761085Orig1s000 - Food and Drug Administration · 2019. 2. 28. · 8. The current test volume for DS total aerobic microbial count (TAMC) is low and thus, the bioburden release test

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

761085Orig1s000

MULTI-DISCIPLINE REVIEW

Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review

Clinical Review and EvaluationMemorandum

Resubmission of BLA 761085

Supporting Document Number 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46Sponsor: Evolus, Inc.Drug: JEUVEAU (prabotulinumtoxin A)Proposed Indication: For the temporary improvement in the appearance

of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients.

Correspondence Date: 2-AUG-2018Review Date: 28-JAN-2019Reviewer: Gary T Chiang MD, MPH, DDDPTeam Lead: David Kettl MD, DDDPProject Manager: Matthew White

1. Introduction

1.1. Executive Summary

This application is a resubmission of the BLA in response to the Agency’s Complete Response (CR) letter dated 15-MAY-2018 for JEUVEAU (prabotulinumtoxin A), designated DWP-450, manufactured by Daewoong Pharmaceuticals (Evolus Inc.) for the treatment of temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adults.

The Agency CR letter list many deficiencies, all related to product quality and manufacturing issues:

Drug Substance:

1. The Clostridium botulinum culture purity

Provide the bacterial purity data from three batches. In addition, provide the limit and a description of the new test method.

2. You did not provide data to demonstrate that the DWP-450 drug substance (DS) is free of Clostridium botulinum spores. Provide spore monitoring data

Reference ID: 4381812

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BLA 761085JEUVEAU (prabotulinumtoxin A)

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3. You provided insufficient data to demonstrate that DWP-450 DS is free of Clostridium botulinum vegetative cells Provide monitoring data of Clostridium botulinum

4. You provided no in-process bioburden and endotoxin data to demonstrate adequate microbial control of the DWP-450 DS . Provide bioburden data

. In addition, provide the qualification data for the bioburden and endotoxin test methods . Furthermore, establish and provide limits for these bioburden and endotoxin samples.

5. You provided no bioburden and endotoxin data to demonstrate adequate microbial control . Provide microbiology

validation data at commercial scale to demonstrate effective microbial control .

6. You provided no microbiology validation data of the DWP450 DS to ensure adequate microbial control

. Provide microbiology validation data .

7. You did not establish endotoxin limits for the DWP450 DS . Establish and provide endotoxin limits for the DWP450 DS .

8. The current test volume for DS total aerobic microbial count (TAMC) is low and thus, the bioburden release test may not have sufficient sensitivity.

. Provide bioburden qualification data of the DS

and DS bioburden release data from three lots. Update the BLA with a description of the test method and the new DS bioburden specification.

Drug Product:

9. You performed validation using the DWP-450 DP vials. No information was provided to

assess . Demonstrate that DWP-450 commercial DP vials effectively reduces endotoxin by a minimum of 3 logs and provide summary data and the validation report in the BLA resubmission.

10. You did not perform validation of the worst-case parameters on the DWP-450 DP vials to ensure that commercial vials are sealed appropriately, and that container closure is integral. The vials used in the commercial manufacture of DWP-450 DP were not used to validate the process. In addition, worst-case

parameters were not used during validation. Submit container closure integrity data to support the proposed parameters in the BLA resubmission.

11. You performed the validation study with the DWP-450 DP vials. No information was provided to assess

. Demonstrate that DWP-450 DP vials is effective


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and provide summary data and the validation report in the BLA resubmission.

12. The maximum sterile hold for DWP-450 DP is not supported . Provide data to support the sterile hold of for

DWP-450 DP . Include a summary of the environmental monitoring data in the BLA resubmission.

13. You did not demonstrate that the container closure integrity test detects breaches that may allow for bacterial ingress. You did not include positive controls in the method validation. Submit information to demonstrate that the container closure integrity testing can detect breaches ≤ and include positive controls during routine testing.

14. You did not perform low endotoxin recovery testing of DWP-450 DP to assess whether the bacterial endotoxin test method can consistently detect endotoxin in the drug product. Certain product formulations have been reported to mask the detectability of endotoxin in the USP Bacterial Endotoxin Test (BET). Evaluate the effect of hold time on endotoxin detection by spiking a known amount of standard endotoxin (RSE or purified CSE) into undiluted DP and test for recoverable endotoxin over time

. Submit the report in the BLA resubmission.15. You did not routinely monitor bioburden to verify continued

microbial control of the drug product . Implement routine bioburden monitoring . In addition, provide a description of the bioburden test method and provide method qualification, summary data, and the qualification report.

Product Quality: Drug Substance and Drug Product:

16. Reference materials play a critical role in confirming the suitability of analytical tests and the quality of the product during release and stability testing. The information you provided in the BLA suggests that your DS reference material management program does not generate sufficient quantities of a given reference material lot to support all the required testing. Revise your reference material qualification procedures to ensure that you generate sufficient quantities of reference material to support all the necessary testing, including qualification of future reference materials. In addition, revise the DS reference material qualification and requalification protocol to include adequate stability monitoring of the reference materials.

17. In your December 1, 2017 response to the November 13, 2017 information request to update the DP stability testing protocols to include DP reconstitution time, it appears that additional changes were made to the post-approval stability protocol originally submitted in the BLA to remove the testing points at 3, 6, 9, and 18 months. You did not provide sufficient stability data to support a reduced stability testing program. Therefore, the updated annual post-approval stability protocol in section 3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment (Table 3.2.P.8.2-2) received on December 1, 2017 is not adequate to ensure that potential changes to commercial DP during storage are detected in a timely manner. Revise your annual stability protocol to include testing at 3, 6, 9, and 18 months as recommended by ICH Q5C guidelines.

18. In your March 9, 2018 response to the March 2, 2018 information request to describe Evolus’ role in DWP-450 lot release, you stated that some of Evolus’ quality responsibilities will be delegated via quality agreements and standard operating procedures (SOPs) to your “soon to be established distributor”. Your response indicates that the distributor may be responsible for: visual inspection for shipping or water damage; verification of release certifications (Certificate of Analysis) from Daewoong Pharmaceuticals Co., Ltd.; verification of shipment quantity and lots numbers; and


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verification that appropriate temperature was maintained during shipment. You also state that you will rely on the distributor’s SOPs and Quality Assurance unit for these activities. If your distributor is responsible for performing release operations for Evolus then they appear to fit the definition of a manufacturer rather than a distributor per 21 CFR 600.3 (t), (u), and (aa) and should be listed as a manufacturer in the license application.

The applicant provided a response to the CR letter deficiencies in their resubmission. The deficiencies have been remedied. There is no new safety or efficacy issues with the application. The completed biostatistical and clinical review has been finalized in the multi-review format and identified no issues which would preclude approval. No new clinical data was submitted as part of the current applicant response to the Complete Response letter.

This BLA application 761085, for JEUVEAU (botulinum toxin, Type A) is approvable from the clinical perspective.

1.2. Scientific and Regulatory Background

JEUVEAU (prabotulinumtoxin A) is manufactured by Daewoong Pharmacuetical Co., Ltd. of Seoul, South Korea and is a 900 kDa botulinum toxin produced by Clostridium botulinum that has the same structural characteristics, and physiochemical and biological properties as Botulinum toxin, Type A. This drug product, given the designation DWP-450 DP, has the same mechanism of action as other botulinum toxins in its class. When injected intramuscularly at therapeutic doses, botulinum toxin produces chemical denervation of the muscle resulting in localized reduction of muscle activity.

The proposed indication for this product is for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adults. Glabellar lines, or also known as frown lines, occur naturally with facial animation because of the impact on the skin from underlying facial musculature, predominantly the procerus and the corrugator supercilii muscles. 1 Other approved uses for the botulinum toxin include: treatment of urinary incontinence, prophylaxis of headaches in patients with chronic migraine, treatment of upper limb spasticity, cervical dystonia and primary axillary hyperhidrosis in adults, blepharospasm, strabismus in patients 12 years of age and above, temporary improvement of lateral canthal lines, and temporary improvement in the appearance of moderate to severe glabellar lines.

Botulinum toxin, Type A was first approved for the use in glabellar lines in 20022, since first approval, the use of botulinum toxin has become a common treatment option for glabellar lines resulting from underlying hyper-functional facial musculature. The pharmacological mechanism by which botulinum toxin, type A works is by blocking the release of the neurotransmitter acetylcholine into the neuromuscular junction, thereby decreasing muscle contractions.3

This product was given the name JEUVEAU (prabotulinumtoxin A) and was designated with the suffix -xvfs. Reviews of both the proprietary name and suffix was deemed acceptable by the Agency review teams.

1 Pierard GE, Lapiere CM. The microanatomical bases of facial frown lines. Arch Dermatol. 1989; 125:1090-2.2 Product Approval: Botulinum toxin, Type A (BOTOX); FDA BLA 103000/5000; April 12, 2002.3 Simpson LL. Current concepts on the mechanism of action of clostridial neurotoxins. In: DasGutpta BR, editor. Botulinum and tetanus neurotoxins. New York: Plenum Press;1993. p. 5-15.



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2. Re-Submission

2.1. CMC Product Quality (Drug Product):

We recommend approval of BLA 761085 from OBP’s product quality perspective. The complete response (CR) review issues regarding the product quality of the drug product (DP) manufacturing process and control strategy have been adequately addressed.

Product Quality Microbiology:The drug product portion of this BLA was reviewed from a sterility assurance and product quality microbiology standpoint and is recommended for approval.

Reviewers Comment:See OBP and Microbiology review for details. The issues outlined in the CR letter have been resolved. The recommendation is for approval.

2.2. Preclinical FindingsPlease see non-clinical review for details. No nonclinical information was included in the current submission.

3. Clinical Summary

3.1. Efficacy

The efficacy of DWP-450 DP was demonstrated in two pivotal clinical trials (EV-001 and EV-002), a 330-subject Phase 3 and a 324-subject Phase 3 clinical trial completed in the US. These two trials provide the primary supporting evidence for the safety and effectiveness of DWP-450 DP for the treatment of temporary improvement in the appearance of moderate to severe glabellar lines in adults. The studies were double-blind and randomized, comparing 20 units (U) of DWP-450 DP with 20 U BOTOX®, injected as 4 U/0.1 mL into each of 5 target sites in the glabellar region of adult subjects with moderate to severe glabellar lines. The primary endpoint was a composite of investigator and patient response on the Glabellar Line Score (GLS) at maximum frown. In addition, an EU pivotal Phase 3 safety and efficacy clinical trial was completed and submitted as supporting evidence. EV-003 represents foreign data with consideration to ICH-E5 regarding the appropriateness of extrapolating foreign data to the US population. Specifically, ethnic factors that impact the drug’s safety, efficacy, dosage, or dosing regimen in specific ethnic populations such as, Europeans, Japanese, African Americans, and Koreans. EV-003 also included an active comparator arm for BOTOX®.

The sponsor also completed 2 open-label, multiple-dose, long-term Phase 2 studies (EV-004 and EV-006) of 1-year duration in over 2100 adult male and female subjects with moderate to severe glabellar lines at maximum frown.

In the US pivotal EV-001 and EV-002 studies, the primary efficacy endpoint was defined as the proportion of subjects classified as responders on Day 30. This was a composite endpoint in which a responder was a subject with a ≥2-point improvement on the GLS from Day 0 to Day 30 at maximum frown, only if independently agreed by both Investigator and subject assessment.



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The percentages of responders in the ITT Population for the composite primary endpoint (a two-point composite) in each of the US controlled single dose studies were:

EV-001: 1.2% Placebo, 67.5% DWP-450 DP; Absolute difference 66.3%, 95% CI (59.0, 72.4)

EV-002: 1.3% Placebo, 70.4% DWP-450 DP; Absolute difference 69.1%, 95% CI (61.5, 75.1)

The primary efficacy endpoint in the EU pivotal EVB-003 study was defined as the proportion of subjects classified as responders on Day 30, where a responder was a subject with a GLS score of 0 or 1, by Investigator assessment at maximum frown.

Reviewer comment: The efficacy of the drug product was demonstrated in the clinical trials for this product. The full Biostatistical review is documented in the already completed multidiscipline-review.

3.2. Safety

The adverse events characteristics for botulinum toxin, Type A are well understood. The safety considerations are recommended by the Agency’s draft guidance documents entitled “Guidance for Industry. Upper Facial Lines: Developing Botulinum Toxin Drug Products”. The adverse events in the clinical trials were collected, including adverse events of special interest, treatment related adverse events, and possible hypersensitivity reactions. The safety population (any exposed to DWP-450 DP) totaled 2116 subjects who participated in the US/EU clinical development program (EV-001, EV-002, EV-003, EV-004, and EV-006). In all, 1659 received treatment with DWP-450 DP, 246 received treatment with BOTOX® (only in EV-003), and 211 received treatment with Placebo. In addition, 192/2116 (9.1%) subjects who were ≥65 years of age, including 154/1659 (9.3%) DWP-450 DP subjects, 19/246 (7.7%) BOTOX® subjects, and 19/211 (9.0%) Placebo subjects. Of the 1659 subjects treated with DWP-450 DP, 816 received a single treatment of 20 U (737 were in the three-controlled single-dose studies), 150 received a total of 2 treatments (i.e., 40 U), 325 received a total of 3 treatments (i.e., 60 U) and 368 received a total of 4 treatments (i.e., 80 U). All 737 subjects randomized to DWP-450 DP in the three-controlled single dose EV-001, EV-002 and EVB-003 studies received 20 U. The 922 subjects in the open-label multiple doses EV-004 and EV-006 studies received a mean total dose of 61.3 ± 18.98 U of DWP-450 DP; the median dose was 60 U – i.e., 3 treatments.

Headache was the most common adverse event and the only adverse event that occurred in ≥5% of DWP-450 DP subjects. Headache was also the most common adverse event assessed as related to study drug. The only other adverse events assessed as drug related that were reported in ≥1% of subjects were two eye disorders: eyelid ptosis reported by 1.0% (17/1659) of All DWP-450 DP subjects and eyelid sensory disorder reported by 1.6% (4/246) of BOTOX® subjects. A single subject died during the conduct of the five studies in the DWP-450 DP US/EU clinical development program. A serious adverse event reported as a drug overdose resulted in death. Altogether, 3 serious adverse events resulted in study discontinuation. One BOTOX® subject (1/246, 0.4%) discontinued the study due to cardiac valve fibroelastoma and the two DWP-450 DP subjects (2/1659, 0.1%) who discontinued the study due to a serious adverse event included one due to a transient ischemic attack (also considered to be an adverse event of special interest) and the other due to the previously noted unrelated drug overdose that resulted in the subject’s death. Adverse events of special interest were reported in 2.8%



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(47/1659) of All DWP-450 DP subjects and 1.6% (4/246) of BOTOX® subjects, compared with 0.5% (1/211) of pooled Placebo subjects. Eye disorders were the only system organ class with ≥1% of subjects with an adverse event of special interest: 1.9% (32/1659) of All DWP-450 DP subjects, 1.6% (4/246) of BOTOX® subjects, and no Placebo subjects. Eyelid ptosis was the only preferred term with ≥1% of subjects with an adverse event of special interest: 1.4% (24/1659) of All DWP-450 DP subjects and no Control subjects. None of the 25 events of eyelid ptosis reported in DWP-450 DP subjects were severe; 3 were moderate and the rest were mild. Eyelid ptosis is a complication that is known to occur as a result of treatment of glabellar lines with botulinum toxin. A total of 34 adverse events identified as possible hypersensitivity reactions were reported by 1.8% (30/1659) of subjects in the DWP-450 DP Pooled All group. A comparable 2.0% (5/246) of BOTOX® subjects reported 6 events and 1.4% (3/211) of Placebo subjects reported 3 events. None of the adverse events identified as possible hypersensitivity reactions were serious and none led to study discontinuation.

Most subjects were less than 65 years of age; 9.0% of all Placebo and 9.5% of all DWP-450 DP subjects were ≥65 years. Compared with those less than 65, the absolute difference in the percentages of responders between all DWP-450 DP and all Placebo subjects was 13.7% less for subjects 65 years of age and older (52.9% vs. 66.6%).

Reviewer comment: The relatively low risk profile of DWP-450 DP for the treatment of glabellar lines is supported by the safety data in the two US clinical trials, the EU clinical trial, and the long-term open-label studies. It is the opinion of this reviewer; the benefits of this product outweigh the risk for the temporary treatment of glabellar lines in adults.

3.3. Labeling Labeling negotiations with the applicant is ongoing. Final Physicians Insert and Patient Labeling will be available in the approval letter.

3.4. Pediatrics A full waiver is acceptable for children and adolescents under 18 years of age. See

multidisciplinary review for details of the pediatric waiver request.

4. Summary and Conclusions The applicant has addressed all the manufacturing and drug product concerns. It is this

reviewer’s opinion that JEUVEAU (prabotulinumtoxin A) should be approved for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adults pending final agreement on product labeling.

No PMC/PMR is recommended from clinical.

5. Recommended Regulatory Action

Approval


--------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically. Following this are manifestations of any and allelectronic signatures for this electronic record.--------------------------------------------------------------------------------------------/s/------------------------------------------------------------

GARY T CHIANG01/28/2019 09:24:07 AM

DAVID L KETTL01/28/2019 10:33:07 AM

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BLA Multi-Disciplinary Review and Evaluation (BLA 761085) DWP-450 (JEUVEAU)

1 (BLA 761085 JEUVEAU)

NDA/BLA Multi-Disciplinary Review and Evaluation Application Type Biological Licensing Application

Application Number(s) 761085Priority or Standard Standard

Submit Date(s) 12-MAY-2017Received Date(s) 15-MAY-2017

PDUFA Goal Date 15-MAY-2018Division/Office DDDP/ODE3

Review Completion Date See DARRTS electronic signature pageEstablished Name Botulinum toxin, type A

(Proposed) Trade Name JEUVEAUPharmacologic Class Neuromuscular inhibitor

Code name NA – Complete ResponseApplicant Evolus, Inc. by Daewoong Pharmaceutical Co., Ltd.

Formulation(s) For injection: 100 Units vacuum-dried powder in a single use vial for reconstitution

Dosing Regimen 0.1mL (4 units) by intramuscular injection into each of five sites, for a total dose of 20 units

Applicant Proposed Indication(s)/Population(s)

For the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients

Recommendation on Regulatory Action

Complete Response

Recommended Indication(s)/Population(s)

(if applicable)

For the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients




Table of Contents

Reviewers Team and Signature Approval Section ................................................................. 9

Additional Reviewers of Application ........................................................................................ 12

Glossary ....................................................................................................................................... 13

1 Executive Summary ............................................................................................................ 15 Product Introduction .................................................................................................... 15 Conclusions on the Substantial Evidence of Effectiveness .................................. 16 Benefit-Risk Assessment ........................................................................................... 18 Patient Experience Data ............................................................................................. 21

2 Therapeutic Context ........................................................................................................... 22 Analysis of Condition .................................................................................................. 22 Analysis of Current Treatment Options .................................................................... 22

3 Regulatory Background ..................................................................................................... 24 U.S. Regulatory Actions and Marketing History ..................................................... 24 Summary of Presubmission/Submission Regulatory Activity ............................... 24

4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ....................................................................................................... 25

Office of Scientific Investigations (OSI) .................................................................... 25 Product Quality ............................................................................................................ 25

Recommendation and Conclusion on Approvability ................................ 25 Summary of Complete Response Issues .................................................. 26 Complete Response Letter Language ....................................................... 26 Benefit/Risk Considerations ........................................................................ 30

Clinical Microbiology ................................................................................................... 31 Devices and Companion Diagnostic Issues ............................................................ 31

5 Nonclinical Pharmacology/Toxicology ............................................................................. 32 Executive Summary .................................................................................................... 32 Referenced NDAs, BLAs, DMFs ............................................................................... 33 Pharmacology .............................................................................................................. 33 ADME/PK ...................................................................................................................... 34




Toxicology ..................................................................................................................... 34 General Toxicology ....................................................................................... 34 Genetic Toxicology ....................................................................................... 45 Carcinogenicity .............................................................................................. 45 Reproductive and Developmental Toxicology .......................................... 46 Other Toxicology Studies ............................................................................ 46

Labeling ......................................................................................................................... 46

6 Clinical Pharmacology ........................................................................................................ 50 Executive Summary .................................................................................................... 50

Recommendations ........................................................................................ 50 Post-Marketing Requirements and Commitments ................................... 50

Summary of Clinical Pharmacology Assessment ................................................... 50 Pharmacology and Clinical Pharmacokinetics ......................................... 50

6.2.1.1. Mechanism of action and pharmacodynamics ......................................... 50 6.2.1.2. Pharmacokinetics .......................................................................................... 51 6.2.1.3. Drug interactions ........................................................................................... 516.2.1.4. Immunogenicity ............................................................................................. 51

General Dosing and Therapeutic Individualization .................................. 51 6.2.2.1. General dosing .............................................................................................. 51 6.2.2.2. Therapeutic individualization ....................................................................... 51

Outstanding Issues ....................................................................................... 51 Comprehensive Clinical Pharmacology Review ..................................................... 52

General Pharmacology and Immunogenicity ........................................... 52 Clinical Pharmacology Questions............................................................... 53

7 Statistical and Clinical and Evaluation ............................................................................. 56 Sources of Clinical Data and Review Strategy ....................................................... 56

Table of Clinical Studies .............................................................................. 56 Review Strategy ............................................................................................ 59

Review of Relevant Individual Trials Used to Support Efficacy ........................... 60 Pivotal Phase 3 Trials (Trials EV-001 and EV-002) ................................ 60

7.2.1.1. Study Design and Endpoints ....................................................................... 60 7.2.1.2. Statistical Methodologies ............................................................................. 61




7.2.1.3. Patient Disposition, Demographics and Baseline Disease Characteristics ................................................................................................................ 637.2.1.4. Results for the Primary Efficacy Endpoint ................................................ 66 7.2.1.5. Results for the Secondary Efficacy Endpoints ......................................... 68 7.2.1.6. Patient Reported Outcomes (PROs) ......................................................... 68 7.2.1.7. Efficacy Over Time ....................................................................................... 69 7.2.1.8. Agreement between Investigator’s and Subject’s Assessments ........... 72 7.2.1.9. Findings in Special/Subgroup Populations ............................................... 73 7.2.1.9.1. Sex, Race, Age and Baseline Disease Severity ................................... 73 7.2.1.9.2. Study Site .................................................................................................... 75

Review of Safety .......................................................................................................... 77 Safety Review Approach ............................................................................. 77 Review of the Safety Database .................................................................. 77 Adequacy of Applicant’s Clinical Safety Assessments ........................... 82 Safety Results ............................................................................................... 83 Analysis of Submission-Specific Safety Issues ........................................ 95 Safety Analyses by Demographic Subgroups .......................................... 95 Specific Safety Studies/Clinical Trials ....................................................... 98 Additional Safety Explorations .................................................................... 98 Safety in the Postmarket Setting ................................................................ 99

Integrated Assessment of Safety ............................................................... 99 SUMMARY AND CONCLUSIONS ........................................................................... 99

Statistical Issues ........................................................................................... 99 Conclusions and Recommendations ....................................................... 100

8 Advisory Committee Meeting and Other External Consultations .............................. 101

9 Pediatrics ............................................................................................................................ 102

10 Labeling Recommendations ............................................................................................ 103 Prescribing Information ......................................................................................... 103 Patient Labeling...................................................................................................... 121

11 Risk Evaluation and Mitigation Strategies (REMS) ..................................................... 122

12 Postmarketing Requirements and Commitments ........................................................ 122




13 Appendices ........................................................................................................................ 122 References .............................................................................................................. 122 Financial Disclosure .............................................................................................. 123 Clinical/Biostatistics ............................................................................................... 123 Nonclinical Pharmacology/Toxicology ................................................................ 124 OCP Appendices (Technical documents supporting OCP recommendations)

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14 Office Director (ODE III) ................................................................................................... 127




Table of Tables

Table 1: Patient Experience Data Relevant to this Application .......................................... 21 Table 2: FDA-Approved Treatment for Glabellar Lines ........................................................ 22 Table 3: Multiples of human exposure for NOAELs identified in pivotal toxicology studies....................................................................................................................................................... 48 Table 4: Summary of clinical pharmacology and immunogenicity of JEUVEAU. ............ 52 Table 5: Summary of immunogenicity results in subjects who had antibodies to DWP-450 in Phase 2 and Phase 3 clinical trials. ............................................................................ 54 Table 6: Tabular Listing of All Clinical Studies ...................................................................... 57 Table 7: Subject Disposition for Trials EV-001 and EV-002 ................................................ 63 Table 8: Baseline Demographics for Trials EV-001 and EV-002 (ITT).............................. 64 Table 9: Baseline Disease Severity for Trials EV-001 and EV-002 (ITT) ......................... 66 Table 10: Missing Data for the Primary Efficacy Endpoint at Day 30 (Trials EV-001 and EV-002 - ITT) .............................................................................................................................. 66 Table 11: Results for the Primary Efficacy Endpoint at Day 30 (Statistical Reviewer’s Analysis - MI) .............................................................................................................................. 67 Table 12: Results for the Primary Efficacy Endpoint at Day 30 (Applicant's Analysis based on Observed Data) ......................................................................................................... 67 Table 13: Results of the Primary Endpoint at Day 30 with Different Approaches for Handling Missing Data (Trials EV-001 and EV-002 – ITT) .................................................. 68 Table 14: Cross-tabulation of Investigator and Subject GLS Ratings at Maximum Frown at Baseline for Trials EV-001 and EV-002 ............................................................................. 72 Table 15: Cross-tabulation of Investigator and Subject GLS Ratings at Maximum Frown at Day 30 for Trials EV-001 and EV-002 (Observed Data) ................................................. 72 Table 16: Percentages of agreement/disagreement between Investigator and Subject GLS Ratings at Maximum Frown at Day 30 for Trials EV-001 and EV-002 (Observed Data) ............................................................................................................................................. 72 Table 17: Agreement in Success based on the Investigator and Subject assessment at Day 30 at Maximum Frown (DWP-450 Subjects) for Trials EV-001 and EV-002 (ITT -MI)....................................................................................................................................................... 73 Table 18: Baseline Demographics – Safety Population ....................................................... 79 Table 19: Baseline Glabellar Line Characteristics – Safety Population ............................ 81 Table 20: Treatment-Emergent Adverse Events by Severity – Safety Population .......... 84 Table 21: Summary of Severe Treatment-Emergent Adverse Events by System Organ Class and Preferred Term – Safety Population ..................................................................... 85 Table 22: Study Drug Related Treatment-Emergent Adverse Events as Assessed by Relationship – Safety Population ............................................................................................. 89 Table 23: Important Treatment-1% --Safety Population .............................................................................................................. 90 Table 24: Treatment-Emergent Adverse Events of Special Interest by SOC and PT –Safety Population ....................................................................................................................... 92 Table 25: Extent of Exposure (Units and Number of Treatments), Multiple Dose Studies Only, Overall and by Subgroups – Safety Population .......................................................... 96




Table 26. Dilution Instructions for PRODUCT NAME Vials (100 Units) ......................... 106

NAME Group Compared to the Placebo Group .................................................................. 110




Table of Figures

Figure 1: Injection Points for Trials EV-001 and EV-002 ..................................................... 60 Figure 2: Treatment Success Rates over Time for Trials EV-001 and EV-002 ............... 69 Figure 3: Success Rates on the Individual Assessment over Time (Trial EV-001) ........ 70 Figure 4: Success Rates on the Individual Assessment over Time (Trial EV-002) ........ 71 Figure 5: Forest Plot for the Composite Success at Day Center by Age, Gender, Race and Baseline GLS Score for Trial EV-001 (ITT - MI) ............................................................ 74 Figure 6: Forest Plot for the Composite Success at Day Center by Age, Gender, Race and Baseline GLS Score for Trial EV-002 (ITT - MI) ............................................................ 75 Figure 7: Results for the Primary Efficacy Endpoint (Composite Success) by Site (ITT, MI) for Trials EV-001 and EV-002 ........................................................................................... 76 Figure 8: Glabellar Line Scale (GLS) .................................................................................... 123




Reviewers Team and Signature Approval Section

DISCIPLINE REVIEWER OFFICE/DIVISIONSECTIONS

AUTHORED/ACKNOWLEDGED/

APPROVED


APPROVED

Product Quality Team Lead

Frances Namuswe, PhD DBRIII/OBP/OPQ 4.2

Select one: ____ Authored

____ Acknowledged

____ Approved

Signature:

Nonclinical Reviewer

Jianyong Wang, PhD ODE III/DDDP Sections 5 and 13.4


____ Acknowledged

____ Approved

Signature:

Nonclinical Supervisor

Barbara Hill, PhD ODE III/DDDP Sections 5 and 13.4


____ Acknowledged

____ Approved

Signature:

Clinical Pharmacology Reviewer

Jie Wang, PhD OCP/DCP III Section 6


____ Acknowledged

____ Approved


Frances Namuswe -SDigitally signed by Frances Namuswe -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 0.9.2342.19200300.100.1.1=0014299619, cn=Frances Namuswe -S Date: 2018.05.11 10:12:50 -04'00'

Barbara A. Hill -SDigitally signed by Barbara A. Hill -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 0.9.2342.19200300.100.1.1=1300098991, cn=Barbara A. Hill -S Date: 2018.05.11 10:44:28 -04'00'

Jianyong Wang -SDigitally signed by Jianyong Wang -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, cn=Jianyong Wang -S, 0.9.2342.19200300.100.1.1=1300213674 Date: 2018.05.14 14:12:03 -04'00'

Frances Namuswe -S

Digital y signed by Frances Namuswe S DN: c=US o=U S Government ou=HHS ou=FDA ou=People 0 9 2342 19200300 100 1 1=0014299619 cn=Frances Namuswe S Date: 2018 05 14 17 54:37 04'00'





APPROVED


APPROVED

Signature:

Clinical Pharmacology Team Leader/Division Director (DCPIII)

Chandrahas G Sahajwalla, PhD OCP/DCP III Section 6


____ Acknowledged

____ Approved

Signature:

BiostatisticsReviewer

Matthew Guerra, PhD OB/DB III

Sections: 7.1, 7.2, 7.4, and 13.3.


____ Acknowledged

____ Approved

Signature:

BiostatisticsReviewer

Marilena Flouri, PhD OB/DB III

Sections: 7.1, 7.2, 7.4, and 13.3.


____ Acknowledged

____ Approved

Signature:

Biostatistics Team Leader

Mohamed Alosh, PhD OB/DB III

Sections: 7.1, 7.2, 7.4, and 13.3.


____ Acknowledged

____ Approved

Signature:


Jie Wang -SDigitally signed by Jie Wang -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, cn=Jie Wang -S, 0.9.2342.19200300.100.1.1=2000739081 Date: 2018.05.11 12:38:46 -04'00'

Chandrahas G. Sahajwalla -S

Digitally signed by Chandrahas G. Sahajwalla -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 0.9.2342.19200300.100.1.1=1300079192, cn=Chandrahas G. Sahajwalla -S Date: 2018.05.11 14:43:37 -04'00'

Marilena Flouri -SDigitally signed by Marilena Flouri -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 0.9.2342.19200300.100.1.1=2002168509, cn=Marilena Flouri -S Date: 2018.05.14 11:58:22 -04'00'

Matthew W. Guerra -SDigitally signed by Matthew W. Guerra -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 0.9.2342.19200300.100.1.1=2000828126, cn=Matthew W. Guerra -S Date: 2018.05.14 12:02:42 -04'00'

Mohamed A. Alosh -SDigitally signed by Mohamed A. Alosh -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 0 9 2342.19200300.100.1.1=1300089441, cn=Mohamed A. Alosh -S Date: 2018.05.14 13:10:26 -04'00'





APPROVED


APPROVED

Acting Division Director (DBIII)

Laura Lee Johnson, PhD OB/DB III

Sections: 7.1, 7.2, 7.4, and 13.3.


____ Acknowledged

____ Approved

Signature:

ClinicalReviewer

Gary T. Chiang, MD, MPH ODE III/DDDP

Sections: 1, 2, 3, 7.3, 8, 9, 10, 11, 12,

13.1


____ Acknowledged

____ Approved

Signature:

Clinical Team Leader

David Kettl, MD ODE III/DDDPSections: 1, 2, 3,

7.3, 8, 9, 10, 11, 12, 13.1


____ Acknowledged

____ Approved

Signature:

Deputy Director

Jill A. Lindstrom, MD ODE III/DDDP

Entire Document(Approved)


____ Acknowledged

____ Approved

Signature:


Gary Chiang -SDigitally signed by Gary Chiang -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, cn=Gary Chiang -S, 0.9.2342.19200300.100.1.1=2000332370 Date: 2018.05.11 14:56:53 -04'00'

David L. Kettl -SDigitally signed by David L. Kettl -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, cn=David L. Kettl -S, 0.9.2342.19200300.100.1.1=1300383857 Date: 2018.05.14 10:58:59 -04'00'

Laura L. Johnson -SDigitally signed by Laura L. Johnson -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 0.9.2342.19200300.100.1.1=0011413414, cn=Laura L. Johnson -S Date: 2018.05.14 19:27:38 -04'00'

Kendall A. Marcus -SDigitally signed by Kendall A. Marcus -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 0.9.2342.19200300.100.1.1=1300160022, cn=Kendall A. Marcus -S Date: 2018.05.15 11:48:00 -04'00'





APPROVED


APPROVED

Director

Julie Beitz, MD ODE III

Section 14(Authored)

Entire Document(Approved)


____ Acknowledged

____ Approved

Signature:

Additional Reviewers of Application

OPQ Ennan Guan (Drug Substance)Davinna Ligons (Drug Product and Immunogenicity)Aimee Cunningham (Micro)Bo Chi (Micro)Viviana Matta (Facilities)Kelly Ballard (OPRO RPM)

OPDP Jina Kwak, PharmDOSI Bei Yu, PhDOSE/DEPI Michelle R. Iannacone, PhDOSE/DMEPA Carlos Mena-Grillasca, BSPharmOSE/DRISK Charlotte Jones, MD, PhD, MSPH

OPQ=Office of Pharmaceutical QualityOPDP=Office of Prescription Drug PromotionOSI=Office of Scientific InvestigationsOSE= Office of Surveillance and EpidemiologyDEPI= Division of EpidemiologyDMEPA=Division of Medication Error Prevention and AnalysisDRISK=Division of Risk Management


Julie G. Beitz -SDigitally signed by Julie G. Beitz -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, cn=Julie G. Beitz -S, 0.9.2342.19200300.100.1.1=1300090403 Date: 2018.05.15 12:07:31 -04'00'



Glossary

AC advisory committeeADME absorption, distribution, metabolism, excretion AE adverse eventBCA best case scenarioBLA biologics license applicationBPCA Best Pharmaceuticals for Children ActBRF Benefit Risk FrameworkCBER Center for Biologics Evaluation and ResearchCDER Center for Drug Evaluation and ResearchCDRH Center for Devices and Radiological HealthCDTL Cross-Discipline Team LeaderCFR Code of Federal RegulationsCMC Chemistry, Manufacturing, and ControlsCMH Cochran-Mantel-HaenszelCOSTART Coding Symbols for Thesaurus of Adverse Reaction TermsCRF case report formCRO contract research organizationCRT clinical review templateCSR clinical study reportCSS Controlled Substance StaffDDDP Division of Dermatology and Dental ProductsDHOT Division of Hematology Oncology ToxicologyDMC data monitoring committeeECG electrocardiogrameCTD electronic common technical documentETASU elements to assure safe useFDA Food and Drug AdministrationFDAAA Food and Drug Administration Amendments Act of 2007FDASIA Food and Drug Administration Safety and Innovation ActGCP good clinical practiceGLS Glabellar Line ScaleGRMP Good Review Management PracticeICH International Conference on HarmonizationIND Investigational New DrugISE integrated summary of effectivenessISS integrated summary of safetyITT intent to treatMCMC Markov Chain Monte CarloMedDRA Medical Dictionary for Regulatory ActivitiesMI multiple imputationNCI-CTCAE National Cancer Institute-Common Terminology Criteria for Adverse Event




NDA new drug applicationNME new molecular entityNRI non-responder imputationOCS Office of Computational ScienceODE Office of Drug EvaluationOPQ Office of Pharmaceutical QualityOSE Office of Surveillance and EpidemiologyOSI Office of Scientific InvestigationPBRER Periodic Benefit-Risk Evaluation ReportPD pharmacodynamicsPI prescribing informationPK pharmacokineticsPMC postmarketing commitmentPMR postmarketing requirementPP per protocolPPI patient package insertPREA Pediatric Research Equity ActPRO patient reported outcomePSUR Periodic Safety Update reportREMS risk evaluation and mitigation strategySAE serious adverse eventSAP statistical analysis planSGE special government employeeSOC standard of careSPA Special Protocol AssessmentTEAE treatment emergent adverse eventWCS worst case scenario




1 Executive Summary

Product Introduction

Botulinum toxin type A manufactured by Daewoong Pharmaceutical Co., Ltd. of Seoul, South Korea is a 900 kDa botulinum toxin produced by Clostridium botulinum and is claimed to have the same structural characteristics, and physiochemical and biological properties as botulinum toxin, type A. This drug product, given the designation DWP-450 or JEUVEAU (botulinum toxin type A), has the same mechanism of action as otherbotulinum toxins in its class. When injected intramuscularly at therapeutic doses, botulinum toxins produce chemical denervation of the muscle resulting in localized reduction of muscle activity.

The proposed indication for this product is for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adults. Glabellar lines, or also known as frown lines, occur naturally with facial animation because of the impact on the skin from underlying facial musculature, predominantly the procerus and the corrugator supercilii muscles.

Other approved uses for the botulinum toxin include: treatment of urinary incontinence, prophylaxis of headaches in patients with chronic migraine, treatment of upper limb spasticity, cervical dystonia and primary axillary hyperhidrosis in adults, blepharospasm, strabismus in patients 12 years of age and above, temporary improvement of lateral canthal lines, and temporary improvement in the appearance of moderate to severe glabellar lines.

Botulinum toxin type A was first approved for the use in glabellar lines in 2002; since first approval, the use of botulinum toxin has become a common treatment option for glabellar lines resulting from underlying hyper-functional facial musculature. The pharmacological mechanism by which botulinum toxin type A works is by blocking the release of the neurotransmitter acetylcholine into the neuromuscular junction, thereby decreasing muscle contractions.




Conclusions on the Substantial Evidence of Effectiveness

The efficacy of JEUVEAU (botulinum toxin type A) was demonstrated in two pivotal clinical trials (EV-001 and EV-002), a 330-subject and a 324-subject Phase 3 clinical trial completed in the US. These two trials provide the primary supporting evidence for the safety and effectiveness of JEUVEAU for the treatment of temporary improvement in the appearance of moderate to severe glabellar lines in adults.

The trials were double-blind and randomized, comparing 20 units (U) of JEUVEAU with placebo, injected as 4 U/0.1 mL into each of 5 target sites in the glabellar region of adult subjects with moderate to severe glabellar lines. The primary endpoint was a composite of investigator and subject response on the Glabellar Line Score (GLS) at maximum frown. In addition, an EU pivotal Phase 3 safety, efficacy, and comparison to an active arm (Botox®) clinical trial was completed and submitted as supporting evidence.

EV-003 represents foreign data with consideration to ICH-E5 regarding the appropriateness of extrapolating foreign data to the US population, specifically, ethnic factors that impact the drug’s safety, efficacy, dosage, or dosing regimen in specific ethnic populations such as, Europeans, Japanese, African Americans, and Koreans. EV-003 also included an active comparator arm for Botox® (onabotulinumtoxinA) approved by the FDA for glabellar lines in October 2017.

The sponsor also completed two open-label, multiple-dose, long-term Phase 2 studies (EV-004 and EV-006) of 1-year duration in over 2100 adult male and female subjects with moderate to severe glabellar lines at maximum frown.

In the US pivotal EV-001 and EV-002 clinical trials, the primary efficacy endpoint was defined as the proportion of subjects classified as responders on Day 30. This was a

-point improvement on the GLS from Day 0 to Day 30 at maximum frown, only if independently agreed by both Investigator and subject assessment. The percentages of responders in the ITT Population for the composite primary endpoint (a two-point composite) in each of the US controlled single dose studies were:

EV-001: 1.2% Placebo, 67.5% JEUVEAU (botulinum toxin type A); Absolute difference 66.3%, 95% CI (59.0, 72.4)EV-002: 1.3% Placebo, 70.4% JEUVEAU (botulinum toxin type A); Absolute difference 69.1%, 95% CI (61.5, 75.1)

The primary efficacy endpoint in the EU pivotal EVB-003 study was defined as the proportion of subjects classified as responders on Day 30, where a responder was a subject with a GLS score of 0 or 1, by Investigator assessment at maximum frown.

From a Clinical perspective, the BLA for JEUVEAU (botulinum toxin type A) is approvable for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult




patients at a dose of 0.1 mL (4 Units) by intramuscular injector into each of five sites, for a total dose of 20 Units. However, the Office of Pharmaceutical Quality (OPQ) recommends a Complete Response (CR) due to the lack of information required to ensure product quality.


BLA

Mul

ti-Di

scip

linar

y Re

view

and

Eva

luat

ion

(BLA

761

085)

DW

P-45

0 (JE

UVE

AU)

18

(BLA

761

085

JEUV

EAU)

Ben

efit-

Ris

k A

sses

smen

t

Ben

efit-

Ris

k Su

mm

ary

and

Asse

ssm

ent

JEU

VEAU

(bot

ulin

um to

xin

type

A)i

s a

botu

linum

toxi

nty

pe A

man

ufac

ture

d by

Dae

woo

ng P

harm

aceu

tical

Co.

, Ltd

. of S

eoul

, Sou

th K

orea

that

ha

s th

e sa

me

stru

ctur

al c

hara

cter

istic

san

d ph

ysic

oche

mic

al a

nd b

iolo

gica

l pro

perti

es a

s bo

tulin

um to

xin

type

A. W

hen

inje

cted

intra

mus

cula

rly

at th

erap

eutic

dos

es, b

otul

inum

toxi

n pr

oduc

es c

hem

ical

den

erva

tion

of th

e m

uscl

e re

sulti

ng in

loca

lized

redu

ctio

n of

mus

cle

activ

ity.

The

indi

catio

n so

ught

for t

his

prod

uct i

s fo

r the

tem

pora

ry im

prov

emen

t in

the

appe

aran

ce o

f mod

erat

e to

sev

ere

glab

ella

r lin

es a

ssoc

iate

d w

ith

corr

ugat

or a

nd/o

r pro

ceru

s m

uscl

e ac

tivity

in a

dults

. The

effi

cacy

of J

EUVE

AU w

as d

emon

stra

ted

in tw

o pi

vota

l, do

uble

-blin

d, ra

ndom

ized

cl

inic

al tr

ials

(EV-

001

and

EV-0

02),

a 33

0-su

bjec

t Pha

se 3

and

a 3

24-s

ubje

ct P

hase

3 c

linic

al tr

ial c

ompl

eted

in th

e U

S. T

he P

hase

3 c

linic

al

2-po

int i

mpr

ovem

ent o

n th

e G

LS fr

om D

ay 0

to D

ay 3

0 at

m

axim

um fr

own,

onl

y if

inde

pend

ently

agr

eed

by b

oth

Inve

stig

ator

and

sub

ject

ass

essm

ent.

The

abs

olut

e di

ffere

nce

of re

spon

ders

in th

e IT

T Po

pula

tion

for t

he c

ompo

site

prim

ary

endp

oint

(a tw

o-po

int c

ompo

site

) in

each

of t

he U

S co

ntro

lled

sing

le d

ose

trial

sw

ere

66.3

% (9

5%C

I 59.

0,

72.4

) for

EV-

001

and

69.1

% (9

5%C

I 61.

5, 7

5.1)

for E

V-00

2. I

n ad

ditio

n, a

n EU

stu

dyw

as c

ondu

cted

and

sub

mitt

ed (E

V-00

3) a

s su

ppor

ting

safe

ty a

nd e

ffica

cy fo

r JEU

VEAU

.

The

adve

rse

even

t cha

ract

eris

tics

for b

otul

inum

toxi

nty

pe A

are

wel

l und

erst

ood.

The

saf

ety

cons

ider

atio

ns a

re re

com

men

ded

by th

e Ag

ency

’s

draf

t gui

danc

e do

cum

ents

ent

itled

“Gui

danc

e fo

r Ind

ustry

. Upp

er F

acia

l Lin

es: D

evel

opin

g B

otul

inum

Tox

in D

rug

Prod

ucts

”. Th

e ad

vers

e ev

ents

in

the

clin

ical

tria

ls w

ere

colle

cted

, inc

ludi

ng a

dver

se e

vent

s of

spe

cial

inte

rest

, tre

atm

ent r

elat

ed a

dver

se e

vent

s, a

nd p

ossi

ble

hype

rsen

sitiv

ity

reac

tions

. Th

e sa

fety

pop

ulat

ion

(any

exp

osed

to J

EUVE

AU) t

otal

ed 2

116

subj

ects

who

par

ticip

ated

in th

e U

S/EU

clin

ical

dev

elop

men

t pro

gram

(E

V-00

1, E

V-00

2, E

V-00

3, E

V-00

4, a

nd E

V-00

6). I

n al

l, 16

59 re

ceiv

ed tr

eatm

ent w

ith J

EUVE

AU, 2

46 re

ceiv

ed tr

eatm

ent w

ith B

otox

®(o

nly

in

EV-0

03),

and

211

rece

ived

trea

tmen

t with

Pla

cebo

. In

addi

tion,

19

65 y

ears

of a

ge, i

nclu

ding

154

/165

9 (9

.3%

) JEU

VEAU

sub

ject

s, 1

9/24

6 (7

.7%

) Bot

ox®

sub

ject

s, a

nd 1

9/21

1 (9

.0%

) Pla

cebo

sub

ject

s. O

f the

165

9 su

bjec

ts tr

eate

d w

ith J

EUVE

AU,

816

rece

ived

a s

ingl

e tre

atm

ent o

f 20

U (7

37 w

ere

in th

e 3-

cont

rolle

d si

ngle

-dos

e st

udie

s), 1

50 re

ceiv

ed a

tota

l of 2

trea

tmen

ts (i

.e.,

40 U

), 32

5 re

ceiv

ed a

tota

l of 3

trea

tmen

ts (i

.e.,

60 U

) and

368

rece

ived

a to

tal o

f 4 tr

eatm

ents

(i.e

., 80

U).

All 7

37 s

ubje

cts

rand

omiz

ed to

JEU

VEAU

in th

e 3-

cont

rolle

dsi

ngle

dos

e EV

-001

, EV-

002

and

EVB-

003

stud

ies

rece

ived

20

U. T

he 9

22 s

ubje

cts

in th

e op

en-la

bel m

ultip

le d

oses

EV-

004

and

EV-0

06 s

tudi

es re

ceiv

ed a

mea

n to

tal d

ose

of 6

1.3

± 18

.98

U o

f JEU

VEAU

; the

med

ian

dose

was

60

U –

i.e.,

3 tre

atm

ents

.

Hea

dach

e w

as5%

of J

EUVE

AUsu

bjec

ts. H

eada

che

was

als

o th

e m

ost c

omm

on a

dver

se e

vent

ass

esse

d as

rela

ted

to s

tudy

dru

g. T

he o

nly

othe

r adv

erse

eve

nts

asse

ssed

as

drug

rela

ted

that

wer

e re

porte

d1%

of s

ubje

cts

wer

e tw

o ey

e di

sord

ers:

eye

lid p

tosi

s re

porte

d by

1.0

% (1

7/16

59) o

f All

JEU

VEAU

subj

ects

and

eye

lid s

enso

ry d

isor

der

repo

rted

by 1

.6%

(4/2

46) o

f BO

TOX

® s

ubje

cts.

A s

ingl

e su

bjec

t die

d du

ring

the

cond

uct o

f the

five

stu

dies

in th

e JE

UVE

AU U

S/EU

clin

ical

de

velo

pmen

t pro

gram

. A s

erio

us a

dver

se e

vent

repo

rted

as a

dru

g ov

erdo

se re

sulte

d in

dea

th. A

ltoge

ther

, 3 s

erio

us a

dver

se e

vent

s re

sulte

d in

st

udy

disc

ontin

uatio

n. O

ne B

otox

®su

bjec

t (1/

246,

0.4

%) d

isco

ntin

ued

the

stud

y du

e to

car

diac

val

ve fi

broe

last

oma

and

the

two

JEU

VEAU

Ref

eren

ce ID

: 426

3152

BLA

Mul

ti-Di

scip

linar

y Re

view

and

Eva

luat

ion

(BLA

761

085)

DW

P-45

0 (JE

UVE

AU)

19

(BLA

761

085

JEUV

EAU)

subj

ects

(2/1

659,

0.1

%) w

ho d

isco

ntin

ued

the

stud

y du

e to

a s

erio

us a

dver

se e

vent

incl

uded

one

due

to a

tran

sien

t isc

hem

ic a

ttack

(als

o co

nsid

ered

to b

e an

adv

erse

eve

nt o

f spe

cial

inte

rest

) and

the

othe

r due

to th

e pr

evio

usly

not

ed u

nrel

ated

dru

g ov

erdo

se th

at re

sulte

d in

the

subj

ect’s

dea

th. A

dver

se e

vent

s of

spe

cial

inte

rest

wer

e re

porte

d in

2.8

% (4

7/16

59) o

f All

JEU

VEAU

sub

ject

s an

d 1.

6% (4

/246

) of B

otox

®

subj

ects

, com

pare

d w

ith 0

.5%

(1/2

11) o

f poo

led

Plac

ebo

subj

e1%

of s

ubje

cts

with

an

adv

erse

eve

nt o

f spe

cial

inte

rest

: 1.9

% (3

2/16

59) o

f All

JEU

VEAU

sub

ject

s, 1

.6%

(4/2

46) o

f Bot

ox®

subj

ects

, and

no

Plac

ebo

subj

ects

. Ey

elid

pto

sis

was

the

only

pre

ferr

ed te

rm1%

of s

ubje

cts

with

an

adve

rse

even

t of s

peci

al in

tere

st: 1

.4%

(24/

1659

) of A

ll JE

UVE

AU

subj

ects

and

no

Con

trol s

ubje

cts.

Non

e of

the

25 e

vent

s of

eye

lid p

tosi

s re

porte

d in

JEU

VEAU

sub

ject

s w

ere

seve

re; 3

wer

e m

oder

ate

and

the

rest

wer

e m

ild. E

yelid

pto

sis

is a

com

plic

atio

n th

at is

kno

wn

to o

ccur

bec

ause

of t

reat

men

t of g

labe

llar l

ines

with

bot

ulin

umto

xin.

A to

tal o

f 34

adve

rse

even

ts id

entif

ied

as p

ossi

ble

hype

rsen

sitiv

ity re

actio

ns w

ere

repo

rted

by 1

.8%

(30/

1659

) of s

ubje

cts

in th

e JE

UVE

AU p

oole

d Al

l gro

up.

Aco

mpa

rabl

e 2.

0% (5

/246

) of B

otox

®su

bjec

ts re

porte

d 6

even

ts a

nd 1

.4%

(3/2

11) o

f Pla

cebo

sub

ject

s re

porte

d 3

even

ts. N

one

of th

e ad

vers

e ev

ents

iden

tifie

d as

pos

sibl

e hy

pers

ensi

tivity

reac

tions

wer

e se

rious

and

non

e le

d to

stu

dy d

isco

ntin

uatio

n.

The

maj

ority

ofs

ubje

cts

wer

e le

ss th

an 6

5 ye

ars

of a

ge; 9

.0%

of a

ll Pl

aceb

o an

d 9.

5% o

f all

JEU

VEAU

th

ose

less

than

65,

the

abso

lute

diff

eren

ce in

the

perc

enta

ges

of re

spon

ders

bet

wee

n al

l JEU

VEAU

and

all

Plac

ebo

subj

ects

was

13.

7% le

ss fo

r su

bjec

ts 6

5 ye

ars

of a

ge a

nd o

lder

(52.

9% v

s. 6

6.6%

).

In s

umm

ary,

the

rela

tivel

yto

lera

ble

safe

ty p

rofil

e of

JEU

VEAU

for t

he tr

eatm

ent o

f gla

bella

r lin

es is

sup

porte

d by

the

safe

ty d

ata

in th

e tw

o U

S cl

inic

al tr

ials

, the

EU

clin

ical

stu

dy, a

nd th

e lo

ng-te

rm o

pen-

labe

l stu

dies

. Th

e cl

inic

al s

tudi

es c

ondu

cted

sup

port

the

conc

lusi

on th

atth

e cl

inic

al

bene

fits

of th

is p

rodu

ct o

utw

eigh

the

iden

tifie

d ris

ksof

trea

tmen

t of g

labe

llar l

ines

in a

dults

. H

owev

er,p

rodu

ct q

ualit

y an

d m

icro

biol

ogy

defic

ienc

ies

prec

lude

mar

ketin

g ap

prov

alat

this

tim

e.A

Com

plet

e R

espo

nse

lette

r will

be is

sued

des

crib

ing

thes

e de

ficie

ncie

s in

det

ail.

Dim

ensi

onEv

iden

ce a

nd U

ncer

tain

ties

Con

clus

ions

and

Rea

sons

Anal

ysis

of

Con

ditio

n

Gla

bella

r lin

es, o

r fro

wn

lines

, occ

ur n

atur

ally

with

faci

al a

nim

atio

n be

caus

e of

the

impa

ct o

n th

e sk

in fr

om u

nder

lyin

g fa

cial

m

uscu

latu

re, p

redo

min

antly

the

proc

erus

and

the

corr

ugat

or

supe

rcilii

mus

cles

. Te

mpo

rary

den

erva

tion

of th

ese

mus

cles

resu

lts

in lo

caliz

ed re

duct

ion

of m

uscl

e ac

tivity

and

ther

efor

e re

duct

ion

of

the

glab

ella

r lin

es.

Red

uctio

n of

gla

bella

r lin

es b

y bo

tulin

um to

xin

inje

ctio

ns, f

or a

esth

etic

pur

pose

s, h

asbe

com

e a

com

mon

trea

tmen

t opt

ion

sinc

e 20

02 w

hen

the

first

bot

ulin

um to

xin

was

app

rove

d fo

r thi

s in

dica

tion.

Ref

eren

ce ID

: 426

3152

BLA

Mul

ti-Di

scip

linar

y Re

view

and

Eva

luat

ion

(BLA

761

085)

DW

P-45

0 (JE

UVE

AU)

20

(BLA

761

085

JEUV

EAU)

Dim

ensi

onEv

iden

ce a

nd U

ncer

tain

ties

Con

clus

ions

and

Rea

sons

Cur

rent

Tr

eatm

ent

Opt

ions

Ther

e ar

e se

vera

l pot

entia

l tre

atm

ents

for g

labe

llar l

ines

. Sur

gica

l re

leas

e of

the

mus

cles

is p

ossi

ble;

how

ever

, it i

s in

vasi

ve, c

an

caus

e sc

arin

g an

d is

non

-rev

ersi

ble.

Non

surg

ical

trea

tmen

ts a

re

less

inva

sive

, but

do

not a

ddre

ss th

e un

derly

ing

mus

cula

ture

re

spon

sibl

e fo

r the

faci

al li

nes.

Col

lage

n, h

yalu

roni

c ac

id a

nd fa

t im

plan

ts c

an te

mpo

raril

y fil

l the

line

or p

lum

p th

e gl

abel

lar a

rea;

ho

wev

er, t

his

is a

dan

gero

us a

rea

to in

ject

any

type

of f

iller o

r bul

k ag

ent s

ince

the

unde

rlyin

g va

scul

atur

e is

con

nect

ed to

the

retin

al

bloo

d su

pply

, and

em

bolic

dam

age

to th

e re

tina

and

optic

ner

ve

resu

lting

in b

lindn

ess

has

been

repo

rted

afte

r fat

inje

ctio

ns.

Botu

linum

toxi

n in

ject

ions

pro

duce

chem

ical

de

nerv

atio

n of

the

mus

cles

resu

lting

in

loca

lized

redu

ctio

n of

mus

cle

activ

ity th

at in

te

mpo

rary

. Th

is a

llow

s th

e ph

ysic

ian

to ta

ilor

the

use

of b

otul

inum

toxi

n to

the

clin

ical

pr

esen

tatio

n an

d de

sire

d ou

tcom

es o

f the

patie

nt.

Ben

efit

The

key

bene

fit o

f JEU

VEAU

is a

esth

etic

(i.e

., an

impr

ovem

ent i

n th

e ap

pear

ance

of g

labe

llar l

ines

), of

impo

rtanc

e to

pat

ient

s w

ho s

eek

out t

his

type

of t

reat

men

t.

The

botu

linum

toxi

n pr

oduc

t is

a te

mpo

rary

ef

fect

and

can

be

disc

ontin

ued

if ad

vers

e re

actio

ns o

ccur

. O

ther

trea

tmen

ts, s

uch

as

surg

ical

inte

rven

tion,

are

mor

e in

vasi

ve.

Ris

k

Mos

t of t

he a

dver

se e

vent

s ob

serv

ed in

the

clin

ical

stu

dies

wer

e no

t as

sess

ed b

y ei

ther

the

appl

ican

t or t

he re

view

team

to b

e dr

ug

rela

ted

and

mos

t wer

e ei

ther

min

or o

r mod

erat

e in

sev

erity

. The

re

wer

e no

ser

ious

adv

erse

eve

nts

rela

ted

to th

e dr

ug a

nd d

rop

outs

du

e to

dru

g re

late

d ad

vers

e ev

ents

wer

e ve

ry lo

w. T

here

wer

e on

ly

two

drug

rela

ted

adve

rse

even

ts w

ith a

freq

uenc

y of

1%

or g

reat

er,

head

ache

and

eye

lid p

tosi

s. L

abel

ing

will

inco

rpor

ate

all r

elev

ant

war

ning

s an

d pr

ecau

tions

est

ablis

hed

from

the

hist

oric

al u

se o

f bo

tulin

um to

xin.

N

umer

ous

prod

uct q

ualit

y an

d m

icro

biol

ogy

defic

ienc

ies

have

bee

nid

entif

ied

that

prec

lude

mar

ketin

g ap

prov

al a

t thi

s tim

e.

The

Agen

cy h

as e

stab

lishe

d th

at d

ista

nt

spre

ad o

f tox

in is

a ri

sk th

at re

quire

s a

Box

War

ning

, alth

ough

no

even

ts w

ere

obse

rved

in

this

dev

elop

men

t pro

gram

. Se

ctio

n 5

War

ning

s an

d Pr

ecau

tions

will

cont

ain

all

rele

vant

saf

ety

issu

es.

Ris

k M

anag

emen

t

Prod

uct l

abel

ing

is s

uffic

ient

to m

anag

e th

e id

entif

ied

risks

, if

appr

oved

.R

isk

man

agem

ent s

trate

gies

bey

ond

prod

uct

labe

ling

are

not n

eede

d fo

r thi

s pr

oduc

t, if

appr

oved

.A

REM

S is

not

requ

ired.

Ref

eren

ce ID

: 426

3152



Patient Experience Data

Patient experience data pertaining and submitted with this application are outlined in Table 2.

Table 1: Patient Experience Data Relevant to this Application

x The patient experience data that was submitted as part of the application include:

Section where discussed, if applicable

x Clinical outcome assessment (COA) data, such asx Patient reported outcome (PRO) Studies EV-001, EV-002

Observer reported outcome (ObsRO)x Clinician reported outcome (ClinRO) Studies Ev-001, EV-002

Performance outcome (PerfO)Qualitative studies (e.g., individual patient/caregiver interviews, focus group interviews, expert interviews, Delphi Panel, etc.)Patient-focused drug development or other stakeholder meeting summary reports

x Observational survey studies designed to capture patient experience data

x Natural history studies Patient preference studies (e.g., submitted studies or scientific publications)Other: (Please specify)

Patient experience data that were not submitted in the application, but were considered in this review:

Input informed from participation in meetings with patient stakeholders Patient-focused drug development or other stakeholder meeting summary reportsObservational survey studies designed to capture patient experience dataOther: (Please specify)

Patient experience data was not submitted as part of this application.




2 Therapeutic Context

Analysis of Condition

Glabellar lines, also known as frown lines, occur naturally with facial animation because of the impact on the skin from underlying facial musculature, predominantly the procerus and the corrugator supercilii muscles.1 There are a few potential treatments for glabellar lines. Surgical release of the muscles is possible; however, it is invasive, can cause scaring and is non-reversible. Nonsurgical treatments are less invasive, but do not address the underlying musculature responsible for the facial lines. Since 2002 when first approved by the FDA for this use, botulinum toxin type A has become a common aesthetic treatment option for glabellar lines resulting from underlying hyper-functional facial musculature.

Analysis of Current Treatment Options

The FDA originally approved botulinum toxin type A, marketed under the trade name Botox®, in December 1989 for the treatment of blepharospasm associated with dystonia and for the treatment of strabismus. In April 2002, the FDA approved a supplement to the BLA for the indication of the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients < 65 years of age. Under this approval, the product was marketed and labeled as Botox® Cosmetic.

Table 2: FDA-Approved Treatment for Glabellar Lines

Product (s) Name Relevant Indication

Year of Approval

Dosing/Administration

Efficacy Information

Important Safety and Tolerability Issues

DysportAbobotulinumtoxinA

Moderate to severe glabellar lines

2009 50 Units IM injection in five equal aliquots of 10 Units

GL1 (55%)GL2 (52%)GL3 (60%)

Spread of toxin, dysphagia and breathing difficulties

XeominIncobotulinumtoxinA



GL1 (60%)GL2 (48%)


Botox CosmeticOnabotulinumtoxinA



Study 1 (61%)Study 2 (46%)


Source: FDA approved Physician’s Inserts from Drugs@FDA

1 Pierard GE, Lapiere CM. The microanatomical bases of facial frown lines. Arch Dermatol. 1989;125:1090-2.




Following the original Botox® approval, the FDA approved one type B botulinum toxin (BT-B) and two other BT-A products. These differ in potency from each other and from the Botox® products, and are not interchangeable and unit strength is not consistent. To reinforce the differences between the products, the FDA and the United States Adopted Names Council (USAN) revised the established names for the botulinum toxins in 2009. The established name for the Botox® products was changed to onabotulinumtoxinA.




3 Regulatory Background

U.S. Regulatory Actions and Marketing History

This drug product is not marketed in the US.

Summary of Presubmission/Submission Regulatory Activity

Evolus Inc. proposed the initial development program for JEUVEAU (DWP-450), a botulinum toxin type A for the treatment of moderate-to-severe glabellar lines, during a Pre-IND meeting on 12-MAR-2014 under IND 121493. During the teleconference, the Agency provided extensive responses to the sponsor’s questions regarding the CMC, non-clinical, and clinical development program. The sponsor planned to conduct two studies (EV-001 and EV-002) in the US and one European Study (EV-003). In September of 2014, the sponsor received a “Study May Proceed” letter following the review of their Phase 2, open-label, multiple-dose, safety study, EV-004. This study was submitted to open the IND and was reviewed as a 30-Day safety IND. The sponsor subsequently followed their Phase 2 study with a Special Protocol Assessment (SPA) request for review of two identical Phase 3 protocols EV-001 and V-002 in moderate-to-severe glabellar lines. This SPA was withdrawn due to a lack of agreement with the population proposed for the Phase 3 trials. The SPA was resubmitted in November of 2014 and reviewed. An Agency letter for SPA agreement was sent in December of 2014. The sponsor requested a Pre-BLA meeting which was held October 12, 2016. Evolus Inc. was provided with extensive responses to their BLA submission questions.

The Korean MFDS approved DWP-450 for marketing on November 29, 2013. In October 2013, Daewoong Pharmaceuticals reached a licensing agreement with the US-based company Evolus Inc. to supply and distribute

Documents

761085Orig1s000 - Food and Drug Administration · 2019. 2. 28. · 8. The current test volume for DS total aerobic microbial count (TAMC) is low and thus, the bioburden release test