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| FDA Briefing Document NDA/BLA# 214697 Drug name: ARS-1 (intranasal epinephrine) Applicant: ARS Pharmaceuticals Pulmonary-Allergy Drug Advisory Committee Meeting | FDA has posted an Addendum to Briefing Document on its website that was circulated to members of the AdCom | |||
| 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 |
The attached package contains background information prepared by the Food and
Drug Administration (FDA) for the panel members of the Advisory Committee. The FDA background package often contains assessments and/or conclusions and recommendations written by individual FDA reviewers. Such conclusions and recommendations do not
necessarily represent the final position of the individual reviewers, nor do they necessarily represent the final position of the Review Division or Office. We have brought NDA 214697, ARS-1, to this Advisory
Committee in order to gain the Committee s insights and opinions, and the background package may not include all issues relevant to the final regulatory recommendation and instead is intended to focus on issues identified by the Agency for
discussion by the Advisory Committee. The FDA will not issue a final determination on the issues at hand until input from the Advisory Committee process has been considered and all reviews have been finalized. The final determination may be affected
by issues not discussed at the Advisory Committee meeting.
| ARS COMMENT LEGEND | ||||||
| Green circle with number represents ARS commentary, and references to FDA s Addendum to Briefing Document | Red circle with number represents inclusion of correction from FDA s Errata to Briefing Document | |||||
| Blue circle with number beside highlighted content represents corresponding primary FDA briefing book material referenced in the ARS commentary |
| Table of Contents | 2 | |||
| Table of Tables | 3 | |||
| Table of Figures | 4 | |||
| Glossary | 6 | |||
| 1 Executive Summary/Draft Points for Consideration by the Advisory Committee | 7 | |||
| 1.1 Purpose/Objective of the AC Meeting | 7 | |||
| 1.2 Context for Issues to Be Discussed at the AC | 7 | |||
| 1.3 Brief Description of Issues for Discussion at the AC | 8 | |||
| 1.3.1 Key Aspects of Development Program of ARS-1 | 8 | |||
| 1.3.2 Key Results | 13 | |||
| 1.4 Summary and Draft Points for Consideration | 21 | |||
| 2 Introduction and Background | 22 | |||
| 2.1 Background of the Condition/Standard of Clinical Care | 22 | |||
| 2.1.1 Analysis of the Condition | 22 | |||
| 2.1.2 Barriers to Use of Epinephrine Injection Products | 23 | |||
| 2.1.3 Pharmacology of Epinephrine from the Literature | 24 | |||
| 2.2 Pertinent Drug Development and Regulatory History | 25 | |||
| 2.2.1 Epinephrine Regulatory History | 26 | |||
| 2.2.2 ARS Regulatory History | 28 | |||
| 3 Summary of Issues for the AC | 35 | |||
| 3.1 Efficacy Issues | 35 | |||
| 3.1.1 Sources of Data for Efficacy | 35 | |||
| 3.1.2 Clinical Pharmacology Summary | 38 | |||
| 3.1.3 ARS-1 Pediatric Development | 62 | |||
| 3.1.4 Summary of Efficacy Issues | 64 | |||
| 3.2 Safety Issues | 68 | |||
| 4 Benefit-Risk Framework | 70 | |||
| 5 References | 71 | |||
| 6 Appendix | 74 | |||
| 6.1 Nonclinical Supportive Data | 74 | |||
| 6.1.1 Nasal Mucosal Damage | 74 | |||
| 6.1.2 PK and Cardiovascular Assessment Under Anaphylaxis Condition in Dog | 74 | |||
| 6.2 Human Factors | 75 | |||
| 6.2.1 Human Factors Overview | 75 | |||
| 6.2.2 HFVS Conducted for NDA 214697 | 76 | |||
| 6.2.3 Human Factors Discussion and Conclusion | 84 |
| Table 1. Intranasal Epinephrine PK/PD Development Program | 8 | |||
| Table 4. ARS-1 Clinical Pharmacology Development Plan | 8 | |||
| Table 2. Approved Epinephrine Products | 26 | |||
| Table 3. Approved Doses of Epinephrine in the Medical and Community Settings | 27 | |||
| Table 4. ARS-1 Clinical Pharmacology Development Plan | 28 | |||
| Table 5. ARS Pharmacology Trials | 36 | |||
| Table 6. PK Parameters Following a Single Dose of ARS-1 vs. a Single Dose of Intramuscular Injection Using Adrenalin 0.3 mg or EpiPen 0.3 mg in Healthy Subjects | 44 | |||
| Table 7. Proportion of Subjects Who Failed to Reach 100 pg/mL Following a Single Dose of ARS-1 2, Adrenalin 0.3 mg, or EpiPen 0.3 mg | 45 | |||
| Table 8. Maximum Change of SBP From Baseline in 60 Min Following a Single Dose | 46 | |||
| Table 9. PK Parameters 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 | 48 | |||
| Table 10. 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 | 50 | |||
| Table 11. Maximum SBP Change From Baseline in 60 Min Following Repeat Doses | 51 | |||
| Table 12. Maximum SBP Change from Baseline in 60 Min In Subjects With Allergic Rhinitis | 55 | |||
| Table 13. Common Adverse Events Occurring at 3% Frequency in a Treatment Arm, Primary Safety Population, Safety Pooling (EPI 15, 16, 17) | ||||
| Table 14. Summary of HFVS #1 Results | 79 | |||
| Table 15. Summary of Supplemental HFVS #2 Results | 84 |
| 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 | 13 | |||
| Figure 2. Epinephrine Geometric Mean ( Standard Error) Plasma Concentration-Time Profiles in Subjects With Allergic Rhinitis | 14 | |||
| Figure 3. Epinephrine Geometric Mean Concentration-Time Profiles From Study EPI 11b | 38 | |||
| Figure 4. Epinephrine Geometric Mean ( Standard Error) Concentration-Time Profile for Single-Dose EpiPen 0.3 mg (A) and Single-Dose Adrenalin 0.3 mg (B) Across Studies in ARS-1 Clinical Program | 39 | |||
| Figure 5. Epinephrine Geometric Mean ( Standard Error) Concentration-Time Profile Following a Single Dose of ARS-1 vs. a Single Dose of Intramuscular Injection Using Adrenalin 0.3 mg or EpiPen 0.3 mg in Healthy Subjects | 43 | |||
| 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 | 44 | |||
| 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 | 46 | |||
| 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 | 47 | |||
| 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 | 50 | |||
| 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 | 51 | |||
| Figure 11. Epinephrine Geometric Mean ( Standard Error) Plasma Concentration-Time Profiles in Subjects With Allergic Rhinitis | 54 | |||
| Figure 12. Median PD Responses (SBP and PR Changes From Baseline) in Subjects With Allergic Rhinitis | 55 | |||
| 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 | 56 | |||
| Figure 14. Median PD Responses (SBP Change From Baseline) in Subjects With Allergic Rhinitis Following Nasal Allergen Challenge by Nasal Congestion Score Subgroup Analysis | 58 | |||
| 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) | 60 | |||
| Figure 16. Epinephrine Geometric Mean ( Standard Error) Plasma Concentration-Time Profiles Following a Self-Administered Single Dose of ARS-1 2 mg by Administration Issue (EPI 17) | 62 |
| Figure 17. Epinephrine Geometric Mean ( Standard Error) Plasma Concentration-Time Profiles Following a Single Dose of ARS-1 (1 mg or 2 mg) in Pediatric Subjects 30 kg and a Single Dose of ARS-1 (2 mg) in Adult Healthy Subjects From Study EPI 15 | 63 | |||
| Figure 18. Median PD Responses (SBP and PR Change From Baseline) Following a Single Dose of ARS-1 (1 mg or 2 mg) in Pediatric Subjects 30 kg and a Single Dose of ARS-1 (2 mg) in Adult Healthy Subjects From Study EPI 15 | 64 | |||
| Figure 19. Carton (Top); Blister Pack With QRG Printed on Back and Nasal Spray Device (Middle); IFU (Bottom) | 78 | |||
| Figure 20. QRG Evaluated in HFVS #1 (Left); Revised QRG (Right) | 80 | |||
| Figure 21. IFU Evaluated in HFVS #1 | 81 | |||
| Figure 22. Revised IFU | 82 |
| AC | Advisory Committee | |
| AUC | area under the concentration-time curve | |
| BP | blood pressure | |
| C max | maximum plasma concentration | |
| DBP | diastolic blood pressure | |
| FDA | Food and Drug Administration | |
| HF | human factors | |
| HFVS | human factors validation study | |
| HR | heart rate | |
| IFU | Instructions for Use | |
| IM | intramuscular | |
| IN | intranasal | |
| IV | intravenous | |
| NDA | new drug application | |
| PD | pharmacodynamic | |
| PK | pharmacokinetic | |
| PR | pulse rate | |
| QRG | quick reference guide | |
| SBP | systolic blood pressure | |
| T max | time to maximum plasma concentration | |
| URRA | use-related risk analysis |
| 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 | ||||
| ARS initiated discussions with the Division regarding their ARS-1 development program in 2018. ARS proposed a development program based upon PK/PD and safety data, comparing ARS-1 to approved epinephrine injection products; clinical efficacy trials were not included in the development program given the feasibility constraints of conducting such trials in anaphylaxis. ARS and the Division discussed clinical efficacy trial scenarios (see Section 2.2.2.2), all of which had limitations. While the Division recognized the challenges of conducting a clinical trial, it had concerns regarding the sufficiency of PK/PD data to support an anaphylaxis indication, and whether data from healthy volunteers would be similar in patients during an anaphylaxis episode. 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 the emergency treatment of allergic reactions (Type I) including anaphylaxis , as outlined in Table 1. Throughout the interactions with ARS, the Division noted areas of uncertainty with a PK/PD approach that would need discussion with an FDA AC panel. Each clinical pharmacology study was designed and conducted to address specific questions, as outlined below. | ||||
| Table 1. Intranasal Epinephrine PK/PD Development Program Table 2. ARS-1 Clinical Pharmacology Development Plan |
| PK/PD/Safety Trial | Purpose | |||||||
| Dose ranging (, 11b, ) | Determine an appropriate intranasal epinephrine dose compared to epinephrine injection based on PK similarity. | |||||||
| 1. FDA Errata to Briefing Document | PK matching (EPI 15) | Bracket the single-dose PK profile of intranasal epinephrine with epinephrine injection products with support of comparable safety and PD profiles. | ||||||
| Second dose (EPI 15) | Assess the PK/PD and safety of two doses of intranasal epinephrine compared to two doses of epinephrine injection. | |||||||
| Nasal allergen challenge (EPI 16) | Assess the effect of nasal congestion on the PK/PD and safety of intranasal epinephrine compared to epinephrine injection. | |||||||
| PK/PD/Safety Trial | Purpose | |||||||
| Self-administration (EPI 17) | Assess if self-administration of intranasal epinephrine spray changes the PK/PD and safety compared to epinephrine injection (staff-administered). | |||||||
| Pediatric PK (EPI 10) | Assess the PK/PD and safety of various doses of intranasal epinephrine in pediatric allergy subjects. |
| 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 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 2-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 2-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 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 |
| Table 3. Approved Epinephrine Products | ||||||||||
| Drug Product (Sponsor) | Year of Approval | Dosage Strength | Dosage Form | |||||||
| EpiPen/EpiPen JR (Mylan Specialty LP) | 1987 | 0.15 mg/injection 0.3 mg/injection | Single dose, autoinjector | |||||||
| Generic EpiPen/EpiPen JR (Teva) | 2018 | 0.15 mg/injection 0.3 mg/injection | Single dose, autoinjector | |||||||
| Adrenaclick and Authorized Generic (Impax Labs, Inc.) | 2003 | 0.15 mg/injection 0.3 mg/injection | Single dose, autoinjector | |||||||
| Auvi-Q (Kaleo, Inc.) | 2012 | 0.1 mg/injection 0.15 mg/injection 0.3 mg/injection | Single dose, autoinjector | |||||||
| Symjepi (Adamis Pharms Corp) | 2017 | 0.3 mg/0.3 mL | Single dose, prefilled syringe | |||||||
| Adrenalin and Epinephrine Injection (Multiple companies) Medical setting only | 2012 | 1 mg base/mL | Singe use and multidose vial |
| Body Weight | ||||||||||
| Epinephrine | 7.5 kg to 15 kg | 15 kg to 30 kg | 30 kg | |||||||
| Medical setting | 0.01 mg/kg (maximum dose 0.3 mg for subjects 7.5 to 30 kg) | 0.3 to 0.5 mg | ||||||||
| Community setting | 0.1 mg | 0.15 mg | 0.3 mg |
| PK/PD/Safety Trial | Purpose | |||||
| Dose ranging (EPI 11, 11b, 12) | Determine an appropriate intranasal epinephrine dose compared to epinephrine injection based on PK similarity. | |||||
| PK matching (EPI 15) | Bracket the single-dose PK profile of intranasal epinephrine with epinephrine injection products with support of comparable safety and PD profiles. | |||||
| Second dose (EPI 15) | Assess the PK/PD and safety of two doses of intranasal epinephrine compared to two doses of epinephrine injection. | |||||
| Nasal Allergen challenge (EPI 16) | Assess the effect of nasal congestion on the PK/PD and safety of intranasal epinephrine compared to epinephrine injection. | |||||
| Self-administration (EPI 17) | Assess if self-administration of intranasal epinephrine spray changes the PK/PD and safety compared to epinephrine injection (staff-administered). |
| 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 15: | ||||
| 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. | ||||
| 3. | Impact of IN Epinephrine on Absorption | |||
| Unlike the vasodilatory effect observed in skeletal muscle following IM injection of epinephrine, IN administration of epinephrine is expected to cause vasoconstriction in the nasal mucosa, a mechanism utilized by alpha adrenergic agonistic nasal decongestants. The Division questioned whether the absorption of a second IN dose of epinephrine, if needed, may be impaired due to local vasoconstriction following the first IN dose of epinephrine. Therefore, the Division requested ARS to evaluate and compare epinephrine PK profiles following a second dose, between ARS-1 and the listed epinephrine injection products. We note that the effect of IN epinephrine on the absorption of subsequent IN doses could differ between healthy volunteers and patients with anaphylaxis due to the pathophysiology of anaphylaxis, such as nasal mucosal edema, affecting epinephrine pharmacology. |
| 4. | 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. | ||||
| Please refer to ARS Comment 4. | ||||
| 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 |
2 See the Cross-Discipline Team Leader Review for Narcan Nasal Spray (NDA 208411) dated
20 January 2016, available at:
docs/nda/2015/208411Orig1s000CrossR.pdf.
3 See the FDA Review for Narcan Nasal Spray (NDA 208411) dated 9 November 2015, available at
docs/nda/2015/208411Orig1s000TOC.cfm.
Table 6. ARS Pharmacology Trials
| Study Name | Study Design | Objective of the Study | Test Product | Number of Subjects | Population | |||||
| EPI 11b | Phase 1, two-group, five-period, five-treatment, single-dose, crossover study | Assess the comparative bioavailability of different formulations of ARS-1 with various strengths of absorption enhancing excipient in healthy volunteers | 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 | Healthy subjects | |||||
| EPI 15 | Phase 1, two-part, six-treatment, six-period, single and repeat-dose crossover study | 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 | Healthy subjects |
| Study Name | Study Design | Objective of the Study | Test Product | Number of Subjects | Population | |||||
| EPI 16 | Phase 1, partially randomized, four-treatment, crossover study | 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 | Subjects with history of seasonal allergic rhinitis | |||||
| EPI 17 | Phase 1, single-dose, two-treatment, two-period, randomized crossover study | 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 | Subjects with Type I allergies (systemic reactions to food, insects or other venoms, drugs, urticaria, or rhinitis) | |||||
| EPI 10 | Phase 1, single-dose, single-treatment study | Assess the PK/PD of three doses of ARS in pediatric allergy subjects | 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 |
Source: FDA Clinical Reviewer.
Subjects who received at least one dose of treatment and have 3 PK samples after 30 min postdose were included in the PK analysis conducted by FDA.
The formulation used in EPI11b is not the final to-be-marketed formulation used
Abbreviations: IM, intramuscular; L, left; PD, pharmacodynamics; PK, pharmacokinetics; R, right
3.1.2 Clinical Pharmacology Summary
3.1.2.1 General PK Considerations
Study EPI 11b, designed to mitigate the carryover effect described in Section 2.2.2.1, is the dose-ranging study the Applicant used to support the dose selection of 2 mg; doses higher than 2 mg were not
evaluated in this study. EPI 11b was a single-dose, crossover study in healthy subjects to explore various doses of ARS-1 and with different formulations. The study adopted a design to administer ARS-1 with alternating nares between different IN treatment periods to ensure at least a 12-day washout period between two ARS-1
treatments given in the same naris to minimize the carryover effect. Two groups of subjects were evaluated in Study EPI 11b. In group 1, a total of 13 subjects were evaluated compared to Symjepi 0.3 mg in a crossover manner. In group 2, another 13
subjects were evaluated compared to EpiPen 0.3 mg, also in a crossover manner. The 2 mg ARS-1 dose was the highest dose studied.
The PK results from Epi11b are shown in Figure 3.
Figure 3. Epinephrine Geometric Mean Concentration-Time Profiles From Study EPI 11b
Source: Clinical Pharmacology Reviewer. Based on adpc.xpt for Study EPI 11b. All the
results are from group 2 in a crossover fashion except the Symjepi result from a separate group (group 1).
| 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. |
PK Comparison with the Approved Epinephrine Injection Products and Rationale for the PK Bracketing Approach
| 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 |
Figure 4. Epinephrine Geometric Mean ( Standard Error) Concentration-Time Profile
for Single-Dose EpiPen 0.3 mg (A) and Single-Dose Adrenalin 0.3 mg (B) Across Studies in ARS-1 Clinical Program
Source: Clinical Pharmacology Reviewer.
Adrenalin was administered by staff. Studies EPI 3, 4, 7 were clinical pharmacology studies that compared 1 mg ARS-1 with epinephrine injection products in healthy subjects; EPI 12 and 13 were clinical pharmacology studies conducted in patients with Type 1 allergies that evaluated 1 mg
ARS-1 and 2 mg ARS-1, respectively, in comparison to epinephrine injection products. Study 11b was dose-ranging study in healthy subjects that compared the
pharmacokinetics of multiple dose levels of ARS-1 with epinephrine injection products. Subjects with an insufficient number (< 3) of samples within 30 min postdose were excluded.
Abbreviations: All, staff and self-administration; self, self-administration; staff, staff administration
The cross-product PK comparison of epinephrine injection products generally demonstrated earlier Tmax, higher Cmax, and greater early partial AUCs for epinephrine following EpiPen IM injection compared to Adrenalin (needle-syringe) IM
injection. Given the paucity of available PK data, this observation was not
previously reported and the root cause is unknown. Since both products are approved for the treatment of anaphylaxis and there is no reported difference in efficacy, the Agency considered that
bracketing the ARS-1 PK profile by PK profiles of two different epinephrine injection products with different delivery systems (i.e., autoinjector versus needle-syringe) would be a reasonable approach to
establish a scientific and regulatory bridge between ARS-1 and approved epinephrine injection products. Moreover, although EpiPen demonstrates
higher intra-product PK variability, EpiPen is widely prescribed for community use and is therefore considered a clinically relevant comparison.
Baseline Epinephrine Considerations
The baseline concentration of epinephrine was collected at 10 and 5 min predose in all the clinical pharmacology studies in
the ARS-1 clinical program. The mean and median baseline concentrations were similar across all treatment periods (geometric mean: 17 to 22 pg/mL and median: 10 to 27 pg/mL) and treatment arms in all the
studies, and the values are close to the literature reported baseline epinephrine value of 35 pg/mL (Lake et al. 1984).
The Division agreed with the Applicant that it was not necessary to adjust
epinephrine plasma concentrations by baseline during the analysis for the following reasons: 1) the mean baseline epinephrine plasma concentrations were generally less than 10% of the mean Cmax
values following the epinephrine treatment; 2) a few subjects had some postdose epinephrine concentrations lower than their baseline values, which can result in negative baseline-adjusted values that become invalid for calculating geometric mean
values during the traditional PK analysis; 3) the baseline-uncorrected value of epinephrine plasma concentration is expected to be more clinically relevant during the PK/PD analysis. Instead, the mean/median baseline values by different treatment
arms should be listed for reference when PK results are reported.
Selection of Time Frame
Anaphylaxis is an acute life-threatening disease that presents with rapid onset. Data from fatal anaphylaxis cases suggest
that the interval between initial development of anaphylaxis and death can be <30 minutes. For example, registry data from the U.K. note that the median time interval between anaphylaxis onset and respiratory and cardiac arrest was 30 min in
food-induced fatal anaphylaxis cases (Pumphrey 2000). Thus, the Division focused our analysis on the first 60 min
postdose during the review.
Considerations for Presenting PK Results
3.1.2.2 ARS-1 PK/PD Under Normal
Study EPI 15 was a two-part, six-treatment, six-period, single and repeat dose, incomplete crossover PK/PD study. Part 1 was a single-dose comparative bioavailability study in which subjects (N=42) were
randomized to receive each of the following treatments in each period: a single IN dose of ARS-1 in the left naris, a single dose of EpiPen IM 0.3 mg in the left thigh, and a single dose of Adrenalin IM 0.3 mg
in the right thigh. The washout period between each treatment period was 24 hours.
Part 2 was a repeat-dose comparative
bioavailability study. Subjects (N=42) received two doses of either ARS-1 IN (same naris or opposite naris) or EpiPen IM 0.3 mg, separated by 10 min between each dose.
The study sequence adopted a sandwich design (ARS-1
EpiPen ARS-1) with a washout period of 6 days between each treatment period to mitigate the carryover effect. A
total of 26 subjects participated in both Part 1 and Part 2.
The purpose of this trial was to provide pivotal PK and PD
data comparing ARS-1 with epinephrine injection products (EpiPen 0.3 mg and Adrenalin 0.3 mg) following a single and repeat dose.
3.1.2.2.1 Single-Dose PK Results
For Part 1, the epinephrine concentration-time profiles within 60 min postdose and PK parameters