CBERIsolagen Therapy (IT)BLA 125348

FDA Clinical Review

Agnes Lim, MD Yao-Yao Zhu, MD, PhD

DCEPT/OCTGT/CBER, FDA

October 9, 2009 Advisory Committee Meeting

CBER

Presentation OutlinePresentation Outline

Overview of Pivotal StudiesOverview of Pivotal StudiesStudies IT-R-005 and IT-R-Studies IT-R-005 and IT-R-006006

Study ResultsStudy ResultsEfficacy Results Efficacy Results Safety ResultsSafety Results

CBER

Overview of Pivotal StudiesOverview of Pivotal StudiesIT-R-005 and IT-R-006IT-R-005 and IT-R-006

Proposed indicationProposed indication Treatment of moderate to severe Treatment of moderate to severe

nasolabial fold wrinkles in adults nasolabial fold wrinkles in adults

Title: A Phase 3, Multicenter, Title: A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Double-Blind, Randomized, Placebo-Controlled Trial of the Efficacy and Controlled Trial of the Efficacy and Safety of Isolagen Therapy in the Safety of Isolagen Therapy in the Treatment of Nasolabial Fold Treatment of Nasolabial Fold WrinklesWrinkles

CBER

IT AdministrationIT AdministrationDosage: Dosage: 0.1 mL/linear cm, up to 2 mL/Tx(1.0-2.0 x 107 cells/mL)

Three treatment visits, at intervals of 5 ± 1 week

Control: vehicle-medium onlyControl: vehicle-medium only

CBER

Subject Wrinkle AssessmentSubject Wrinkle Assessment

““How do you feel How do you feel about the wrinkles in about the wrinkles in the lower part of the lower part of your face today”?your face today”?

-2-2 Very Very Dissatisfied Dissatisfied

--11 DissatisfiedDissatisfied 00 Somewhat Somewhat

Satisfied Satisfied +1+1 Satisfied Satisfied +2+2 Very SatisfiedVery Satisfied

CBER

Evaluator Wrinkle Severity Evaluator Wrinkle Severity Assessment Assessment

(Lemperle) with Photoguide(Lemperle) with Photoguide

Grade 0 No wrinkleGrade 0 No wrinkle

Grade 1 Just perceptible Grade 1 Just perceptible

Grade 2 ShallowGrade 2 Shallow

Grade 3 Moderately deep Grade 3 Moderately deep

Grade 4 Deep, well defined edgeGrade 4 Deep, well defined edgeGrade 5 Very deep, redundantGrade 5 Very deep, redundant fold fold

CBERKey Eligibility Criteria Key Eligibility Criteria IT-R-005 and IT-R-006IT-R-005 and IT-R-006

InclusionInclusion M or F ≥M or F ≥ 18 years old 18 years old Pre-specified nasolabial fold wrinkle Pre-specified nasolabial fold wrinkle

gradings of moderate/severe by both gradings of moderate/severe by both subjects and evaluatorssubjects and evaluators

Post-auricular skin acceptable for biopsyPost-auricular skin acceptable for biopsy

ExclusionExclusion Total treatment area > 20 cm in length Total treatment area > 20 cm in length Pre-specified skin conditionsPre-specified skin conditions Pre-specified previous facial cosmetic Pre-specified previous facial cosmetic

procedures, dermal fillers or Rxprocedures, dermal fillers or Rx Basal cell carcinoma Basal cell carcinoma

CBER

Treatment SchemaTreatment Schema

Efficacy evaluation at 6 months following last treatment injection (Visit 6)

Co-primary efficacy endpoints:Subject Wrinkle AssessmentEvaluator Wrinkle Severity Assessment

Safety assessment every visit; Final safety assessment by telephone at 12 month

1. Severity ≥ Grade 3 of bilateral nasolabial fold wrinkles by evaluator 2. Subjects Dissatisfied or Very Dissatisfied with appearance of wrinkles in lower face3. Met entrance criteria

Skin biopsy/Baseline; biopsy meet acceptance criteria; randomized by site

IT, n= 100Up to 2mL (1-2x107 cells/mL) / Tx

Every 5 ± 1 wkTotal 3 treatments

Vehicle-control, n = 100Every 5 ± 1 wk

Total 3 treatments

CBER

Primary Efficacy Primary Efficacy EndpointsEndpoints

Co-primary Co-primary EndpointsEndpoints

Wrinkle Wrinkle AssessmentAssessment

at at BaselineBaseline

Success Success

at at 6 month6 month

Evaluator Evaluator Wrinkle Wrinkle Severity Severity AssessmentAssessment

Grade Grade >>33 2-point or better 2-point or better improvement improvement for both sidesfor both sides

Subject Subject Wrinkle Wrinkle AssessmentAssessment

-1: dissatisfied-1: dissatisfied

-2: very dissatisfied-2: very dissatisfied2-point or better 2-point or better improvementimprovement

CBER

Secondary EndpointsSecondary Endpoints

Wrinkle Wrinkle AssessmentAssessment

at at BaselineBaseline

Success Success

at at Visits 3,4,5Visits 3,4,5

Evaluator Evaluator Wrinkle Wrinkle Severity Severity AssessmentAssessment

Grade Grade >>33 2-point or better 2-point or better improvement on improvement on both sidesboth sides

Subject Wrinkle Subject Wrinkle AssessmentAssessment

-1: dissatisfied-1: dissatisfied

-2: very dissatisfied-2: very dissatisfied2-point or better 2-point or better improvementimprovement

CBERSecondary Endpoints Secondary Endpoints (cont.)(cont.)

Photos at BaselinePhotos at Baseline

versusversus

Photos at Visits 3,4,5,6Photos at Visits 3,4,5,6Subject Subject ImprovemeImprovement nt AssessmentAssessment

Scale used for rating wrinkle/appearance on photos:-2= much worse than before -1= worse than before 0= the same as before +1= better than before +2= much better than before

Evaluator Evaluator ImprovemeImprovement nt AssessmentAssessment

CBER

Statistical PlanAnalysis populations:Analysis populations: ITT = all randomized ITT = all randomized MITT = MITT = received ≥ one treatment EE (Efficacy Evaluable) = met entrance EE (Efficacy Evaluable) = met entrance

criteria, received all 3 treatments, and no criteria, received all 3 treatments, and no major protocol violationmajor protocol violation

80% power at a two-sided significance level of 0.05 Response rates > 40% of IT; 20% for

vehicle-control Missing data imputed as treatment failures

CBER

IT-R-005 and IT-R-006 Study Results

CBER

IT-R-005 and IT-R-006IT-R-005 and IT-R-006EnrollmentEnrollment

StudyStudyITIT ControlControl # of # of

SitesSitesStudy Study PeriodPeriod

IT-R-005IT-R-005

n=203n=203100100 103103 77 10/06-10/06-

06/0806/08

IT-R-006IT-R-006

n=218n=218110110 108108 66 11/06-11/06-

06/0806/08

CBER

Demographics of ITT Demographics of ITT PopulationPopulation

Population Population CategoriesCategories

IT-R-005IT-R-005 IT-R-006IT-R-006

ITIT

n=100n=100ControContro

ll

n=103n=103

ITIT

n=110n=110ControContro

ll

n=108n=108Ages (Years) Mean (SD)

Median

Range

57.5 (8.3)57.5 (8.3)

5757

38-7538-75

55.9 (7.9)55.9 (7.9)

5656

35-7835-78

53.9 53.9 (10.4)(10.4)

5555

23-7523-75

55.4 (9.9)55.4 (9.9)

5555

26-8126-81

Age Groups n (%)

< 50

> 50, < 65

> 65

19 (19%)19 (19%)

60 (60%)60 (60%)

21 (21%)21 (21%)

25 (24%)25 (24%)

62 (60%)62 (60%)

16 (16%)16 (16%)

39 (35%)39 (35%)

56 (51%)56 (51%)

15 (14%)15 (14%)

34 (31%)34 (31%)

55 (51%)55 (51%)

19 (18%)19 (18%)

Gendern (%)

Female

Male

88 (88%)88 (88%)

12 (12%)12 (12%)94 (91%)94 (91%)

9 (9%)9 (9%)103 103 (94%)(94%)

7 (6%)7 (6%)

95 (88%)95 (88%)

13 (12%)13 (12%)

Racen (%)

White

Black or African-American

Asian

American Indian or Alaska

Others

94 (94%)94 (94%)

1 (1%)1 (1%)

2 (2%)2 (2%)

00

3 (3%)3 (3%)

99 (96%)99 (96%)

2 (2%)2 (2%)

00

1 (1%)1 (1%)

1 (1%)1 (1%)

98 (89%)98 (89%)

1 (1%)1 (1%)

00

00

11 (10%)11 (10%)

95 (88%)95 (88%)

1 (1%)1 (1%)

00

00

12 (11%)12 (11%)

Ethnicity n (%)Ethnicity n (%) Hispanic/Latino 10 (10%)10 (10%) 7 (7%)7 (7%) 12 (11%)12 (11%) 12 (11%)12 (11%)

CBER

Key DemographicsKey DemographicsDemographics similar between Demographics similar between studies IT-R-005 and IT-R-006studies IT-R-005 and IT-R-006Age: Age: Median 56 years old; range 23-Median 56 years old; range 23-8181

Gender: Gender: 90% Female90% Female

Race: Race: 92% White92% White 1% Black/African-American1% Black/African-American 1% Asian1% Asian

Ethnicity: Ethnicity: 10% Hispanic/Latino10% Hispanic/Latino

CBER

Disposition of SubjectsDisposition of SubjectsIT-R-005IT-R-005 IT-R-006IT-R-006 TotalTotal

ITIT

n=100n=100ControlControl

n=103n=103ITIT

n=110n=110ControlControl

n=108n=108 n=421n=421

Study Completion Study Completion Status:Status: Completed StudyCompleted Study

Early TerminationEarly Termination

80 (80%)80 (80%)

20 (20%)20 (20%)88 (85%)88 (85%)

15 (15%)15 (15%)93 (85%)93 (85%)

17 (15%)17 (15%)98 (91%)98 (91%)

10 (9%)10 (9%)359 359 (85%)(85%)

62 (15%)62 (15%)

Reasons for Early Reasons for Early Termination:Termination: Subject WithdrawalSubject Withdrawal

Sponsor RequestSponsor Request

Adverse EventAdverse Event

Protocol Non-Protocol Non-ComplianceCompliance

Lost to Follow-UpLost to Follow-Up

OthersOthers

7 (7%)7 (7%)

5 (5%)5 (5%)

1 (<1%)1 (<1%)

3 (3%)3 (3%)

1 (1%)1 (1%)

3 (3%)3 (3%)

6(6%)6(6%)

1 (<1%)1 (<1%)

1 (<1%)1 (<1%)

1 (<1%)1 (<1%)

3 (3%)3 (3%)

3 (3%)3 (3%)

3 (3%)3 (3%)

10 (9%)10 (9%)

1 (<1%)1 (<1%)

2 (2%)2 (2%)

00

1 (<1%)1 (<1%)

4 (4%)4 (4%)

4 (4%)4 (4%)

1 (<1%)1 (<1%)

1 (<1%)1 (<1%)

00

00

20 (5%)20 (5%)

20 (5%)20 (5%)

4 (<1%)4 (<1%)

7 (2%)7 (2%)

4 (<1%)4 (<1%)

7 (2%)7 (2%)

CBER

Manufacturing FailureManufacturing FailureThe total IT manufacturing failure in the two The total IT manufacturing failure in the two pivotal studies was 11% (24/210)pivotal studies was 11% (24/210)

IT/Control pairing to maintain IT/Control pairing to maintain randomization/study blind for re-biopsies due to randomization/study blind for re-biopsies due to manufacturing failuresmanufacturing failures

Type of FailureType of Failure

IT-R-005IT-R-005N=203N=203

IT-R-006IT-R-006N=218N=218

ITITn=100n=100

ControlControln=103n=103

ITITn=110n=110

ControlControln=108n=108

No product No product produced, Totalproduced, Total

5 (5%)5 (5%) 1 (1%)1 (1%) 8 (7%)8 (7%) 4 (4%)4 (4%)

Insufficient product, Insufficient product, Total:Total:

3 (3%)3 (3%) 00 8 (7%)8 (7%) 1 (1%)1 (1%)

1 Tx received1 Tx received 1 (1%)1 (1%) 00 4 (4%)4 (4%) 00 2 Tx received2 Tx received 2 (2%)2 (2%) 00 4 (4%)4 (4%) 1 (1%)1 (1%)

CBER

Primary Endpoints Primary Endpoints Success Rate at 6 MonthSuccess Rate at 6 Month

Co-Primary Co-Primary EndpointsEndpoints

IT-R-005IT-R-005N=203N=203

IT-R-006IT-R-006N=218N=218

ITIT

n=100n=100ControlControl

n=103n=103p-valuep-value ITIT

n=110n=110ControlControl

n=108n=108p-valuep-value

Evaluator Evaluator Wrinkle Wrinkle Severity Severity AssessmenAssessmentt

3333

(33%)(33%)7 7

(7%)(7%)<0.000<0.000

11

2121

(19%(19%))

8 8

(7%)(7%)0.00750.0075

Subject Subject Wrinkle Wrinkle AssessmenAssessmentt

5757

(57%)(57%)3131

(30%)(30%)0.00010.0001

5050

(45%(45%))

1919

(18%)(18%)<0.000<0.000

11

CBER

Efficacy ConclusionsEfficacy ConclusionsBoth co-primary endpoints at six Both co-primary endpoints at six months were met in each of the months were met in each of the pivotal studies pivotal studies

Results of secondary endpoints Results of secondary endpoints supportive of primary efficacy supportive of primary efficacy resultsresults

Efficacy of IT > 6 months has not Efficacy of IT > 6 months has not been demonstratedbeen demonstrated

No studies conducted for effects of No studies conducted for effects of repeating treatment cyclesrepeating treatment cycles

CBER

Safety Results

CBER

Safety OverviewSafety OverviewSafety databaseSafety database

Commercial experienceCommercial experience

Safety PopulationSafety Population ITITVehicle-Vehicle-ControlControl TotalTotal

IT-R-005 & 006IT-R-005 & 006 181181 191191 372372

7 clinical trials 7 clinical trials

(integrated (integrated safety safety

population)population)

508508 354354 862862

CBER

Safety Monitoring Schedule in 005 & Safety Monitoring Schedule in 005 & 006006

5 wks 5 wks 8 wks 8 wks 8 wks 28 wks

Total Safety Observation Period : 62 weeks

Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Telephone Call

Treatment Visits

* Acute Study: Visits 1, 2, 3, 4, 5, & 6: 34 weeks

* Long-Term Study: a telephone call at 12 months from Visit 3

CBERAdverse Events in IT-R-005 > Adverse Events in IT-R-005 > 1%1%

Preferred TermsPreferred TermsIT N=83IT N=83 Control N=92Control N=92

SubjectsSubjects EventsEvents SubjectsSubjects EventsEvents

All treatment-emergent AEAll treatment-emergent AE 51 (61%)51 (61%) 193193 57 (62%)57 (62%) 219219

Administration site conditionsAdministration site conditions 31 (37%)31 (37%) 119119 32 (35%)32 (35%) 9494

(Related to Treatment)(Related to Treatment) 28 (33%)28 (33%) 112112 24 (26%)24 (26%) 7676

Injection-site erythemaInjection-site erythema 23 (28%)23 (28%) 5353 17 (19%)17 (19%) 2828

Injection-site swellingInjection-site swelling 18 (22%)18 (22%) 4141 15 (16%)15 (16%) 2727

Injection-site pain Injection-site pain 5 (6%)5 (6%) 66 4 (4%)4 (4%) 55

Injection-site bruisingInjection-site bruising 4 (5%)4 (5%) 55 12 (13%)12 (13%) 1717

Injection-site nodulesInjection-site nodules 2 (2%)2 (2%) 33 2 (2%)2 (2%) 22

Injection-site reactionInjection-site reaction 2 (2%)2 (2%) 22 2 (2%)2 (2%) 22

Injection-site papulesInjection-site papules 2 (2%)2 (2%) 22 1 (1%)1 (1%) 11

CBER

Adverse Events in IT-R-006 > Adverse Events in IT-R-006 > 1%1%

Preferred TermsPreferred TermsIT n=98IT n=98 Control n=99Control n=99

SubjectsSubjects EventEventss

SubjectsSubjects EventEventss

All treatment-emergent All treatment-emergent AEAE 62 (63%)62 (63%) 161161 56 (57%)56 (57%) 172172

Administration site Administration site conditionsconditions 32 (33%)32 (33%) 6969 32 (32%)32 (32%) 8484

(Related to Treatment)(Related to Treatment) 29 (30%)29 (30%) 6363 31 (31%)31 (31%) 8080

Injection-site Injection-site erythemaerythema 14 (14%)14 (14%) 1919 6 (6%)6 (6%) 99

Injection-site Injection-site hemorrhagehemorrhage 10 (10%)10 (10%) 3030 15 (15%)15 (15%) 4545

Injection-site bruisingInjection-site bruising 5 (5%)5 (5%) 66 13 (13%)13 (13%) 2020

Injection-site papulesInjection-site papules 4 (4%)4 (4%) 44 2 (2%)2 (2%) 22

Injection-site irritationInjection-site irritation 3 (3%)3 (3%) 66 1 (1%)1 (1%) 33

Injection-site swellingInjection-site swelling 3 (3%)3 (3%) 33 00 00

CBER

Related-Adverse Events < 1% in IT-R-005 & Related-Adverse Events < 1% in IT-R-005 & 006006

StudStudyy

GroupGroup Preferred TermsPreferred Terms Onset from Onset from treatmenttreatment DurationDuration SeveritSeverit

y y ActionAction

005005 ITIT Basal cell cancerBasal cell cancer 7 months after 7 months after 11stst

n/an/a moderatmoderatee

excisionexcision

005005 ITIT Herpes simplex of lipHerpes simplex of lip 5 days after 15 days after 1stst 4 days4 days mildmild medsmeds

005005 ITIT Post-procedural Post-procedural headacheheadache

On 2 On 2 rdrd treatmenttreatment

2 days2 days mildmild medsmeds

005005 ControlControl Swelling under left eyeSwelling under left eye 2 days after 12 days after 1stst 5 days5 days mildmild nonenone

005005 ControlControl HeadacheHeadache On 1On 1stst treatmenttreatment

1 day1 day moderatmoderatee

medsmeds

005005 ControlControl Injection site anesthesiaInjection site anesthesia 3.5 months 3.5 months after 3after 3rdrd

5.5 months5.5 months mildmild nonenone

005005 ControlControl Pain in jawPain in jaw On 1On 1stst treatmenttreatment

2 days2 days mildmild nonenone

005005 ControlControl Paraesthesia right Paraesthesia right upper lipupper lip

2 days after 12 days after 1stst 3 days3 days mild mild nonenone

005005 ControlControl Post-procedural Post-procedural discomfortdiscomfort

On 1On 1stst treatmenttreatment

1 day1 day mild mild nonenone

006006 ITIT Bilateral eyelid edemaBilateral eyelid edema 1 day after 1 day after each of 3 each of 3 treatmentstreatments

11stst , 2 , 2rdrd: 1 : 1 weekweek

33rdrd: > 1 year: > 1 year

mildmild nonenone

006006 ITIT Skin hyperpigmentationSkin hyperpigmentation 1 day after 21 day after 2rdrd 3 weeks3 weeks mildmild nonenone

006006 ControlControl Injection site Injection site hypersensitivityhypersensitivity

On 1On 1stst treatmenttreatment

2 days2 days moderatmoderatee

nonenone

CBER

Basal Cell CarcinomaBasal Cell Carcinoma76 y.o. white female with “sun damage”76 y.o. white female with “sun damage”Three IT treatments in IT-R-005Three IT treatments in IT-R-005Detection time: 7 months after first injectionDetection time: 7 months after first injectionRight upper lip near nasolabial fold, tumor: Right upper lip near nasolabial fold, tumor: 0.4 cm x 0.4 cm; solar keratosis was found 0.4 cm x 0.4 cm; solar keratosis was found at bridge of noseat bridge of nosePossibly related per investigatorPossibly related per investigatorIntervention: biopsy and Mohs ExcisionIntervention: biopsy and Mohs ExcisionOther AEs: erythema and swelling for 3 daysOther AEs: erythema and swelling for 3 daysWrinkle outcome: non-responder per Wrinkle outcome: non-responder per investigatorinvestigatorMost recent f/u: no evidence of recurrence Most recent f/u: no evidence of recurrence 18 months after the surgery18 months after the surgery

CBER

Integrated Safety Data in 7 trialsIntegrated Safety Data in 7 trials StudyStudy PhasesPhases

Safety Safety ObservatioObservatio

nn(Months)(Months)

SubjectsSubjectsIT/ControlIT/Control

TreatmenTreatmentt

IntervalInterval(Weeks)(Weeks)

IndicationsIndications

IT-R-001IT-R-001 Phase 2Phase 2 1212 30/1030/10 1-21-2 Rhytids and scars (14 Rhytids and scars (14 facial areas)facial areas)

IT-R-002IT-R-002 Phase 2Phase 2 1212 111/40111/40 1-21-2 Rhytids and scars (14 Rhytids and scars (14 facial areas) facial areas)

IT-R-IT-R-003A003A Phase 3Phase 3 1212 48/5948/59 1-21-2 Nasolabial and Nasolabial and

glabellar (4 areas)glabellar (4 areas)

IT-R-IT-R-003B003B Phase 3Phase 3 1212 52/5452/54 1-21-2 Nasolabial and Nasolabial and

glabellar (4 areas)glabellar (4 areas)

IT-R-005IT-R-005 PivotalPivotal 1515 83/9283/92 4-64-6 Nasolabial (2 areas)Nasolabial (2 areas)

IT-R-006IT-R-006 PivotalPivotal 1515 98/9998/99 4-64-6 Nasolabial (2 areas)Nasolabial (2 areas)

IT-R-007IT-R-007 Phase 2Phase 2 1414 44/044/0 4-64-6Forehead, periorbital, Forehead, periorbital,

cheek, perioral (8 cheek, perioral (8 areas)areas)

TotalTotal 77 12-1512-15821821

(467/354(467/354))

1-61-6 2-14 (injected 2-14 (injected areas)areas)

CBER

Injection-Site Reactions (Injection-Site Reactions (>> 1%) 1%) Preferred TermsPreferred Terms IT IT (N=508)(N=508) Control Control

(N=354)(N=354)

Administration Site ConditionsAdministration Site Conditions 343 (67%)343 (67%) 144 (40%)144 (40%)

(Related to Treatment)(Related to Treatment) 265/508 (52%)265/508 (52%) 119/354 (34%)119/354 (34%)

Injection-site Injection-site erythemaerythema

81 (16%)81 (16%) 33 (9%)33 (9%)

Injection-site bruisingInjection-site bruising 54 (11%)54 (11%) 48 (14%)48 (14%)

Injection-site swellingInjection-site swelling 69 (14%)69 (14%) 15 (4%)15 (4%)

Injection-site painInjection-site pain 31(6%)31(6%) 6 (2%)6 (2%)

Injection-site edemaInjection-site edema 22 (4%)22 (4%) 00

Injection-site nodulesInjection-site nodules 20 (4%)20 (4%) 3 (<1%)3 (<1%)

Injection-site Injection-site hemorrhagehemorrhage

13 (3%)13 (3%) 16 (5%)16 (5%)

Injection-site papulesInjection-site papules 8 (2%)8 (2%) 3(<1%)3(<1%)

Injection-site irritationInjection-site irritation 6 (1%)6 (1%) 1 (<1%)1 (<1%)

Injection-site Injection-site dermatitisdermatitis

5 (1%)5 (1%) 2 (<1%)2 (<1%)

Injection-site pruritusInjection-site pruritus 5 (1%)5 (1%) 3 (<1%)3 (<1%)

Injection-site Injection-site reactionsreactions

5 (1%)5 (1%) 2 (<1%)2 (<1%)

Injection-site Injection-site indurationsindurations

5 (1%)5 (1%) 00

CBER

Total Injection Site Reactions in Pivotal Total Injection Site Reactions in Pivotal Trials and Integrated Safety Trials and Integrated Safety

Population>1%Population>1%

StudyStudy IT-R-005IT-R-005 IT-R-006IT-R-006 Integrated safety Integrated safety populationpopulation

SubjectsSubjectsIT IT

N=83N=83Control Control N=92 N=92

IT IT

N=98N=98Control Control N=99N=99

ITIT

N=508N=508ControlControl

N=354N=354

AdministratioAdministration Site n Site

ConditionsConditions

31 31 (37%)(37%)

32 32 (35%)(35%)

32 32 (33%)(33%)

32 32 (32%)(32%)

343 343 (67%)(67%)

144 144 (40%)(40%)

Higher frequency of injection site adverse events in Higher frequency of injection site adverse events in integrated safety populationintegrated safety populationLower frequency of injection site adverse events in 005 & Lower frequency of injection site adverse events in 005 & 006006Reasons for the decreased injection site adverse eventsReasons for the decreased injection site adverse events

Increased treatment intervals, decreased treatment areas, Increased treatment intervals, decreased treatment areas, enhanced physician training for injectionenhanced physician training for injectionIncreased spacing for clinical safety observation intervalsIncreased spacing for clinical safety observation intervals

CBER Related-Adverse Events < 1%Related-Adverse Events < 1% (ISP)(ISP)Preferred TermsPreferred Terms IT N=508IT N=508 Control Control

N=354N=354

AcneAcne 44 00

RashRash 22 00

Eye edemaEye edema 22 11

Face edemaFace edema 33 11

Herpes labialisHerpes labialis 33 00

Injection site vesiclesInjection site vesicles 11 00

HypoaesthesiaHypoaesthesia 22 00

Injection site hypersensitivityInjection site hypersensitivity 00 11

Lip paraesthesia Lip paraesthesia 00 11

Basal cell carcinomaBasal cell carcinoma 11 00

Injection site fibrosis Injection site fibrosis 11 00

Injection site ischemiaInjection site ischemia 22 00

ParapsoriasisParapsoriasis 11 00

Alopecia areataAlopecia areata 11 00

HyperpigmentationHyperpigmentation 11 00

Pain in jawPain in jaw 00 11

HeadacheHeadache 55 22

Post-procedural discomfortPost-procedural discomfort 00 11

ToothacheToothache 00 11

Chapped lipsChapped lips 11 00

DizzinessDizziness 22 00

TotalTotal 32 32 9 9

CBER

Severity of Injection-Site Severity of Injection-Site Adverse Events >1%Adverse Events >1%

Administration-Administration-site conditionssite conditions IT N=343IT N=343 Control N=144Control N=144

MildMild 283 (82.5 %)283 (82.5 %) 131 (91%)131 (91%)

ModerateModerate 55 (16%)55 (16%) 12 (8%)12 (8%)

SevereSevere 5 (1.5%)5 (1.5%) 1 (<1%)1 (<1%)

N=subjects reporting injection site adverse eventsN=subjects reporting injection site adverse events

Severity grading: CTCAE V3 (NCI/NIH)Severity grading: CTCAE V3 (NCI/NIH)6 cases of severe injection-site adverse events6 cases of severe injection-site adverse events

5 IT subjects: erythema (1), ischemia (1), 5 IT subjects: erythema (1), ischemia (1), swelling (2), pain (1)swelling (2), pain (1)1 control subject: bruising1 control subject: bruisingResolved within 10 days, no withdrawalResolved within 10 days, no withdrawal

CBERDuration of Related-Adverse Duration of Related-Adverse Reaction>1%Reaction>1%

AE Duration AE Duration

in Daysin DaysIT: related IT: related

events = 444events = 444Control: related Control: related

events = 207events = 207

<1 to 7<1 to 7 380 (85.5%)380 (85.5%) 187(90%)187(90%)

8 to 148 to 14 23 (5%)23 (5%) 13 (6%)13 (6%)

15 to 3015 to 30 16 (3.6%)16 (3.6%) 1 (0.5%)1 (0.5%)

31 to 6031 to 60 9 (2%)9 (2%) 2 (1%)2 (1%)

61 to 9061 to 90 8 (1.8%)8 (1.8%) 2 (1%)2 (1%)

91 to 12091 to 120 2 (0.4%)2 (0.4%) 00

OngoingOngoing 5 (1%)5 (1%) 00

CBER

Unresolved Adverse Events Unresolved Adverse Events (All Subjects in IT Group)(All Subjects in IT Group)

StudyStudy Adverse Adverse EventsEvents

Treatment Treatment AreasAreas Onset DayOnset Day Duration Duration

in Dayin Day Severity Severity ActionAction

IT-R-IT-R-001001

Red,swelling Red,swelling in glabellarin glabellar

Glabellar,peGlabellar,perioralrioral

2nd2nd

treatmenttreatment357+357+ mildmild BenadrBenadr

ylAleveylAleve

IT-R-IT-R-002002

Flare of Flare of alopecia alopecia areataareata

Nasolabial, Nasolabial, perioralperioral

Third day Third day from 2nd from 2nd treatmenttreatment

354+354+ mildmildAldara, Aldara, KenaloKenalo

gg

IT-R-IT-R-003A003A

Plumpness in Plumpness in upper lipupper lip

Nasolabial, Nasolabial, glabellarglabellar

A month A month from 3rd from 3rd

treatmenttreatment287+287+ mildmild nono

IT-R-IT-R-005005

Ridge in right Ridge in right nasolabial foldnasolabial fold nasolabialnasolabial

A week A week from 2from 2nd nd

treatmenttreatment409+409+ mildmild nono

IT-R-IT-R-006006

Swelling on Swelling on both upper both upper

eye lidseye lidsnasolabialnasolabial Third Third

treatmenttreatment 396+396+ mildmild nono

CBER

SubgroupsSubgroupsUnder-represented subgroups in integrated Under-represented subgroups in integrated safety populationsafety population

Safety profilesSafety profiles– Similar common injection-site reactionsSimilar common injection-site reactions– No keloid formation reportedNo keloid formation reported– Limited information due to small sample Limited information due to small sample

sizessizes

Sub-groupsSub-groupsIT IT

N=467*N=467*Control Control N=354N=354

TotalTotal

N=821N=821

>65 yo>65 yo 44 (9%)44 (9%) 41 (12%)41 (12%) 85 (10%)85 (10%)

MaleMale 42 (9%)42 (9%) 34 (10%)34 (10%) 76 (9%)76 (9%)

Non-whiteNon-white 43 (9%)43 (9%) 35 (10%)35 (10%) 78 (10%)78 (10%)

* 41 cross-over subjects not included* 41 cross-over subjects not included

CBER

Commercial ExperienceCommercial ExperienceUS: 1,200 + subjects (1995-1999) US: 1,200 + subjects (1995-1999)

UK: 7,800 + subjects (2002-2007)UK: 7,800 + subjects (2002-2007)

Retrospective chart reviews, limited Retrospective chart reviews, limited registryregistry

Common AEs: red, swelling, rash, lumpCommon AEs: red, swelling, rash, lump

Three serious adverse event reportsThree serious adverse event reports– AngioedemaAngioedema– Severe systemic allergic reactionSevere systemic allergic reaction– Lump on the eyelid, requiring surgeryLump on the eyelid, requiring surgery

CBERSafety SummarySafety SummaryAdverse events in >1%Adverse events in >1%

injection site redness, bruising, swelling, pain, injection site redness, bruising, swelling, pain, nodules, hemorrhage, papules, irritation, nodules, hemorrhage, papules, irritation, dermatitis, pruritusdermatitis, pruritus

Adverse events in <1%Adverse events in <1%Probable facial allergic reactions, flare of herpes Probable facial allergic reactions, flare of herpes labialis, change of skin sensation, post-procedural labialis, change of skin sensation, post-procedural discomfortdiscomfort

Severity and duration of adverse reactionsSeverity and duration of adverse reactionsMild/moderate in severityMild/moderate in severity5% injection-site events lasting beyond 30 days5% injection-site events lasting beyond 30 days

Five cases unresolved beyond one yearFive cases unresolved beyond one yearOne case of injection-site basal cell cancerOne case of injection-site basal cell cancerTwo cases of serious allergic reactions in UKTwo cases of serious allergic reactions in UKSmall sample sizes for male, elderly, and non-whiteSmall sample sizes for male, elderly, and non-whiteSafety observation limited to 12 to 15 monthsSafety observation limited to 12 to 15 months

CBER

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