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CBER Isolagen 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.

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Presentation on theme: "CBER Isolagen 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."— Presentation transcript:

1 CBER Isolagen Therapy (IT) BLA FDA Clinical Review Agnes Lim, MD Yao-Yao Zhu, MD, PhD DCEPT/OCTGT/CBER, FDA October 9, 2009 Advisory Committee Meeting

2 CBER Presentation Outline Overview of Pivotal Studies  Studies IT-R-005 and IT-R-006 Study Results  Efficacy Results  Safety Results

3 CBER Overview of Pivotal Studies IT-R-005 and IT-R-006 Proposed indication  Treatment of moderate to severe nasolabial fold wrinkles in adults Title: A Phase 3, Multicenter, Double- Blind, Randomized, Placebo- Controlled Trial of the Efficacy and Safety of Isolagen Therapy in the Treatment of Nasolabial Fold Wrinkles

4 CBER IT Administration Dosage: Dosage: 0.1 mL/linear cm, up to 2 mL/Tx ( x 10 7 cells/mL) Three treatment visits, at intervals of 5 ± 1 week Control: vehicle-medium only

5 CBER Subject Wrinkle Assessment “ How do you feel about the wrinkles in the lower part of your face today”? -2 Very Dissatisfied - 1Dissatisfied 0 Somewhat Satisfied 0 Somewhat Satisfied +1 Satisfied +2 Very Satisfied

6 CBER Evaluator Wrinkle Severity Assessment (Lemperle) with Photoguide Grade 0 No wrinkle Grade 1 Just perceptible Grade 2 Shallow Grade 3 Moderately deep Grade 4 Deep, well defined edge Grade 5 Very deep, redundant fold

7 CBER Key Eligibility Criteria IT-R-005 and IT-R-006 Inclusion  M or F ≥ 18 years old  Pre-specified nasolabial fold wrinkle gradings of moderate/severe by both subjects and evaluators  Post-auricular skin acceptable for biopsy Exclusion  Total treatment area > 20 cm in length  Pre-specified skin conditions  Pre-specified previous facial cosmetic procedures, dermal fillers or Rx  Basal cell carcinoma

8 CBER Treatment Schema Efficacy evaluation at 6 months following last treatment injection (Visit 6) Co-primary efficacy endpoints: Subject Wrinkle Assessment Evaluator 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 face 3. Met entrance criteria Skin biopsy/Baseline; biopsy meet acceptance criteria; randomized by site IT, n= 100 Up to 2mL (1-2x10 7 cells/mL) / Tx Every 5 ± 1 wk Total 3 treatments Vehicle-control, n = 100 Every 5 ± 1 wk Total 3 treatments

9 CBER Primary Efficacy Endpoints Co-primary Endpoints Wrinkle Assessment at Baseline Success at 6 month Evaluator Wrinkle Severity Assessment Grade >3 2-point or better improvement for both sides Subject Wrinkle Assessment -1: dissatisfied -2: very dissatisfied 2-point or better improvement

10 CBER Secondary Endpoints Wrinkle Assessment at Baseline Success at Visits 3,4,5 Evaluator Wrinkle Severity Assessment Grade >3 2-point or better improvement on both sides Subject Wrinkle Assessment -1: dissatisfied -2: very dissatisfied 2-point or better improvement

11 CBER Secondary Endpoints (cont.) Photos at Baseline versus Photos at Visits 3,4,5,6 Subject Improvement Assessment 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 Improvement Assessment

12 CBER Statistical Plan Analysis populations:  ITT = all randomized  MITT =  MITT = received ≥ one treatment  EE (Efficacy Evaluable) = met entrance criteria, received all 3 treatments, and no major 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

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

14 CBER IT-R-005 and IT-R-006 Enrollment Study ITControl # of Sites Study Period IT-R-005n= /06-06/08 IT-R-006n= /06-06/08

15 CBER Demographics of ITT Population Population Categories IT-R-005IT-R-006 ITn=100Controln=103ITn=110Controln=108 Ages (Years) Mean (SD) Median Range 57.5 (8.3) (7.9) (10.4) (9.9) Age Groups n (%) < 50 > 50, < 65 > (19%) 60 (60%) 21 (21%) 25 (24%) 62 (60%) 16 (16%) 39 (35%) 56 (51%) 15 (14%) 34 (31%) 55 (51%) 19 (18%) Gender n (%) Female Male 88 (88%) 12 (12%) 94 (91%) 9 (9%) 103 (94%) 7 (6%) 95 (88%) 13 (12%) Race n (%) White Black or African-American Asian American Indian or Alaska Others 94 (94%) 1 (1%) 2 (2%) 0 3 (3%) 99 (96%) 2 (2%) 0 1 (1%) 98 (89%) 1 (1%) (10%) 95 (88%) 1 (1%) (11%) Ethnicity n (%) Hispanic/Latino 10 (10%) 7 (7%) 12 (11%)

16 CBER Key Demographics Demographics similar between studies IT-R-005 and IT-R-006 Age: Median 56 years old; range Gender: 90% Female Race: 92% White 92% White 1% Black/African-American 1% Black/African-American 1% Asian 1% Asian Ethnicity: 10% Hispanic/Latino

17 CBER Disposition of Subjects IT-R-005IT-R-006Total ITn=100Controln=103ITn=110Controln=108 n=421 Study Completion Status: Completed Study Completed Study Early Termination Early Termination 80 (80%) 20 (20%) 88 (85%) 15 (15%) 93 (85%) 17 (15%) 98 (91%) 10 (9%) 359 (85%) 62 (15%) Reasons for Early Termination: Subject Withdrawal Subject Withdrawal Sponsor Request Sponsor Request Adverse Event Adverse Event Protocol Non-Compliance Protocol Non-Compliance Lost to Follow-Up Lost to Follow-Up Others Others 7 (7%) 5 (5%) 1 (<1%) 3 (3%) 1 (1%) 3 (3%) 6(6%) 1 (<1%) 3 (3%) 10 (9%) 1 (<1%) 2 (2%) 0 1 (<1%) 4 (4%) 1 (<1%) (5%) 4 (<1%) 7 (2%) 4 (<1%) 7 (2%)

18 CBER Manufacturing Failure The total IT manufacturing failure in the two pivotal studies was 11% (24/210) IT/Control pairing to maintain randomization/study blind for re-biopsies due to manufacturing failures Type of Failure IT-R-005N=203IT-R-006N=218 ITn=100Controln=103ITn=110Controln=108 No product produced, Total 5 (5%) 1 (1%) 8 (7%) 4 (4%) Insufficient product, Total: 3 (3%) 0 8 (7%) 1 (1%) 1 Tx received 1 Tx received 1 (1%) 0 4 (4%) 0 2 Tx received 2 Tx received 2 (2%) 0 4 (4%) 1 (1%)

19 CBER Primary Endpoints Success Rate at 6 Month Co-Primary Endpoints IT-R-005N=203IT-R-006N=218 ITn=100Controln=103p-valueITn=110Controln=108p-value Evaluator Wrinkle Severity Assessment 33(33%)7(7%)< (19%)8(7%) Subject Wrinkle Assessment 57(57%)31(30%) (45%)19(18%)<0.0001

20 CBER Efficacy Conclusions Both co-primary endpoints at six months were met in each of the pivotal studies Results of secondary endpoints supportive of primary efficacy results Efficacy of IT > 6 months has not been demonstrated No studies conducted for effects of repeating treatment cycles

21 CBER Safety Results

22 CBER Safety Overview Safety database Commercial experience Safety Population IT Vehicle- Control Total IT-R-005 & clinical trials (integrated safety population)

23 CBER Safety Monitoring Schedule in 005 & 006 Safety Monitoring Schedule in 005 & 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

24 CBER Adverse Events in IT-R-005 > 1% Preferred Terms Preferred Terms IT N=83 Control N=92 SubjectsEventsSubjectsEvents All treatment-emergent AE 51 (61%) (62%) 219 Administration site conditions Administration site conditions 31 (37%) (35%) 94 (Related to Treatment) (Related to Treatment) 28 (33%) (26%) 76 Injection-site erythema Injection-site erythema 23 (28%) (19%) 28 Injection-site swelling Injection-site swelling 18 (22%) (16%) 27 Injection-site pain Injection-site pain 5 (6%) 6 4 (4%) 5 Injection-site bruising Injection-site bruising 4 (5%) 5 12 (13%) 17 Injection-site nodules Injection-site nodules 2 (2%) 3 2 Injection-site reaction Injection-site reaction 2 (2%) 2 2 Injection-site papules Injection-site papules 2 (2%) 2 1 (1%) 1

25 CBER Adverse Events in IT-R-006 > 1% Preferred Terms Preferred Terms IT n=98 Control n=99 SubjectsEventsSubjectsEvents All treatment-emergent AE 62 (63%) (57%) 172 Administration site conditions 32 (33%) (32%) 84 (Related to Treatment) (Related to Treatment) 29 (30%) (31%) 80 Injection-site erythema Injection-site erythema 14 (14%) 19 6 (6%) 9 Injection-site hemorrhage Injection-site hemorrhage 10 (10%) (15%) 45 Injection-site bruising Injection-site bruising 5 (5%) 6 13 (13%) 20 Injection-site papules Injection-site papules 4 (4%) 4 2 (2%) 2 Injection-site irritation Injection-site irritation 3 (3%) 6 1 (1%) 3 Injection-site swelling Injection-site swelling 3 (3%) 300

26 CBER Related-Adverse Events < 1% in IT-R-005 & 006 StudyGroup Preferred Terms Onset from treatment DurationSeverityAction 005IT Basal cell cancer 7 months after 1 st n/amoderateexcision 005IT Herpes simplex of lip 5 days after 1 st 4 days mildmeds 005IT Post-procedural headache On 2 rd treatment 2 days mildmeds 005Control Swelling under left eye 2 days after 1 st 5 days mildnone 005ControlHeadache On 1 st treatment 1 day moderatemeds 005Control Injection site anesthesia 3.5 months after 3 rd 5.5 months mildnone 005Control Pain in jaw On 1 st treatment 2 days mildnone 005Control Paraesthesia right upper lip 2 days after 1 st 3 days mildnone 005Control Post-procedural discomfort On 1 st treatment 1 day mildnone 006IT Bilateral eyelid edema 1 day after each of 3 treatments 1 st, 2 rd : 1 week 3 rd : > 1 year mildnone 006IT Skin hyperpigmentation 1 day after 2 rd 3 weeks mildnone 006Control Injection site hypersensitivity On 1 st treatment 2 days moderatenone

27 CBER Basal Cell Carcinoma 76 y.o. white female with “sun damage” Three IT treatments in IT-R-005 Detection time: 7 months after first injection Right upper lip near nasolabial fold, tumor: 0.4 cm x 0.4 cm; solar keratosis was found at bridge of nose Possibly related per investigator Intervention: biopsy and Mohs Excision Other AEs: erythema and swelling for 3 days Wrinkle outcome: non-responder per investigator Most recent f/u: no evidence of recurrence 18 months after the surgery

28 CBER Integrated Safety Data in 7 trials StudyPhases Safety Observation (Months)SubjectsIT/ControlTreatmentInterval(Weeks)Indications IT-R-001 Phase /101-2 Rhytids and scars (14 facial areas) IT-R-002 Phase /401-2 Rhytids and scars (14 facial areas) IT-R-003A Phase /591-2 Nasolabial and glabellar (4 areas) IT-R-003B Phase /541-2 Nasolabial and glabellar (4 areas) IT-R-005Pivotal1583/924-6 Nasolabial (2 areas) IT-R-006Pivotal1598/994-6 IT-R-007 Phase /04-6 Forehead, periorbital, cheek, perioral (8 areas) Total (467/354) (injected areas)

29 CBER Injection-Site Reactions (> 1%) Preferred Terms Preferred Terms IT (N=508) Control (N=354) Administration Site Conditions 343 (67%) 144 (40%) (Related to Treatment) (Related to Treatment) 265/508 (52%) 119/354 (34%) Injection-site erythema Injection-site erythema 81 (16%) 33 (9%) Injection-site bruising Injection-site bruising 54 (11%) 48 (14%) Injection-site swelling Injection-site swelling 69 (14%) 15 (4%) Injection-site pain Injection-site pain31(6%) 6 (2%) Injection-site edema Injection-site edema 22 (4%) 0 Injection-site nodules Injection-site nodules 20 (4%) 3 (<1%) Injection-site hemorrhage Injection-site hemorrhage 13 (3%) 16 (5%) Injection-site papules Injection-site papules 8 (2%) 3(<1%) Injection-site irritation Injection-site irritation 6 (1%) 1 (<1%) Injection-site dermatitis Injection-site dermatitis 5 (1%) 2 (<1%) Injection-site pruritus Injection-site pruritus 5 (1%) 3 (<1%) Injection-site reactions Injection-site reactions 5 (1%) 2 (<1%) Injection-site indurations Injection-site indurations 5 (1%) 0

30 CBER Total Injection Site Reactions in Pivotal Trials and Integrated Safety Population>1% StudyIT-R-005IT-R-006 Integrated safety population SubjectsITN=83 Control N=92 ITN=98 Control N=99 ITN=508ControlN=354 Administration Site Conditions 31 (37%) 32 (35%) 32 (33%) 32 (32%) 343 (67%) 144 (40%) Higher frequency of injection site adverse events in integrated safety population Lower frequency of injection site adverse events in 005 & 006 Reasons for the decreased injection site adverse events Increased treatment intervals, decreased treatment areas, enhanced physician training for injection Increased spacing for clinical safety observation intervals

31 CBER Related-Adverse Events < 1% (ISP) Related-Adverse Events < 1% (ISP) Preferred Terms IT N=508 Control N=354 Acne40 Rash20 Eye edema 21 Face edema 31 Herpes labialis 30 Injection site vesicles 10 Hypoaesthesia20 Injection site hypersensitivity 01 Lip paraesthesia 01 Basal cell carcinoma 10 Injection site fibrosis 10 Injection site ischemia 20 Parapsoriasis10 Alopecia areata 10 Hyperpigmentation10 Pain in jaw 01 Headache52 Post-procedural discomfort 01 Toothache01 Chapped lips 10 Dizziness20 Total329

32 CBER Severity of Injection-Site Adverse Events >1% Administration-site conditions IT N=343 Control N=144 Mild 283 (82.5 %) 131 (91%) Moderate 55 (16%) 12 (8%) Severe 5 (1.5%) 1 (<1%) N=subjects reporting injection site adverse events Severity grading: CTCAE V3 (NCI/NIH) 6 cases of severe injection-site adverse events 5 IT subjects: erythema (1), ischemia (1), swelling (2), pain (1) 1 control subject: bruising Resolved within 10 days, no withdrawal

33 CBER Duration of Related-Adverse Reaction>1% AE Duration in Days IT: related events = 444 Control: related events = 207 <1 to (85.5%) 187(90%) 8 to (5%) 13 (6%) 15 to (3.6%) 1 (0.5%) 31 to 60 9 (2%) 2 (1%) 61 to 90 8 (1.8%) 2 (1%) 91 to (0.4%) 0 Ongoing 5 (1%) 0

34 CBER Unresolved Adverse Events (All Subjects in IT Group) Study Adverse Events Treatment Areas Onset Day Duration in Day SeverityAction IT-R- 001 Red,swelling in glabellar Glabellar,perio ral 2ndtreatment357+mild Benadryl Aleve IT-R- 002 Flare of alopecia areata Nasolabial, perioral Third day from 2nd treatment 354+mild Aldara, Kenalog IT-R- 003A Plumpness in upper lip Nasolabial, glabellar A month from 3rd treatment 287+mildno IT-R- 005 Ridge in right nasolabial fold nasolabial A week from 2 nd treatment 409+mildno IT-R- 006 Swelling on both upper eye lids nasolabial Third treatment 396+mildno

35 CBERSubgroups Under-represented subgroups in integrated safety population Safety profiles –Similar common injection-site reactions –No keloid formation reported –Limited information due to small sample sizes Sub-groupsITN=467* Control N=354 TotalN=821 >65 yo 44 (9%) 41 (12%) 85 (10%) Male 42 (9%) 34 (10%) 76 (9%) Non-white 43 (9%) 35 (10%) 78 (10%) * 41 cross-over subjects not included

36 CBER Commercial Experience US: 1,200 + subjects ( ) UK: 7,800 + subjects ( ) Retrospective chart reviews, limited registry Common AEs: red, swelling, rash, lump Three serious adverse event reports –Angioedema –Severe systemic allergic reaction –Lump on the eyelid, requiring surgery

37 CBER Safety Summary Adverse events in >1% injection site redness, bruising, swelling, pain, nodules, hemorrhage, papules, irritation, dermatitis, pruritus Adverse events in <1% Probable facial allergic reactions, flare of herpes labialis, change of skin sensation, post-procedural discomfort Severity and duration of adverse reactions Mild/moderate in severity 5% injection-site events lasting beyond 30 days Five cases unresolved beyond one year One case of injection-site basal cell cancer Two cases of serious allergic reactions in UK Small sample sizes for male, elderly, and non-white Safety observation limited to 12 to 15 months

38 CBER THANK YOU


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