS-1 2 mg with challenge (red line with error bars) overlaps with Adrenalin 0.3 mg (light dotted blue line with error bars) for the entire 60-minute period postdose with respect to SBP, and for at least the first 30 minutes postdose with respect to PR.

Therefore, durability of PK/PD is not of concern as PD is higher than Adrenalin 0.3 mg, and a repeat dose nasal allergen challenge PK/PD study or higher dose should not be necessary for approval.

Figure 12. Median PD Responses (SBP and PR Changes From Baseline) in Subjects With Allergic Rhinitis

Source: Clinical Pharmacology Reviewer. Based on adxd.xpt

of Study EPI 16. Subjects who were included in the PK

analysis were included in the PD analysis. Error bars

represent 25% and 75% percentile of the PD values.

Abbreviations: PD, pharmacodynamics; PK, pharmacokinetics; PR, pulse rate; SBP, systolic blood pressure

1.4  Summary and Draft Points for Consideration

There is no regulatory precedent for approval of a noninjectable epinephrine product for treatment of anaphylaxis. Given that ARS-1 is proposed for emergency treatment and that clinical efficacy data are not available, we expect the available comparative PK/PD data to be robust to support approval, and that residual uncertainties regarding efficacy and safety are minimized. We also expect that potential risks of treatment are adequately studied to factor into assessment of benefit-risk. We ask the panel to consider the available clinical pharmacology (PK/PD) and safety data from the ARS-1 program and whether the data are sufficiently robust to support a favorable benefit-risk assessment of ARS-1 for the emergency treatment of anaphylaxis. If the available data are not sufficient, we ask the committee to discuss additional data that would be necessary to support a favorable benefit-risk assessment, including additional dose-ranging studies, repeat dose studies in the nasal allergen challenge model, or clinical efficacy data. Below are the topics and questions for consideration.

Thank you for your participation in this AC meeting.

•   Discuss the PK/PD approach for establishing efficacy for ARS-1, specifically: The PK-bracketing approach using approved epinephrine injection products.

The relevant PK/PD parameters to support clinical efficacy for the intended indication, including the significance of the following findings:

◾   The lower concentration of epinephrine in the first 10 min following single-dose ARS-1 IN administration compared to epinephrine injection products.

◾   The diminished PK/PD sustainability in subjects with allergen-induced nasal congestion.

ARS Comment 9:

See Figure 15 and Figure 7, and ARS Comments 4, 5, 6, 7 and 8.

The uncertainty of translation of PK/PD results from healthy subjects to patients with anaphylaxis, or whether clinical data are needed.

•   Do the PK/PD results support a favorable benefit-risk assessment for ARS-1 in adults ≥30 kg for the emergency treatment of allergic reactions and anaphylaxis? If not, what additional data are needed?

•   Do the data support a favorable benefit-risk assessment for ARS-1 in children (<18 years of age) ≥30 kg for the emergency treatment of allergic reactions and anaphylaxis? If not, what additional data are needed?

2   Introduction and Background

2.1   Background of the Condition/Standard of Clinical Care

2.1.1   Analysis of the Condition

Anaphylaxis is a severe, potentially fatal, systemic allergic reaction that occurs suddenly, usually after contact with an allergy-causing substance in a sensitized individual (Sampson et al. 2006). Anaphylaxis is a complex condition and presenting symptoms can be varied and progression can be unpredictable. Typical symptoms include, but are not limited to, hives, swelling, vomiting, difficulty breathing, and hypotension. Common triggers of anaphylaxis include food, drugs, and Hymenoptera venom, but idiopathic cases have also been described in which no trigger is identified.

The lifetime prevalence of anaphylaxis is estimated to range from 1.6% to 5.1% (Shaker et al. 2020). An estimated 1% of hospitalizations and 0.1% of emergency department admissions for anaphylaxis result in a fatal outcome (Turner et al. 2017). Fatal anaphylaxis, although rare, usually occurs within 60 min of exposure to an allergenic substance, and most frequently within 5 to 35 min of exposure (Pumphrey 2000). Although fatal anaphylaxis is rare, the number of people who are at risk for anaphylaxis, such as those who have food allergy, venom allergy, and drug allergy, among others, is common. Systemic reactions to Hymenoptera venom affect around 3% of the U.S. population, while food allergy impacts approximately 10% of the U.S. population, and adverse drug reactions (not limited to hypersensitivity reactions) affect up to 10% of the population. In a review of International Classification of Diseases, 10^th Edition codes from a U.S. National Morality Database (1999 to 2010), 2458 fatal anaphylaxis cases were coded leading to an estimated prevalence of fatal anaphylaxis of 0.69 per million (approximately 232 deaths/year based on the U.S. population) (Jerschow et al. 2014).

Epinephrine is the first-line and only life-saving treatment for anaphylaxis. The use of epinephrine for the treatment of anaphylaxis is based on historical and anecdotal use (Section 2.2.1) and is considered

the standard of care by national and international guidelines. Epinephrine is a direct-acting, nonselective, sympathomimetic, alpha and beta-adrenergic agonist that, at high plasma and tissue concentrations, can correct the pathophysiologic conditions of anaphylaxis within minutes (Brown et al. 2020). Epinephrine causes vasoconstriction, relaxation of airway smooth muscle , and increased rate and force of cardiac contractions, leading to decreased mucosal edema, bronchodilation, and increased cardiac output (Simons and Simons 2010). In addition, epinephrine has been shown to prevent additional release of histamine, tryptase, and other mediators, preventing escalation of anaphylaxis (Sampson et al. 2006). Epinephrine can be administered intramuscularly, subcutaneously, or intravenously. Intravenous (IV) infusion or bolus administration of epinephrine is generally limited to situations where patients do not respond to IM injections of epinephrine and is only administered in a monitored hospital setting where dosing can be titrated with continuous hemodynamic monitoring (Kanwar et al. 2010). For purposes of discussion, in the remainder of this document we will focus solely on the IM/subcutaneous route of administration, given this is the route approved for community use (administered by individuals without medical training in community settings without the need for additional supplies or assembly before use).

2.1.2   Barriers to Use of Epinephrine Injection Products

Although epinephrine is the first-line treatment for anaphylaxis, underuse and delayed use of epinephrine are common. Review of epinephrine for treatment of anaphylaxis across multiple countries demonstrated varying use from 14% to 56% of anaphylaxis patients receiving epinephrine (Lieberman and Wang 2020). The reasons for this underuse include:

1.  Not recognizing anaphylaxis: Patients, caregivers, and healthcare providers may not recognize signs and symptoms of anaphylaxis. Education on anaphylaxis, however, does not fully explain the lack of epinephrine use. In one Emergency Department study in Minnesota, despite education on signs of anaphylaxis and epinephrine use to Emergency Department staff members, actual real-world epinephrine use in the Emergency Department only increased from 33% to 51% for those who required epinephrine despite having the education and access to epinephrine (Manivannan et al. 2014).

2.  Lack of access to epinephrine: In the United States, high cost, supply chain, and injection device issues lead to issues with procurement (Westermann-Clark et al. 2018; FDA 2022a).

3.  Failure to carry epinephrine: Studies have shown that many patients do not fill epinephrine prescriptions or fail to carry epinephrine with them at all times (Warren et al. 2018). Studies attempting to increase epinephrine carriage with text reminders and financial incentives found these attempts did not lead to a robust increase in the overall carriage rate (Spina et al. 2012; Cannuscio et al. 2015).

4.  Having epinephrine, but failing to use it: Although this issue is less common than not having an epinephrine injection product during a reaction, some patients, despite carrying the epinephrine injection product, fail to use it during a reaction. Studies found that the patient or caregiver did not administer epinephrine as they 1) did not believe the reaction was serious, 2) did not understand how to use the device, and/or 3) had a fear of using the device (Fleischer et al. 2012; Warren et al. 2018).

A needleless route of epinephrine administration may ameliorate some of the factors contributing to underuse and delayed administration, but as outlined above, the reasons for underuse and delayed administration of epinephrine are complex and multifactorial.

2.1.3   Pharmacology of Epinephrine from the Literature

The majority of available epinephrine PK/PD data is derived from healthy volunteers; epinephrine PK/PD data in patients with anaphylaxis is limited. Highlights from the epinephrine PK/PD literature are summarized below to assist with AC’s review.

Mechanism of Action

Epinephrine is an endogenous, sympathetic catecholamine neurotransmitter that nonselectively activates adrenergic receptors. The two major classes of adrenergic receptors are alpha- and beta-adrenergic receptors and they are differentially expressed in various tissues. Alpha-1 receptors are located in vascular (especially pre-capillary arterioles) smooth muscle and are responsible for vasoconstriction when activated. Alpha-2 receptors are involved in autoregulation of norepinephrine release and are located in multiple nerve endings and in the central nervous system. Beta-1 receptors are mainly located in the heart and activation increases cardiac inotropy (i.e., force of contractility). Beta-2 receptors are located in cardiac muscle, airway smooth muscle, and skeletal muscle arteries;

Pharmacokinetics of Epinephrine Injection

Endogenous plasma epinephrine concentrations fluctuate in healthy subjects, but average levels are approximately 35 pg/mL (Lake et al. 1984), with a plasma half-life in the systemic circulation of about 2 to 3 min. The major metabolizing enzymes for epinephrine are monoamine oxidases and catechol-O-methyltransferase (Ebert 2013).

Following intramuscular administration of exogenous epinephrine, plasma epinephrine concentrations demonstrate high inter-subject and intra-subject variability. Using Auvi-Q and EpiPen autoinjectors, the coefficient of variation for the mean C_max and AUC ranged from 51% to 80%; the T_max ranged from 5 to 60 min. These results reflect the highly variable nature of epinephrine PK. ¹ A second peak of epinephrine plasma concentration was observed in some cases, at approximately 30 min following IM injection; the magnitude of this second peak was at times comparable to that of the first peak, which also contributes to the variability of the Tmax. Although the mechanism underlying this second peak is unclear, it is speculated to be a secondary effect of vasodilation in the skeletal muscle due to stimulation of beta-2 receptors, with resultant increased absorption (Westfall 2011). This unique combination of physiological and pharmacological properties represents a potential advantage of epinephrine administration via IM injection for ensuring that injected epinephrine is rapidly and thoroughly absorbed into the systemic circulation.

ARS Comment 10:

FDA correctly observes that when one averages PK values at each time point across a population of subjects receiving epinephrine via injection, there may be an apparent second peak. However, this is due a distribution of primarily single early peaks or single late peaks at the individual subject level.

¹ See the FDA Clinical Pharmacology Review for Epinephrine (NDA 201739), available at

https://www.accessdata.fda.gov/drugsatfda docs/nda/2012/201739Orig1s000ClinPharmR.pdf.

Pharmacodynamics of Epinephrine Injection

At therapeutic concentrations, epinephrine injection increases SBP, decreases DBP, reduces peripheral resistance, increases heart rate, increases skeletal muscle blood flow, and decreases cutaneous and renal blood flow in humans (Westfall 2011).

Epinephrine exerts a concentration-dependent effect on PD (vital signs) responses following continuous IV infusion. In a study of healthy volunteers receiving sequential fixed rates (0.1, 0.5, 1.0, 2.5, and 5.0 µg/min) of continuous epinephrine IV infusion while in supine posture, there was an approximate linear relationship between the real-time epinephrine plasma concentrations and change from baseline values for SBP (increase), DBP (decrease), and HR (increase).

The author suggested several threshold epinephrine plasma concentrations that were required for changes in HR (50 to 100 pg/mL), SBP (75 to 125 pg/mL), and DBP (150 to 200 pg/mL). A simple linear regression model estimated that plasma epinephrine concentrations of approximately 200 pg/mL increased HR by ~10 bpm and SBP by ~10 mmHg. The magnitude of vital sign changes was generally proportional to epinephrine plasma concentration from the threshold of 80 to 200 pg/mL up to approximately 1000 pg/mL (Clutter et al. 1980). The Agency acknowledges that:

•   There are ranges of threshold concentrations that predict PD responses in this study

•   Selected epinephrine threshold concentrations may vary due to the high inter-subject variability (including PD responsiveness)

•   Thresholds may vary by route of administration

•   The study results were obtained from healthy volunteers; whether those PD changes can be extrapolated to patients experiencing anaphylaxis is unclear (Bautista et al. 2002; Mink et al. 2004)

•   There is uncertainty in target thresholds that correlate with efficacy for treatment of anaphylaxis.

In this review, the Agency adopted 100 and 200 pg/mL as arbitrary threshold concentrations for some analyses (Sections 3.1.2.2.1 and 3.1.2.2.3), however, interpretation of these results should account for the considerations noted above.

ARS Comment 11:

FDA comments that 100 pg/mL and 200 pg/mL are “arbitrary threshold concentrations” since the basis is Clutter et al. 1980 – a six subject study in healthy volunteers using continuous slow IV infusion. In contrast, the ARS dataset includes more than 600 subjects (including type I allergy patients) and measured both PK and PD response using the best available current methodologies.

In FDA’s Addendum to the Briefing Document, FDA further clarifies that “these thresholds are arbitrary values used for displaying the proportional results. The clinical relevance of this cut off is unknown. We acknowledge that these values are based on data from subjects receiving epinephrine continuous intravenous infusions, which could allow time for compensatory mechanisms to adjust for PR and SBP and may limit the relevance to acute administration of epinephrine.”

2.2.1   Epinephrine Regulatory History

2.2.1.1   Epinephrine Approval

Epinephrine has been marketed in the U.S. since 1901, predating both the original Federal Food and Drugs Act (1906), which prohibited interstate commerce of adulterated or misbranded drugs, and the Federal Food, Drug, and Cosmetic Act of 1938, which required that new drugs be demonstrated to be safe for approval. In 1962, Congress passed the Kefauver-Harris amendment to the Federal Food, Drug, and Cosmetic Act of 1938, adding the new requirement that new drugs be shown to be effective, as well as safe, to obtain approval. This amendment also required FDA to conduct a retrospective evaluation of the effectiveness of drug products that had been approved by the Agency as safe between 1938 and 1962; the Agency’s administrative implementation of the effectiveness evaluations was called the Drug Efficacy Study Implementation process. Since epinephrine had been marketed since 1901, preceding passage of the 1938 Federal Food, Drug, and Cosmetic Act, it was not subject to a Drug Efficacy Study Implementation review.

In 1987, EpiPen was approved by FDA based upon literature support for efficacy and safety; clinical trials and PK/PD data were not required. More recent approvals of epinephrine injection products for anaphylaxis have been based on the established efficacy and safety of an FDA approved epinephrine injection product for anaphylaxis (e.g., EpiPen), chemistry/manufacturing/device data, and HF assessments to evaluate the user interface with the drug-device combination. PK and in vivo bioequivalence data were not required for the approval of more recent epinephrine injection products because of similarity of the formulations and route of administration between the new epinephrine injection product and the approved reference epinephrine product. Therefore, approved epinephrine injection products on the market today for the treatment of anaphylaxis were not required to submit bioequivalence or clinical data for approval.

Epinephrine is approved in different presentations: autoinjector, prefilled syringe, and as a solution in a vial. The autoinjector and prefilled syringes are for use in the community setting. Adrenalin is approved as a vial presentation of epinephrine for use in a supervised medical setting. The currently approved epinephrine products for the treatment of anaphylaxis are listed in Table 2.

Table 3. Approved Epinephrine Products

EpiPen/EpiPen JR

(Mylan Specialty LP)

0.15 mg/injection

0.3 mg/injection

Generic EpiPen/EpiPen JR

(Teva)

0.15 mg/injection

0.3 mg/injection

Adrenaclick and Authorized Generic

(Impax Labs, Inc.)

0.15 mg/injection

0.3 mg/injection

Auvi-Q

(Kaleo, Inc.)

0.1 mg/injection

0.15 mg/injection

0.3 mg/injection

Symjepi

(Adamis Pharms Corp)

0.3 mg/0.3 mL

Adrenalin and Epinephrine Injection

(Multiple companies)

Medical setting only

1 mg base/mL

Source: Clinical and clinical pharmacology reviewers

2.2.1.2    Approved Epinephrine Dosing

Epinephrine injection (IM or subcutaneous route) is approved for the emergency treatment of anaphylaxis in: 1) unsupervised community settings with fixed doses, and 2) healthcare settings where dosing can be administered at approved fixed doses or as a mg/kg dose, with upper limit doses established (Table 3). Of note, dosing can be repeated with severe persistent anaphylaxis, with national and international guidelines recommending dosing every 5 to 15 mins (Sampson et al. 2006). Although there is limited information regarding the proportion of patients who require a second dose of epinephrine injection, literature reports rates as high as 20% (Boyce et al. 2010).

Table 4. Approved Doses of Epinephrine in the Medical and Community Settings

Body Weight

  Medical setting

0.01 mg/kg (maximum dose 0.3 mg for subjects 7.5 to 30 kg)

  Community setting

ARS Comment 12:

FDA acknowledges that although “optimal dose for treatment of anaphylaxis is unknown,” “approved fixed doses have been used in the community for decades.” In Section 2.2.1.1 Epinephrine Approval, FDA states that “more recent approvals of epinephrine injection products have been based on the established efficacy and safety of an FDA approved injection product for anaphylaxis” and that “approved epinephrine injection markets on the market today for the treatment of anaphylaxis were not required to submit bioequivalence or clinical data for approval.”

In Section 2.1.3 Pharmacology of Epinephrine from Literature, FDA also states that following intramuscular administration of exogeneous epinephrine, plasma epinephrine concentrations demonstrate high inter-subject and intrasubject variability. Using Auvi-Q and EpiPen autoinjectors, the coefficient of variation for the mean Cmax and AUC ranged from 51% to 80%; the Tmax ranged from 5 to 60 min. These results reflect the highly variable nature of epinephrine PK.” In Section 3.1.2.1 General PK Considerations, FDA states that “there were substantial differences in the shape of the PK profile and values of the PK parameters between different injection products and within the same injection products. These substantial differences were observed within the same study with a crossover design (a design to reduce PK variability).”

    ARS Regulatory History

2.2.2.1    ARS PK/PD Program Development

ARS first engaged FDA about its IN epinephrine program in 2018. ARS proposed a PK/PD development program utilizing a 505(b)(2) regulatory pathway, relying on FDA’s previous finding of safety and effectiveness of an approved epinephrine injection product. The major focus of discussions between FDA and ARS during product development was the scope of the program necessary for ARS to establish a scientific and regulatory bridge to an approved epinephrine injection product. FDA raised concerns regarding reliance solely on PK/PD data. Early discussions included whether the focus should be on PK or PD parameters (discussed in more detail below). There were questions about the most relevant PK parameter(s) to predict efficacy, as well as concerns that changes in the nasal mucosa during anaphylaxis may impact epinephrine absorption. The need for clinical efficacy trials was considered and clinical trial scenarios were discussed, but feasibility concerns were acknowledged (Section 2.2.2.2). Ultimately, the Applicant and FDA agreed on a clinical pharmacology program to provide data to provide a scientific bridge/justification to establish the efficacy and safety for ARS-1 (Table 4). Because of uncertainties with a PK/PD approach, FDA noted that this program would need discussion by an FDA AC.

ARS Comment 13:

As noted in ARS Comment 1, “Applicant and FDA agreed on a clinical pharmacology program to provide data to provide a scientific bridge/justification to establish the efficacy and safety for ARS-1.”

As recorded in ARS Pharma’s pre-NDA meeting minutes, “The FDA stated that the approach to bracket PK from Neffy 2 mg between two approved listed injection products (IM injection with needle-syringe and EpiPen) was acceptable. The FDA clarified that with a bracketing approach, PK/PD and safety would all be reviewed and compared to both IM injection and EpiPen.”

In addition, “The FDA stated that they would not be planning to bring ARS’s application to an Advisory Committee if they did not feel the PK/PD data provided by ARS had the potential for approval and confirmed that the PK and PD data provided appears to support that the product should be efficacious and safe to use.”

Table 5. ARS-1 Clinical Pharmacology Development Plan

Bracket the single-dose PK profile of intranasal epinephrine with epinephrine

injection products with support of comparable safety and PD profiles.

Assess if self-administration of intranasal epinephrine spray changes the PK/PD

and safety compared to epinephrine injection (staff-administered).

Source: Clinical and clinical pharmacology reviewers

Abbreviations: PD, pharmacodynamics; PK, pharmacokinetics

Carryover Effect and Dose Selection

ARS initially intended to develop a 1 mg epinephrine dose for adults, as a crossover Study, EPI 3, demonstrated that the mean epinephrine PK profile of 1 mg ARS-1 summarized from several IN treatment periods was within the range of PK profiles from two dose levels of Adrenalin (i.e., 0.3 mg and 0.5 mg) IM injection. However, a subsequent analysis indicated that this mean PK profile of 1 mg ARS-1 was inflated because the epinephrine PK profiles for ARS-1 in the later IN treatment periods of EPI 3 were several times higher than the first IN treatment period. Further, this inflated mean PK profile following ARS-1 administration was consistently confirmed in all the previously conducted PK studies with crossover design for the IN treatment periods. Although the cause was unclear, the phenomenon was referred to as a carryover effect. Interestingly, this carryover effect was not immediately observed for the second dose of ARS-1 administered 10 min after the first dose (see Section 3.1.2.2.3), but peaked around 2 days following the previous ARS-1 administration. Therefore, the mean epinephrine PK profile of 1 mg ARS-1 summarized from EPI 3 is not representative of the actual epinephrine PK profile. Of note, the carryover effect was not observed following IM epinephrine injection in the same crossover design. On review of nonclinical studies, it is hypothesized that epinephrine-related reversible nasal mucosal damage changes may take some time (i.e., no immediate carryover effect) to develop following the first IN administration; and the damage change peaks in 1 to 2 days, which allows for an increase absorption from the second dose of IN epinephrine. Later, ARS successfully mitigated the carryover effect by substantially expanding the washout period between IN treatment periods in crossover trials. After the identification of the carryover effect and implementation of the long washout period, the Applicant reassessed ARS-1 with additional formulation-exploration and dose-ranging studies. Based on the results from these studies, a 2 mg ARS-1 product was selected to move forward in the program (see Section 3.1.2.1 for more details).

Challenges for PK Bridging

1.  General Considerations for PK Extrapolation from Healthy Subjects to Patients with Anaphylaxis

The Division considered that well overlayed PK profiles, between ARS-1 and a listed epinephrine injection product, could reflect similarity of real-time absorption, distribution, and elimination of epinephrine following the two routes of administration in healthy subjects. The Division was concerned that the absorption phase of the PK could be different in healthy volunteers compared to patients experiencing anaphylaxis and the rate and extent of absorption could be affected by products/route of administration. Edema of the nasal mucosa occurring with anaphylaxis could affect absorption of IN epinephrine. Therefore, the Division requested the Applicant characterize the epinephrine PK profile following IN administration under a condition mimicking the nasal mucosa edema seen in anaphylaxis. The Division and Applicant agreed that nasal congestion induced by nasal allergen challenge in subjects with seasonal allergic rhinitis was a reasonable model to address this concern (Section 3.1.2.3).

2.  PK Data Variability, Critical PK Parameters, Bracketing Approach

As will be discussed in Section 3, there is high inter- and intra-product PK variability between epinephrine injection products, as well as variability between batches within one product. This PK variability introduces uncertainties in comparative studies, particularly when there is an absence of clinical data to establish critical PK parameters for efficacy. Thus, selection of appropriate and representative comparators in these comparative PK studies is critical to support accurate interpretation of study results.

In addition to traditional PK parameters, such as C_max and AUC_0-inf/AUC_0-t, the Division also considers the following PK characteristics as meaningful in the evaluation of any epinephrine product to be used to treat anaphylaxis:

•  The initial epinephrine absorption rate/early partial AUC values.

•  The sustainability of epinephrine plasma concentration.

ARS Comment 14:

As recorded in ARS Pharma’s pre-NDA meeting minutes, “FDA agreed that partial AUC is more critical than AUC_0-t for potential efficacy consideration. It will be acceptable if partial AUC is listed as one of the primary PK endpoints. However, some previous studies demonstrated that the median tmax following different epinephrine products could be between 30 minutes and 60 minutes. Therefore, using AUC_0-20 or AUC_0-30 is inappropriate.”

Further, “The FDA recommended that ARS use partial AUC with a later time point for PK comparison. ARS agreed. In addition, the FDA stated that the AUC_0-t value should be calculated and compared as one of the secondary PK endpoints.”

As recorded in ARS Pharma’s pre-NDA meeting minutes, FDA commented:

“Based on the data you provided, we have some safety concerns regarding the higher epinephrine systemic exposure of this dose selection. EPI-11b showed that the epinephrine AUC_0-t following the 2 mg dose is around 50-70% higher than following EpiPen 0.3 mg injection.”

“ARS noted that if in the EPI-15 study that the AUC_0-t of the IN is greater than IM with needle-in-syringe or EpiPen, ARS is willing to include a 0.5 mg epinephrine IM injection as a listed product in the nasal allergen challenge study (EPI 16) to provide a potential safety coverage for high AUC_0-t value. The FDA agreed that inclusion of 0.5 mg IM would help create a wider bracket and appreciated ARS’s suggestion.”

“The FDA asked if ARS agreed to perform Part 1 of the EPI-15 study (i.e., single dose cross-over) before the other studies. ARS confirmed the plan is to first conduct EPI-15, Part 1, and other studies would not be initiated until confirming the results of the single 2 mg Neffy with the listed injection products from EPI-15, Part 1.”

In FDA’s Addendum to the Briefing Document, FDA re-confirms that “based upon these results, the FDA did caution ARS about safety concerns with higher doses given the AUC_0-t with the 2 mg dose of ARS-1 was higher than EpiPen.”

ARS Comment 16:

FDA notes in Section 3.1.2.2.3 Repeat-Dose PK that “the epinephrine C_max and AUC_0-60 values following two doses of ARS-1 approximately doubled compared to a single-dose administration in Part 1.” This would imply that ARS-1 is dose-proportional, and not impaired.

As shown in Figure 11 below from Section 3.1.2.3.1 PK Data in Allergen-Induced Nasal Congestion, FDA comments that “under nasal-allergen challenge conditions, the epinephrine concentration increased more rapidly than the two Adrenalin dose arms followed by a fast decline and the epinephrine concentrations became lower than all comparator arms after 10 to 20 min post dose. PK for ARS-1 2 mg with challenge is higher than Adrenalin 0.3 mg for the first 20 min post dose.” FDA also comments that “epinephrine is expected to function as a nasal decongestant.”

Source: Clinical Pharmacology Reviewer. Based on adpc.xpt of Study EPI 16.

Three subjects in the Adrenalin 0.3 mg arm and one subject in ARS-1 with nasal challenge arm had insufficient number of postdose samples (n<3) within 30 min. Two subjects in the Adrenalin 0.3 mg arm, five subjects in the Adrenalin 0.5 mg arm, and two subjects in the ARS-1 with nasal challenge arm did not have pharmacokinetic data. This is the same figure as Figure 2 in Section 1.3.2.

FDA notes in Section 3.1.2.3.3 that “10 out of 37 subjects treated with ARS-1 after nasal allergen challenge continued to have some degree of nasal congestion for more than 30 min post-dose.” That implies that 73% of allergic rhinitis patients with nasal congestion no longer had any symptoms 30 min post dose with ARS-1 after nasal allergen. FDA also observes that in Section 3.1.2.3 that “the rates of nasal mucosal symptoms such as rhinitis and conjunctivitis range from 2% to 11% in anaphylaxis patients.

These two sets of numbers in the FDA briefing book imply that between 97% to 99.5% of anaphylaxis patients would not experience continued rhinitis at 30 min post-dose after nasal allergen challenge with purified antigen [calculation using FDA numbers: 89 to 98% of cases without nasal mucosal symptoms + 73% resolution* (2 to 11%) with nasal mucosal symptoms]. For the 0.5 to 3% of patients that could experience continued rhinitis beyond 30 minutes, the single dose rhinitis data in Figure 8 supports ARS-1 higher exposures than normal conditions for the first 10 min post dose (which is when clinical response is observed). This enhanced exposure would be expected even for a second dose given when rhinitis persists.

Impact of HF and Actual Use

An HF assessment was required for this development program to assess the user interface. The goal of HF validation studies is to demonstrate that the final finished user interface supports safe and effective use of the product by intended users, for intended uses, and under the expected conditions (including environment(s) of use). See Section 6.2 for more information on the HF program for ARS-1.

To reduce PK variability caused by administration differences, study staff administered ARS-1 to subjects in all the aforementioned clinical pharmacology studies; this represented an idealized use situation. Whether self-administration changed the PK profile of ARS-1 was a question that FDA raised. Therefore, the Division requested the Applicant conduct an actual use PK study (e.g. self- administration clinical study) to characterize epinephrine PK profiles in subjects following self- administered IN spray (see Section 3.1.2.4).

5.

Pediatric Considerations

To comply with the Pediatric Research Equity Act, which requires a pediatric study plan due to the change of administration route of approved epinephrine injection products, the Applicant proposed an ARS-1 pediatric drug development program. Given differences in shape, size, and surface area of the nasal cavity in children compared to adults, the Division also requested a dose-ranging trial in pediatric patients across all ages and body weights. This trial is currently ongoing and discussed in Section 3.1.3.

Challenges for PD Bridging

There are expected differences between healthy volunteers and patients with anaphylaxis in hemodynamics, vasoactive hormone/cytokine levels, and baroreceptor responses; these differences could differentially influence vital sign responses to epinephrine. While PD responses (i.e., SBP, DBP, HR) may reflect physiologic changes that are important for effective treatment of anaphylaxis, and may support PK matching results, PD and PK results did not always correlate in the ARS-1 development program. The PD data generated from the ARS-1 development program demonstrated that there was not a consistent correlation between PK and PD at the individual level and that the PK/PD relationship is generally weak at the population level. In addition, different trends of PK and PD comparison results were observed between ARS-1 and EpiPen without a clear mechanism to explain this discrepancy.

Whether PD results in healthy volunteers translate to similar benefits in the setting of anaphylaxis is unknown. The Division believes that comparative PD results, between ARS-1 and epinephrine injection products, provide supportive evidence to the PK matching approach that is needed for scientific and regulatory bridging in the ARS-1 clinical pharmacology program. Therefore, the Division places emphasis on the PK bracketing results, and views PD results as supportive.

2.2.2.2 Clinical Efficacy Trial Feasibility

The feasibility of performing a clinical efficacy trial in anaphylaxis was discussed with the Applicant and within the FDA. Approaches to designing a clinical efficacy trial that were explored in these discussions included:

•  A trial in emergency departments, in which patients with anaphylaxis would be treated with non- injectable epinephrine as first-line therapy, with rescue epinephrine injection administered as back- up, if needed.

•  A trial in the setting of oral food challenges or subcutaneous allergen immunotherapy.

Concerns raised with these trial designs include: 1) delaying standard of care (epinephrine injection) for potentially life-threatening reactions where the timing of treatment is critical for preventing serious outcomes, 2) the spontaneous nature of events would require a long study duration and large sample size, and 3) challenges in determining meaningful endpoints (e.g., improvement in symptoms, treatment failure). Due to these challenges, it was determined that a clinical efficacy trial would neither be feasible nor provide meaningful data to support the efficacy of IN epinephrine in anaphylaxis.

A histamine infusion trial to elicit symptoms mimicking anaphylaxis was also discussed. Since histamine is only one of many mediators involved in anaphylaxis, this approach, if feasible, was not considered to be sufficiently robust to inform efficacy in the setting of anaphylaxis.

2.2.2.3 Development of Other Emergency-Use IN Products

As there is no regulatory precedent for approval of a noninjectable epinephrine product for treatment of anaphylaxis, the development programs for two other IN therapeutics, naloxone nasal spray (approved November 2015) and diazepam nasal spray (approved January 2020), were considered in evaluation of the IN epinephrine development program, as both are used as emergency treatment and were originally approved with a different route of administration (naloxone injection and diazepam rectal gel). However, due to pharmacologic and safety differences, the approaches used for the naloxone and diazepam nasal spray PK development programs have important differences that limit the applicability to the development of IN epinephrine.

Naloxone nasal spray

Naloxone nasal spray, an opioid antagonist, uses the same device as ARS’s IN epinephrine and is approved for the emergency treatment of known or suspected opioid overdose for all ages. This approval was based on one PK trial in healthy adults in which the bioavailability of the IN spray was compared to a single IM naloxone injection; no clinical efficacy trials were conducted. Naloxone is unique in that it has a wide safety margin with a relatively high systemic exposure following IN administration that is 5- to 10-fold over the minimum therapeutic threshold.^2,3 Therefore, surpassing the therapeutic threshold is the goal of development as safety is not a concern with higher exposures. The higher exposure overcame concerns with translatability of PK in healthy volunteers to patients with opioid overdose. While there may be similarities with Narcan, there are important differences with IN epinephrine that require additional considerations.

ARS Comment 17:

We acknowledge FDA’s concern that unlike NARCAN, where “safety is not a concern with higher exposures,” there is a therapeutic window with epinephrine. This is part of the reason why ARS and FDA agreed to a bracketing approach between approved listed products on exposure (see ARS Comment 1), and why ARS aimed to achieve this bracket with as low a dose of epinephrine (2 mg) as possible.

Diazepam nasal spray is a benzodiazepine indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures), that are distinct from a patient’s usual seizure pattern in patients with epilepsy 6 years of age and older. The IN route of administration uses the same device as ARS-1. Approval was based on comparable bioavailability in healthy subjects and patients with epilepsy relying on adequate and well-controlled efficacy studies for rectal diazepam. A PK study was conducted in adults and pediatric patients with epilepsy comparing seizure versus non-seizure states to address potential differences in PK in healthy subjects compared to patients with epilepsy. Overall, while the diazepam nasal spray program is an example of a nasal spray for emergency use that relied on PK to bridge the efficacy, the diazepam nasal spray program has limitations in its applicability to the ARS-1 program.

3  Summary of Issues for the AC

3.1  Efficacy Issues

3.1.1  Sources of Data for Efficacy

ARS submitted their application under the 505 (b)(2) pathway that relies on FDA’s previous finding of safety and effectiveness of an approved epinephrine injection product; ARS proposes to rely on Adrenalin as the reference listed drug. To support approval, ARS must submit data to provide a scientific bridge/justification to the reference product to establish the efficacy and safety for ARS-1. As discussed in Section 2.2.2.1, ARS proposed a clinical pharmacology program to provide data to provide the bridge to Adrenalin to establish the efficacy and safety of ARS-1. The pivotal clinical pharmacology studies are listed in Table 5.

Group 1:

Single dose of Symjepi 0.3 mg

Single dose of ARS-1 1.3 mg

(excipient strength 1)

Single dose of ARS-1 1.5 mg (excipient strength 2)

Single dose of ARS-1 1.5 mg (excipient strength 1)

Single dose of ARS-1 1.8 mg

(excipient strength 2)

Group 2:

Single dose of EpiPen 0.3 mg

Single dose ARS-1 1 mg

(excipient strength 1, lot 1)

Single dose ARS-1 1 mg

(excipient strength 1, lot 2)

Single dose ARS-1 1.5 mg

(excipient strength 2)

Single dose of ARS-1 2.0 mg

(excipient strength 2)

26 enrolled

Group 1: 13

Group 2: 13

All subjects included in the PK analysis

Assess the comparative bioavailability and PD response of epinephrine after ARS-1 2.0 mg, EpiPen

0.3 mg, and epinephrine IM injection 0.3 mg in healthy volunteers

Single dose of ARS-1 2.0 mg vs. Single dose of EpiPen 0.3 mg vs. Single dose epinephrine IM 0.3 mg

Two doses of ARS-1 2.0 mg both in right naris spaced 10 min apart

Two doses of ARS-1 2.0 mg, one in left and one in right naris, spaced 10 min apart

Two doses of EpiPen 0.3 mg in the left and right thigh, 10 min apart

59 enrolled

Included In PK analysis: Total: 58

(26 subjects participated in both parts with PK data)

Part 1:

ARS-1: 42

EpiPen: 41

Epinephrine IM: 41

Part 2:

ARS-1 (L/R): 38

ARS-1 (R/R): 38

EpiPen (L/R): 42

Assess the comparative bioavailability of epinephrine after ARS-1 2.0 mg, epinephrine IM 0.3 mg and epinephrine IM 0.5 mg in subjects with seasonal allergic rhinitis after nasal

challenge.

ARS-1 2.0 mg

Epinephrine IM 0.3 mg

Epinephrine IM 0.5 mg

ARS-1 2.0 mg after nasal challenge

36 enrolled

Included in PK analysis: ARS-1 (normal): 36

Epinephrine IM 0.3

mg: 31

Epinephrine IM 0.5

mg: 31

ARS-1 (challenge): 33

Assess the comparative bioavailability of epinephrine after self-administration of ARS-1 2.0 mg or staff- administered epinephrine IM injection in subjects with Type I

allergies.

ARS-1 2.0 mg, self-administered

Epinephrine IM 0.3 mg, staff

administered

43 enrolled

Included in PK analysis:

ARS-1: 42

Epinephrine IM: 42

ARS-1 0.65 mg

ARS-1 1.0 mg

ARS-1 2.0 mg

57 (at time of interim analysis) enrolled

Included in PK analysis

>30 kg:

ARS-1 2 mg: 16

ARS-1 1 mg: 25

15 and 30 kg ongoing

Pediatric subjects 4 to <18 years of age with Type I allergies to food, venom, or drugs that require that the subject or caregiver be prescribed an

epinephrine product

We note the markedly different PK profiles for the two epinephrine injection product comparators approved for community use (EpiPen and Symjepi). The results suggested that the epinephrine mean concentration for ARS-1 2 mg is higher than that of EpiPen after approximately 15 min postdose and that of Symjepi after approximately 10 min postdose. However, the epinephrine concentration for ARS-1 2 mg is lower than both injection products in the first 10 min postdose.

ARS Comment 18:

Please refer to Figure 15 in ARS Comment 1 that shows ARS-1 2 mg is higher than Adrenalin 0.3 mg in the first 10 min post dose, and Figure 7 in ARS Comment 6 that shows that the PD response for ARS-1 2 mg is also higher than Adrenalin 0.3 mg in the first 10 min post dose.

The Applicant decided to move forward with 2 mg without investigating higher doses. Whether higher doses may overcome the lower plasma concentrations in the first 10 to 15 min and the clinical significance of the delayed absorption is a topic for AC discussion.

ARS Comment 19:

As recorded in ARS Pharma’s pre-NDA meeting minutes, FDA stated that “Based on the data you provided, we have some safety concerns regarding the higher epinephrine systemic exposure of this dose selection. EPI-11b showed that the epinephrine AUC0-t following the 2 mg dose is around 50-70% higher than following EpiPen 0.3 mg injection.” See ARS Comment 15 for rest of discussion around the importance of minimizing systemic exposure of epinephrine.

During the ARS-1 drug development program, the Applicant and FDA noted that there were substantial differences in the shape of the PK profile and values of PK parameters between different epinephrine injection products and within the same injection products (Figure 4). These substantial differences were observed even within the same study with a crossover design (a design to reduce PK variability).

ARS Comment 20:

See Figure 15 and ARS Comment 4 highlighting the consistency of ARS-1 2 mg PK across studies with FDA acknowledging that “differences in the first 10 minutes is mostly due to Adrenalin PK

ARS Comment:

See Figure 15 and ARS Comment 4 highlighting the consistency of ARS-1 2 mg PK across studies with FDA acknowledging that “differences in the first 10 minutes is mostly due to Adrenalin PK variability.”

From a scientific and regulatory perspective, it is common practice to plot and present drug concentration-time profiles as geometric means. This is particularly pertinent for drugs such as epinephrine with high PK variability, since the arithmetic mean can be more influenced by extreme outlying values than the geometric mean. In addition, the FDA Bioavailability and Bioequivalence Guidance requires applicants to provide geometric mean values with investigational new drug/NDA submissions (FDA 2022b). Different shapes and trends of epinephrine concentration-time profiles were observed between presentations with geometric means and arithmetic means; based upon our review, we believe the geometric mean is the most relevant way to present the PK results as the arithmetic mean may obscure important differences.

ARS Comment 21:

In FDA’s Addendum to the Briefing Document, FDA comments that “FDA presents the PK data in the FDA Briefing Document using geometric means, while ARS presents the PK data in their briefing document using arithmetic means. FDA notes that its guidelines “recommend both arithmetic and geometric mean values of PK parameters submitted in an NDA. It is appropriate to consider different analyses of the PK data. Depending on the nature of the data, there may be reasons to place more emphasis on arithmetic vs. geometric means. When we reviewed both methods, we decided to use geometric means for presentation of the PK data from this program. Given the high variability seen with epinephrine PK, the geometric mean is less influenced by extreme outlier values.”

However, in this same Addendum, FDA states: “We note that despite the different approaches in presentation of the PK data (geometric vs. arithmetic means), the results obtained from either geometric means or arithmetic means are similar.”

PK Data Pooling

For the PK comparisons, the Agency does not consider it appropriate to pool PK data across different studies. FDA’s current bioavailability guidance recommends that PK comparisons be conducted in a dedicated PK study for regulatory purposes (FDA 2022b). A within-study crossover design is preferred to minimize the PK variability. Pooling PK results from different studies with different designs, purposes, and potentially different populations without any clinical/statistical justification may obscure relevant findings from the individual studies.

ARS Comment 22:

We acknowledge FDA’s reference to the 2022 bioavailability guidance, which focuses on PK for demonstrating bioequivalence. As FDA has noted, there is significant variability from study to study for injection products, even within the same injection products, reinforcing why “PD is supportive,” as noted by FDA, and can help to support demonstration of adequate exposure.

Per FDA’s guidance (2015) https://www.fda.gov/media/72335/download, ARS included an integrated summary of effectiveness in the ARS-1 NDA using sources of information relevant to efficacy such as clinical pharmacology studies (e.g. pharmacokinetics, pharmacodynamic) to provide additional information beyond individual study results, given the significant variability of injection products acknowledged by FDA, and to provide greater clarity on the true population values. Per FDA’s guidance (2022) https://www.fda.gov/media/128793/download, ARS included and submitted population PK analyses in its submission including for “deriving exposure metrics for conducting exposure-response analysis” to support the PK/PD relationship.”

FDA acknowledges in its FDA Addendum to the Briefing Document that “pooling of PK can be utilized for certain purposes (e.g. population pharmacokinetics).”

ARS Comment 23:

See Figure 15 from this briefing document that includes data from two of the three ARS-1 primary studies, which is important given the significant variability of epinephrine injection products. In this figure, one can see that both ARS-1 2 mg curves are above Adrenalin 0.3 mg.

ARS Comment 24:

The above table is focused on Figure 1, which was generated from only one of the relevant studies of ARS-1 2 mg. Please refer to Figure 15, as well as Figure 7, which shows that PK/PD response for ARS-1 2 mg is higher than Adrenalin 0.3 mg at all time points, including the 10 minutes. Please also see ARS Comment 4 and ARS Comment 6.

In addition, a statistical comparison of the geometric mean pAUC_0-10 of ARS-1 and Adrenalin from the above table shows the difference between the two values is not statistically significant.

The proportion of subjects whose epinephrine concentration reached 100 pg/mL or 200 pg/mL, arbitrary threshold concentrations suggested by literature following IV infusion (as discussed in Section 2.1.3), at different time points within 60 min post-single dose is shown in Figure 6 (Clutter et al. 1980). The proportion of subjects who failed to reach 100 pg/mL within 30 min and 60 min is shown in Table 7.

Figure 6. Proportion of Subjects with Epinephrine Concentrations of 100 and 200 pg/mL or Greater by Time Following a Single Dose of ARS-1, Adrenalin 0.3 mg, or EpiPen 0.3 mg

ARS Comment 25:

See ARS Comment 11 regarding FDA’s description of “arbitrary threshold concentration.” In FDA’s Addendum to the Briefing Document, FDA further clarifies that “these thresholds are arbitrary values used for displaying the proportional results. The clinical relevance of this cut off is unknown. We acknowledge that these values are based on data from subjects receiving epinephrine continuous intravenous infusions, which could allow time for compensatory mechanisms to adjust for PR and SBP and may limit the relevance to acute administration of epinephrine.”

    Single-Dose PD Results

Figure 7. Median PD Responses (SBP, PR, and DBP Change from Baseline) Following a Single Dose of
ARS-1, Adrenalin 0.3 mg, or EpiPen 0.3 mg in Healthy Subjects

Source: Clinical Pharmacology Reviewer. Based on adxd.xpt of Study EPI 15. Subjects who were included in the PK analysis were included in the PD analysis.

Error bars represent 25% and 75% percentile of the PD values.

Abbreviations: DBP, diastolic blood pressure; PD, pharmacodynamics; PK, pharmacokinetics; PR, pulse rate; SBP, systolic blood pressure

Parameter

ARS-1 (n=42)

EpiPen 0.3 mg (n=41)

Adrenalin 0.3 mg (n=41)  

Mean (SD) (mmHg)

Median (range) (mmHg)

Median Tmax (range) (min)

Source: Clinical Pharmacology Reviewer. Based on adxd.xpt of Study EPI 15. Subjects who were included in the PK analysis were included in the PD analysis.

Abbreviations: PD, pharmacodynamics; PK, pharmacokinetics; SBP, systolic blood pressure; Tmax time to maximum plasma concentration

The SBP and PR responses following single-dose administration of ARS-1 are bracketed by EpiPen and Adrenalin within 10 min postdose. Thereafter, although the shapes of the median SBP and PR time- response curves are similar to the epinephrine mean PK profiles following ARS-1 and EpiPen

administration, respectively, the magnitudes of SBP and PR responses are generally higher for ARS-1 compared to both injection products despite the fact that the epinephrine PK profile of ARS-1 is generally lower compared to EpiPen. The exact mechanism underlying the discrepancy of PK and SBP/PR comparison results between ARS-1 and EpiPen is unclear. In addition, a more stable DBP time profile was observed following ARS-1 when compared to apparent declination profiles from both injection products.

3.1.2.2.3  Repeat-Dose PK Results

In part 2 of EPI 15, two doses of ARS-1 or EpiPen were given 10 min apart. The second dose of ARS-1 was administered in the same naris in one period and in the opposite naris in another period. The epinephrine concentration-time profiles following the first dose (Time 0) and second dose (Time 10 min) are shown in Figure 8. The PK parameters from the repeat dosing are reported in Table 9.

Figure 8. Epinephrine Geometric Mean (±Standard Error) Concentration-Time Profile Following Two Doses of ARS-1 Given in Same Naris (R/R) or Opposite Naris (L/R) vs. Two Doses of Intramuscular Injection Using EpiPen 0.3 mg in Healthy Subjects

Source: Clinical Pharmacology Reviewer. Based on adpc.xpt of Study EPI 15. One subject each in the ARS-1 (R/R) and ARS-1 (L/R) from EPI15 Part 2 were excluded due to insufficient number of postdose samples (n<3) within 30 min. Three subjects each in the ARS-1 (R/R) and ARS-1 (L/R) arms discontinued early and did not have PK data.

Abbreviations: L, left; PK, pharmacokinetics; R, right; RD, repeat doses

Repeat-Dose ARS-1

(L/R) IN (N=38)^b

Repeat-Dose ARS-1

2 mg (R/R) IN (N=38)^b

Repeat-Dose EpiPen  

0.3 mg (L/R) IM (N=42)  

  C_max (pg/mL)

  T_max (min)^a

   AUC_0-10min (pg·min/mL)

   AUC_0-20min (pg·min/mL)

   AUC_0-30min (pg·min/mL)

  AUC_0-60min (pg·min/mL)

Source: Clinical Pharmacology Reviewer. Based on adpc.xpt of Study EPI 15.

^a Median is reported.

^b One subject each in the ARS-1 (R/R) and ARS-1 (L/R) arms from EPI15 Part 2 were excluded due to an insufficient number of postdose samples (n<3) within 30 min. Three subjects each in the ARS-1 (R/R) and ARS-1 (L/R) arms discontinued early and did not have PK data.

Abbreviations: IN, intranasally; L, left; R, right; PK, pharmacokinetics

Based on the results for EPI 15 Part 2, the epinephrine C_max and AUC_0-60min following two doses of EpiPen only increased about 20% and 50%, respectively, compared to that following single-dose administration in Part 1. However, the epinephrine C_max and AUC_0-60min values following two doses of ARS-1 approximately doubled compared to single-dose administration in Part 1. Therefore, the epinephrine C_max and AUC_0-60min values following two doses of ARS-1 are comparable to that of two doses of EpiPen. However, the epinephrine concentration following two doses of ARS-1 remains lower than that of EpiPen during the first 20 min postdose due to the likely lower absorption rate than EpiPen. The clinical relevance of this is an open question; however, conclusions regarding the lower epinephrine exposure with repeat-dose ARS-1 compared to EpiPen within the first 20 minutes is limited as the repeat dose was not bracketed. Epinephrine PK profiles and systemic exposures were similar between ARS-1 administered in the same naris and opposite naris.

ARS Comment 25:

See ARS Comment 6 regarding median PD with single dosing, as well as Figure 10 regarding median PD with repeat dosing of ARS-1 2 mg and EpiPen 0.3 mg, which is reproduced below. ARS-1 2 mg repeat dose provides even higher median PD response than single doses of epinephrine products, including Adrenalin 0.3 mg, as expected.

Figure 10. Median PD Responses (SBP, PR, and DBP Change From Baseline)
Following Two Doses of ARS-1 in Same Naris (R/R) or Opposite Naris (L/R), and Two
Doses of EpiPen 0.3 mg in Healthy Subjects

Source: Clinical Pharmacology Reviewer. Based on adxd.xpt
of Study EPI 15. Subjects who were included in the PK
analysis were included in the PD analysis. Error bars
represent the 25% and 75% percentiles of the PD values.

Abbreviations: DBP, diastolic blood pressure; L, left; PD, pharmacodynamics; PK, pharmacokinetics; PR, pulse rate; R, right; SBP systolic blood pressure; SE, standard error

Figure 9. Proportion of Subjects With Epinephrine Concentrations of 100 pg/mL and 200 pg/mL or Greater Following Two Doses of ARS-1 in Same Naris (R/R) or Opposite Naris (L/R), and Two Doses of EpiPen 0.3 mg

Source: Clinical Pharmacology Reviewer. Based on adpc.xpt of Study EPI 15. One subject each in the ARS-1 (R/R) and ARS-1 (L/R) from EPI15 Part 2 were excluded due to insufficient number of postdose samples (n<3) within 30 min. Three subjects each in the ARS-1 (R/R) and ARS-1 (L/R) arms discontinued early and did not have PK data.

Abbreviations: L, left; R, right

Table 11. Proportion of Subjects Who Failed to Reach 100 pg/mL Following Two Doses of ARS-1 2 in Same Naris (R/R) or Opposite Naris (L/R), and Two Doses of EpiPen 0.3 mg

  Within 30 min

  Within 60 min

Source: Clinical Pharmacology Reviewer. Based on adpc.xpt of Study EPI 15.

Abbreviations: L, left; R, right

Similar to Part 1, the proportions of subjects whose epinephrine concentration reached the threshold of 100 pg/mL and 200 pg/mL was initially low following ARS-1 2 mg dosing and gradually increased over time. The proportion following two doses of ARS-1 approached that following two doses of EpiPen at 60 min postdose. Higher proportions of subjects whose epinephrine concentrations reached 100 pg/mL and 200 pg/mL following two doses of ARS-1 in Part 2 than single dose in Part 1 starting 15 min postdose.

ARS Comment 26:

See ARS Comment 11 regarding FDA’s description of “arbitrary threshold concentration.”

3.1.2.2.4   Repeat-Dose PD Results

The PD response following two doses of ARS-1 2 and EpiPen 0.3 mg are shown in Figure 10. The mean and median of the maximum SBP change from baseline within 60 min as well as the median time to reach the maximum change following repeat doses are shown in Table 11.

Figure 10. Median PD Responses (SBP, PR, and DBP Change From Baseline) Following Two Doses of ARS-1 in Same Naris (R/R) or Opposite Naris (L/R), and Two Doses of EpiPen 0.3 mg in Healthy Subjects

Source: Clinical Pharmacology Reviewer. Based on adxd.xpt of Study EPI 15.

Subjects who were included in the PK analysis were included in the PD analysis.

Error bars represent the 25% and 75% percentiles of the PD values.

Abbreviations: DBP, diastolic blood pressure; L, left; PD, pharmacodynamics; PK, pharmacokinetics; PR, pulse rate; R, right; SBP systolic blood pressure; SE, standard error

Table 12. Maximum SBP Change From Baseline in 60 Min Following Repeat Doses

ARS-1 (L/R)
(n=38)

ARS-1 (R/R)

(n=38)

EpiPen 0.3 mg (L/R) 

(n=42) 

  Mean (SD) (mmHg)

  Median (range) (mmHg)

  Median Tmax (range) (min)

Source: Clinical Pharmacology Reviewer. Based on adxd.xpt of Study EPI 15. Subjects who were included in the PK analysis were included in the PD analysis.

Abbreviations: L, left; PD, pharmacodynamics; PK, pharmacokinetics; R, right; Tmax, time to maximum plasma concentration

Similar to the PD results from Part 1, following two doses of ARS-1 in Part 2, higher SBP and PR responses were observed compared to two doses of EpiPen, despite the comparable AUC0-60min values

between treatments. The discrepancy of PK and PD comparison results between ARS-1 and EpiPen suggests that there may be an unknown PK-independent mechanism regulating SBP and PR responses during the epinephrine treatment following different administration routes. The magnitude of SBP and PR responses are apparently higher following two doses of ARS-1 in Part 2 than single dose of ARS-1 2 mg in Part 1. However, the magnitude of SBP and PR responses following two doses of EpiPen in Part 2 is similar to that following a single dose of EpiPen in Part 1, except for improved sustainability. In addition, a more stable DBP time profile following ARS-1 administration was observed compared to EpiPen.

3.1.2.2.5   PK/PD Summary in Healthy Volunteers

Overall, based on results from EPI 15 in healthy adult subjects, the PK profile of epinephrine for ARS-1 was reasonably bracketed by Adrenalin and EpiPen following a single dose after 10 min postdose and the PK profile of epinephrine following repeat doses of ARS-1 was similar to repeat-dose EpiPen, except for the lower concentration within 20 min postdose. We ask the AC panel to discuss the lower epinephrine exposure with ARS-1 in the first 10 min postdose.

ARS Comment 27:

Table 7 is focused on Figure 1, which was generated from only one of the relevant studies of ARS-1 2 mg. Please refer to Figure 15, as well as Figure 7, which shows that PK/PD response for ARS-1 2 mg is higher than Adrenalin 0.3 mg at all time points, including the 10 minutes.

Please also see ARS Comment 4 and Comment 7.

Conclusions regarding the lower epinephrine exposure with repeat-dose ARS-1 compared to EpiPen within the first 20 minutes is limited as the repeat dose was not bracketed.

ARS Comment 28:

See ARS Comment 5 and ARS Comment 25 regarding repeat dose PK/PD of ARS-1.

Generally higher PD responses (SBP and PR change from baseline) were observed with ARS-1 than both Adrenalin and EpiPen following a single dose or repeat doses. In general, the PD comparison results support the PK bracketing approach for the ARS-1 drug development program. The mechanism underlying the higher PD responses following ARS-1 compared to epinephrine injection products despite lower or similar PK is unclear based on the information available at this time. This PK/PD discrepancy is one of the reasons that FDA focused more on the PK data.

ARS Comment 29:

See ARS Comment 12 regarding variability of PK observed with injection products.

3.1.2.3   ARS-1 PK/PD Under Nasal Congestion Condition

In Study EPI 16, subjects with allergic rhinitis underwent a nasal allergen challenge to induce nasal congestion. ARS-1 and Adrenalin 0.3 mg and Adrenalin 0.5 mg were administered in this study and the PK profile was assessed. Anaphylaxis can impact multiple organ systems, including the nasal mucosa—the site of absorption of ARS-1. Rhinitis and nasal congestion can be features of anaphylaxis; alterations of the nasal mucosa (e.g., vasodilation) may affect the local absorption of epinephrine. The rates of nasal mucosal symptoms such as rhinitis and conjunctivitis range from 2% to 11% in anaphylaxis patients (Brown et al. 2001; Braganza et al. 2006; Gonzalez-Estrada et al. 2017). However, these statistics are limited given these are from retrospective case study reviews. The true incidence of mucosal involvement, particularly nasal mucosal involvement, is unclear. FDA and the Applicant agreed that nasal allergen challenge of subjects with allergic rhinitis with known allergen sensitization may reasonably mimic the findings that could occur in anaphylaxis.

Study EPI 16 was a four-treatment, partially randomized, crossover study involving adult subjects with allergic rhinitis (N=36). The study sequence was of sandwich design (ARS-1 g Adrenalin g Adrenalin g ARS-1) with a washout period of 12 days between the two ARS-1 treatment periods to mitigate the carryover effect.

3.1.2.3.1   PK Data in Allergen-Induced Nasal Congestion

The epinephrine concentration-time profiles within 60 min postdose are shown in Figure 11.

Three subjects each in the Adrenalin 0.3 mg and Adrenalin 0.5 mg IM arms and one subject in ARS-1 with nasal challenge arm had insufficient number of quantifiable postdose samples (n<3) within 30 min. Two subjects in each in the Adrenalin 0.3 mg arm, five subjects in the Adrenalin 0.5 mg arm, and two subjects in the and ARS-1 with nasal challenge arm did not have pharmacokinetic data. This is the same figure as Figure 2 in Section 1.3.2.

ARS Comment 30:

We believe ARS-1 is bracketed by Adrenalin 0.3 mg at all time points, and the data presented by FDA in this briefing book support this observation.

See ARS Comment 7 regarding PK.

See ARS Comment 8 regarding PD that references Figure 12 below.

Figure 12. Median PD Responses (SBP and PR Changes From Baseline) in Subjects With Allergic Rhinitis

Source: Clinical Pharmacology Reviewer. Based on adxd.xpt of Study EPI 16.

Subjects who were included in the PK analysis were included in the PD analysis.

Error bars represent 25% and 75% percentile of the PD values.

Abbreviations: PD, pharmacodynamics; PK, pharmacokinetics; PR, pulse rate; SBP, systolic blood pressure

Table 13. Maximum SBP Change from Baseline in 60 Min In Subjects With Allergic Rhinitis

ARS-1 Normal

(N=36)

ARS-1 Challenge

(N=33)

Adrenalin 0.3 mg

(N=31)

Adrenalin 0.5 mg  

(N=31)  

 Mean (SD) (mmHg)

 Median (range) (mmHg)

 Median T_max (range) (min)

Source: Clinical Pharmacology Reviewer. Based on adxd.xpt of Study EPI16.

Subjects who were included in the PK analysis were included in the PD analysis.

Abbreviations: SBP, systolic blood pressure; T_max, time to maximum plasma concentration

Under nasal allergen challenge conditions, similar to the PK profile, initially higher responses in SBP and PR were observed with ARS-1 which soon declined and became lower compared to normal nasal conditions after around 15 min postdose. The median change of PR response following ARS-1 under nasal allergen challenge conditions fell lower than Adrenalin about 5 min postdose. Additionally, it was noted that some subjects had negative values for the maximum SBP change from baseline within 60 minutes postdose in Study EPI 16 (Table 12). The cause of this observation is unclear, but it indicates that the epinephrine PD response is highly variable and may not be associated with epinephrine plasma concentrations at the individual level.

ARS Comment 31:

See ARS Comment 7 regarding PK and ARS Comment 8 regarding PD under nasal allergen challenge.

3.1.2.3.3   Nasal Congestion and its Effect on PK/PD

Comparing the PK/PD of ARS-1 under normal nasal conditions versus allergen-induced nasal congestion, there is an apparent change in PK/PD profiles. Specifically, there was faster absorption followed by faster reduction of epinephrine plasma concentration and decline of PD responses after 10 to 20 min

postdose observed under nasal allergens challenge conditions.

On a closer look, we noted a lack of local decongestant effect seen in some subjects treated with ARS-1 following nasal allergen challenge in EPI 16. As a nonselective adrenergic agonist, epinephrine is expected to function as a nasal decongestant via local vasoconstriction by activating alpha-1 receptors in vascular smooth muscle. Therefore, we expect most if not all subjects to have improved nasal congestion after ARS-1 administration. However, from the analysis, 10 of the 37 subjects treated with ARS-1 after nasal allergen challenge continued to have some degree of nasal congestion for more than 30 min post-ARS dose, with 7 of those subjects experiencing nasal congestion for 120 min or longer. It appears that some subjects with moderate to severe nasal congestion conditions prior to ARS-1 treatment may continue experiencing nasal congestion. How this continued nasal congestion affects the uptake of a potential second dose of ARS-1 is unknown. The effect of severity and duration of nasal congestion conditions on the PK/PD of ARS-1 is discussed below.

ARS Comment 32:

See ARS Comment 16.

The severity of allergen-induced nasal congestion prior to ARS-1 administration impacted the PK profile of ARS-1, as shown in Figure 13.

Figure 13. Epinephrine Geometric Mean (±Standard Error) Plasma Concentration-Time Profiles in Subjects With Allergic Rhinitis Under Nasal Allergen Challenge Conditions by Predose Nasal Congestion Score (NCS) Subgroup Analysis in Comparison to Without Nasal Allergen Challenge

Source: Clinical Pharmacology Reviewer. Based on adpc.xpt and adyn.xpt of Study EPI 16. Pre-dose refers to prior to ARS-1 administration but after nasal allergen challenge.

Abbreviations: NAC, nasal allergen challenge, NCS, nasal congestion score

The PK of epinephrine in subjects with severe nasal congestion (NCS=3) prior to ARS-1 administration had a slightly faster absorption rate followed by a faster decline, in comparison to subjects with mild to moderate nasal congestion (NCS=1 or 2). In addition, the duration of nasal congestion was found to have

ARS Comment 33:

FDA correctly notes that the patients with severe nasal congestion (NCS = 3) prior to ARS-1 administration “had slightly faster absorption followed by faster decline, in comparison to subjects with mild to moderate nasal congestion (NCS = 1 or 2)”

However, as seen in comparison with Figure 11 reproduced below, this would imply that patients with severe nasal congestion (NCS = 3) are achieving even higher exposures than normal condition vs. Adrenalin 0.3 mg in the first 10 minutes, when a clinical response would be expected to be observed prior to giving a second dose.

Figure 11. Epinephrine Geometric Mean (±Standard Error) Plasma

Concentration-Time Profiles in Subjects With Allergic Rhinitis

Source: Clinical Pharmacology Reviewer. Based on adpc.xpt of Study EPI 16.

Three subjects in the Adrenalin 0.3 mg arm and one subject in ARS-1 with nasal challenge arm had insufficient number of postdose samples (n<3) within 30 min. Two subjects in the Adrenalin 0.3 mg arm, five subjects in the Adrenalin 0.5 mg arm, and two subjects in the ARS-1 with nasal challenge arm did not have pharmacokinetic data. This is the same figure as Figure 2 in Section 1.3.2.

Figure 14. Median PD Responses (SBP Change From Baseline) in Subjects With Allergic Rhinitis Following Nasal Allergen Challenge by Nasal Congestion Score Subgroup Analysis

Source: Clinical Pharmacology Reviewer. Based on adxd.xpt and adyn.xpt of Study EPI 16.

Error bars represent the 25% and 75% percentiles of the PD values.

Abbreviations: NAC, nasal allergen challenge; NCS, nasal congestion score; PD, pharmacodynamics; SBP, systolic blood pressure

ARS Comment 34:

We acknowledge that SBP response (median and error bars) in subjects with NCS 15 min = 0, or NCS 15 min = 2 or do not appear any different until at least 45 minutes.

However, data do not support that “nasal congestion longer than 30 min post-ARS-1 dosing demonstrated a lower SBP response compared to those with a shorter nasal congestion duration.”

As shown in Figure 12 below showing the comparison including injection, SBP response for the entire duration of 60 minutes irrespective of NCS 15 min = 0, or nasal congestion duration >30 minute or <30 minutes, does not appear to be any different from Adrenalin 0.3 mg from the same EPI-16 study.

Figure 12. Median PD Responses (SBP and PR Changes From Baseline) in Subjects With Allergic Rhinitis

Source: Clinical Pharmacology Reviewer. Based on adxd.xpt

of Study EPI 16. Subjects who were included in the PK

3.1.2.3.4   PK/PD Summary in Allergen-Induced Nasal Congestion

Overall, when ARS-1 was administered under nasal allergen challenge conditions, the epinephrine PK profile demonstrated an initial faster absorption phase followed by a faster decline phase compared with normal nasal conditions. The PD responses (median SBP and PR change from baseline) for ARS-1 under nasal allergen challenge conditions also demonstrated a similar pattern (i.e., higher response followed by faster decline) in comparison to normal nasal conditions. In addition, it appears that the nasal congestion severity and duration had an impact on epinephrine PK and PD profiles.

ARS Comment 35:

See ARS Comment 33 and ARS Comment 34.

ARS Comment 36:

See ARS Comment 16 regarding clinical relevance of second dose rhinitis study.

During the preparation of this briefing document, the Applicant submitted simulation data that modeled the epinephrine PK profile following the second dose of ARS-1 under the nasal congestion conditions. The Agency has not fully reviewed the modeling and simulation data. However, the Agency has serious concerns whether modeling and simulation can adequately represent the pathophysiology and pharmacology following a second ARS-1 dose under nasal edema conditions. If the AC panel thinks that additional data are necessary following a second dose of ARS-1 under nasal congestion conditions, we recommend a dedicated PK study to obtain these data.

3.1.2.4   ARS-1 PK/PD Data with Self-Administration

In all the previously discussed clinical pharmacology studies, the staff administered ARS-1 to subjects to reduce the PK variability by ensuring consistent administration. However, ARS-1 is proposed for self- administration and the impact of self-administration on the PK profile was a question raised during development of ARS-1. Therefore, the Division requested the Applicant to conduct an actual use PK study to characterize the epinephrine PK profiles in subjects following self-administration of ARS-1. Note that this self-administration PK assessment is different than the HF assessment, which is discussed in Section 6.2.

The impact of self-administration on the epinephrine PK profile was assessed in Study EPI 17 - a two- period, two-treatment, randomized, crossover study in adult patients with Type 1 allergies. Subjects (N=42) were randomized to receive either a single dose of self-administered ARS-1 or a single dose of staff-administered Adrenalin 0.3 mg. The concentration-time profiles for self-administered ARS-1, staff- administered Adrenalin 0.3 mg as well as staff-administered ARS-1 from Study EPI 15 are shown in Figure 15. Study EPI 17 did not include a staff-administered ARS-1 arm, so a cross-study comparison was performed.

Figure 15. Epinephrine Geometric Mean (±Standard Error) Plasma Concentration-Time Profiles Following a Single Dose of ARS-1 (Self-Administered), Adrenalin 0.3 mg (Staff-Administered) and Single Dose of ARS-1 (Staff-Administered From EPI 15)

 Source: Clinical Pharmacology Reviewer. Based on adpc.xpt of Study EPI 17 and EPI 15.

The epinephrine PK profile following self-administration of single dose ARS-1 was generally higher than that following staff-administered Adrenalin 0.3 mg. The cross-study comparison of the PK profile for ARS-1 between Study EPI 15 (staff-administered) and EPI 17 (self-administered) demonstrated a similar pattern.

ARS Comment 37:

Please refer to Figure 15 below.

Figure 15. Epinephrine Geometric Mean (±Standard Error) Plasma Concentration-Time Profiles Following a Single Dose of ARS-1 (Self-Administered), Adrenalin 0.3 mg (Staff-Administered) and Single Dose of ARS-1 (Staff-Administered From EPI 15)

·   The correlation between PK and PD was inconsistent in the ARS- development program; therefore, the Agency has focused its analyses on comparative PK studies, and views PD data as supportive.

ARS Comment 38:

Please refer to ARS Comment 6 containing Figure 7 regarding PD, which is reproduced below.

Figure 7. Median PD Responses (SBP, PR, and DBP Change from Baseline) Following a Single Dose of ARS-1, Adrenalin 0.3 mg, or EpiPen 0.3 mg in Healthy Subjects

Source: Clinical Pharmacology Reviewer. Based on adxd.xpt of Study EPI 15. Subjects who were included in the PK analysis were included in the PD analysis.

Error bars represent 25% and 75% percentile of the PD values.

Abbreviations: DBP, diastolic blood pressure; PD, pharmacodynamics; PK, pharmacokinetics; PR, pulse rate; SBP, systolic blood pressure

·   Anaphylaxis demonstrates rapid onset and fatalities frequently occur in the first 30 minutes after initiation; therefore, we focused our review and analyses on PK and PD comparisons in the first hour after initial dose is administered; we view analyses over a longer time period as less informative.

·   Presentation of PK and PD data as arithmetic means may obscure important differences; therefore, our analyses are presented as geometric means.

Healthy Volunteer Studies:

·   In the dose-ranging study, epinephrine mean concentration for ARS-1 2 mg, the highest dose studied, was higher than that of EpiPen starting approximately 15 min postdose and that of Symjepi starting approximately 10 min postdose. However, the epinephrine concentration for ARS-1 2 mg was lower than both injection products in the first 10 min following administration. The Applicant selected the 2 mg dose for their development program.

Whether higher doses may overcome the lower plasma concentrations in the first 10 to 15 min and the clinical significance of the delayed absorption is a topic for AC discussion.

ARS Comment 39:

Please refer to ARS Comment 37 regarding PK, as well as ARS Comment 15 regarding concerns about higher doses and exposures.

·   Epinephrine PK/PD profile following a single dose of ARS-1 is reasonably bracketed by Adrenalin and

EpiPen starting 10 min postdose in healthy subjects. However, a lower epinephrine concentration was generally observed following IN administration, within the first 10 min postdose, compared to all injection products, likely due to an initial slower absorption rate.

The significance of the lower PK in the first 10 minutes postdose and potential implications for efficacy in the setting of anaphylaxis is a topic for AC discussion.

ARS Comment 40:

Please refer to ARS comment 37 regarding PK including the first 10 min postdose.

·   Following repeat doses of ARS-1 in the same or opposite naris, the epinephrine exposure was similar to repeat doses of EpiPen 0.3 mg starting 20 min postdose in healthy subjects; however, in the first 20 minutes following administration, plasma epinephrine concentrations are lower for ARS-1, compared to EpiPen. This further implicates a slower initial absorption rate compared to that of EpiPen.

Conclusions regarding the lower epinephrine exposure with repeat-dose ARS-1 compared to EpiPen in the first 20 minutes after administration is limited as the repeat dose was not bracketed.

ARS Comment 41:

Please refer to ARS comment 5 regarding PK with repeat dosing.

·   The proportion of healthy subjects whose plasma epinephrine concentrations reached 100 pg/mL was less than 80% for ARS-1 following both single dose and repeat doses during the first 10 min after administration. A low proportion was also observed with Adrenalin 0.3 mg, but not with EpiPen 0.3 mg.

The clinical significance of this lower proportion of subjects who reached a threshold of 100 pg/mL is uncertain and is a topic for AC discussion.

ARS Comment 42:

Please refer to ARS comment 11 regarding FDA’s description of “arbitrary concentration thresholds.”

·   Higher PD responses (median SBP and PR change from baseline) are observed with both single-dose and repeat-dose ARS-1, in comparison to both Adrenalin and EpiPen, despite the ARS-1 PK profile being lower than that of EpiPen (see Sections 3.1.2.2.2 and 3.1.2.2.4 for more details).

ARS Comment 43:

Please refer to ARS comment 6.

·   Pediatric subjects who weighed greater than 30 kg and were treated with ARS-1 had similar epinephrine PK profiles compared to that of adults treated with the same dose for the first 15 minutes; post-15 minutes the PK curve in pediatric subjects was higher. Conversely, the pediatric PD responses (SBP and PR change from baseline) were slightly lower compared to adults (see Section 3.1.3 for more details).

Nasal Allergen Challenge Study

The nasal allergen challenge study was designed to mimic changes in nasal mucosa expected in anaphylaxis. As a result, the Agency considers PK/PD data from this study important as it is the only available data in a related model to support translation of PK/PD findings to anaphylaxis.

·   The epinephrine exposure of single dose ARS-1 in allergic rhinitis patients without nasal allergen challenge is within the range of single dose Adrenalin following two different approved doses (i.e., 0.3 mg and 0.5 mg).

·   Under nasal allergen challenge conditions, the epinephrine PK following ARS-1 increased more rapidly than the two Adrenalin dose arms (0.3 mg and 0.5 mg), followed by a rapid decline, resulting in the epinephrine concentrations being lower than all comparator arms 10 to 20 min postdose. PD responses followed the same pattern. We note that allergen-induced nasal congestion continued to be reported following IN epinephrine administration in up to 30% of participants, suggesting that nasal congestion conditions may persist for a second dose administration.

The PK/PD profile with repeat doses of ARS-1 under the nasal congested state has not been studied. Since up to 20% of patients with anaphylaxis require a second treatment with epinephrine injection products and since the PK and PD decline rapidly 10 minutes after ARS-1 administration in the nasal allergen challenge study, repeat doses of ARS-1 may be needed. Since repeat dose studies have not been performed in the nasal allergen challenge model, and proposed labeling includes repeating a dose if symptoms persist, there is residual uncertainty in the PK/PD response following a repeat dose and thus uncertainty about ARS-1 efficacy in the treatment of anaphylaxis. Whether additional dose- ranging or a repeat dose nasal allergen challenge study would be necessary is a topic for AC discussion.

ARS Comment 44:

Please refer to ARS comment 16 regarding clinical relevance of repeat dose nasal challenge study.

·   Baseline nasal congestion and rhinorrhea may impact absorption of ARS-1. Implications of these findings for treatment effectiveness in the general population is unclear.

ARS Comment 45:

Please refer to ARS comments 8, 16, 33 and 34 regarding nasal congestion and absorption.