1. Sculptra- P030050 Herbert Lerner, MD Division of General, Restorative and Neurological Devices Plastic and Reconstructive Surgical Devices Branch FDA March 25, 2004

2. Sculptra- Indication for Use Sculptra is intended to correct shape and contour deficiencies resulting from facial fat loss (lipoatrophy) in people with human immunodeficiency virus.

3. Material Sculptra is a sterile solution consisting of: PLLA Sodium Carboxy-methyl cellulose Mannitol Sterile Water

4. SCULPTRA P030050 FDA Review Team Herb Lerner, MD- Clinical & Lead Charles Durfor, PhD- Pre-clinical David Berkowitz, VMD- Toxicology Phyllis Silverman, MS- Statistics Kim Struble- PharmD- Clinical (CDER) Sybil Wellstood- Manufacturing Mary Wollerton- Patient Labeling

5. Sculptra Toxicology Previous Medical uses of Sculptra Components

6. P030050 Toxicology Testing ISO/FDA Test RecommendationResults/Comments CytotoxicityNo cytotoxicity. Test article placed directly on agar surface. SensitizationNo significant sensitization. Sixteen guinea pigs injected intradermally. Systemic ToxicityNo Toxicity. Intraperitoneal injections in mice at IP at 5.6 ml/kg. Subchronic ToxicityNo Toxicity. Intracutaneous 90-days. Normal foreign body reaction to implant material (only 5 sites examined). GenotoxicityNo significant mutagenesis. Bacterial reverse mutation assay. No increase in aberrations. Chromosomal aberration assay. No increase in micronuclei. Mouse micronucleus Assay. HemocompatibilityComplement activation not affected. Measured CH50 and SC5b-9. Normal hemolysis testing not needed.

7. Sculptra Physical Characteristics Molecular weight 40 – 50 thousand PLLA particles irregular shape 40-63 microns ± 2 hours required for optimal suspension Physically chemically and microbiologically stable for 72 hours after suspended.

8. Sculptra Resorption Kinetics No weight loss for 24 weeks in phosphate buffer at pH 7.4 at 37 degrees C. 19% weight loss at 50 degrees C. Foreign material seen histologically after intradermal implantation for 90 days in rats.

9. Resorption rate is function of molecular weight, crystallinity, and particle size. Compact PLLA rods of 95,000 Daltons were implanted subcutaneously in rats. 1 month 19% degraded 3 months40% degraded 6 months56% degraded Published In-Vivo Resorption Studies on PLLA

10. Sculptra New-Fill is the name of the device as it is commercially available outside the US. Sculptra is the intended name of the device as it will be marketed in the US. For this review, the use of these names is interchangeable. The components of the two are identical.

11. SCULPTRA STUDY DESIGN Presented are 5 investigator-sponsored studies. 2 studies are from Europe 3 studies are from the US All were single center studies No study was a randomized, controlled, or blinded study as we are used to seeing for a PMA All were Open label TCT (Total Cutaneous Thickness)

12. Vega Study-France Inclusion Criteria: HIV+ Plasma HIV viral load <5000 copies/ml Current HAART treatment ≥3 months HAART for at least 3 years Buccal adipose tissue <2mm

13. Exclusion Criteria: Cutaneous Kaposi’s Sarcoma of the face Infection or concurrent herpes labialis Previous facial fillers within 6 months Unwilling to meet study follow-up time tables. Vega Study-France

14. Study Design Fifty (50) patients enrolled to study effects if the device over time 47 patients completed the trial, 2 withdrew at 72 weeks (schedules) and 1 withdrew due to an unrelated event. Open label, non-randomized, uncontrolled Vega Study-France

15. Study Design Patients were given bi-weekly injections Safety endpoints designed to look for changes in biological parameters and AE’s Efficacy endpoints change in TCT Vega Study-France

16. Demographics: Age- (mean) 44.9 ± 6.8 Gender- 98% male Race- 84% Caucasian 6% Hispanic 4% North African 2% Black African 4% Carribean Vega Study-France

17. Demographics: AIDS defining event- 50% CD4 count- 397.1± 168 HIV viral load-(median)-200 copies/ml (50- 96k) (viral load <5000 copies/ml- 86% of pts.) TCT cheeks-mean 3.0mm Adipose tissue <2mm Vega Study-France

18. Endpoints: Safety- adverse events Treatment-related events Local and systemic Change from baseline CD4 cells Viral load Blood Lactic Acid levels Vega Study-France

19. Results Bruising- 3% Hematoma- 30% Nodule- 52% Vega Study-France

20. Efficacy- Change from baseline in TCT (mm) Study demonstrated statistically significant increases from baseline to week 96- At 8 weeks mean change 5.2 mm (SD 1.7) At 24 weeks change was 6.4 mm (SD 1.6) At 48 weeks, change was 7.2mm (SD 1.3) At 72 weeks, change was 7.2 mm (SD 1.3) At 96 weeks, change was 7.0mm (SD 1.4) Photographic Assessment Visual Analogue Scale 0-10 scale (with 10 the most satisfying physical/emotional state) Vega Study-France

21. Figure 1: Profile of Dermal Thickness by Ultrasound by Weeks From First Injection Vega Study-France

22. Chelsea & Westminster- England Inclusion Criteria: HIV+ Moderate to severe lipoatrophy Not pregnant or lactating

23. Exclusion Criteria Active opportunistic disease or wasting Current growth hormone therapy Current chemotherapy for malignancy Known hypersensitivity to PLLA Chelsea & Westminster- England

24. Study Design 30 patients Half of group delayed 12 weeks as a comparator 30 pts. Treated 29 pts. Reported (1 declined data disclosure) Chelsea & Westminster- England

25. Study design Two groups of 15, the second group had injections delayed for 12 weeks Clinical exam, serum CD4 and viral loads obtained Facial Ultrasound VAS and HAD (Anxiety/ Depression scores) Chelsea & Westminster- England

26. Demographics: Age- 41 years (mean) Gender- 28 males/ 2 females Race- 72% Caucasian 3% Black 24% Hispanic Chelsea & Westminster- England

27. Demographics: Mead duration of HAART- 5.1 years Mean baseline CD4 count- 473.6 Viral load (median) - 72.0 copies/ml Chelsea & Westminster- England

28. Endpoints: Safety- Change in viral load Change in CD4 count Change in blood chemistry Adverse Events Efficacy- Buccal skin thickness measurements Change in facial appearance- MD and Pt. assessments Chelsea & Westminster- England

29. Chelsea & Westminster Adverse events-combined groups Injection site bruising- 38% Injection site discomfort- 10% Injection site erythema- 10% Injection site inflammation- 10% Injection site nodule- 31% VAS scores improved Clinical lab parameters unchanged

30. BASELINE TO WEEK 12 Chelsea & Westminster

31. Common Finding In Both Studies- Nodule at injection site 52% VEGA 31% C&W Discussion- Onset average up to 218 days (9 to 748) Most reported as mild and not visible No histological data available

32. US Studies APEX-001 Investigator Sponsored Compassionate Use Study Open label, uncontrolled, non-randomized study 100 patients 1-6 treatment sessions (average-3) 1-8 cc of New-Fill per treatment session Demographics similar to previous studies HIV+ 14 years Mean age 44.5 82/96 patients Caucasian

33. Inclusion Criteria HIV+ Demonstrable photographic lipoatrophy Exclusion Criteria Active Infection, Kaposi’s sarcoma or Herpes on the face Facial injections within last 3 months Treatment with interferon or steroids US Studies

34. Safety results- Adverse events considered mild 6 nodules reported in 85 patients at 3 weeks 39 nodules in 70 patients seen at 12 months Efficacy results- High patient satisfaction- 8.8/10 High investigator rating – from 3.2 to 1.36 (lower score is better) US Studies

35. APEX002 Investigator sponsored IDE HIV+ 100 patients Average of 3.5 treatments/patient Similar demographics Average time HIV+ 11.9 yrs Average years HAART therapy- 13 US Studies

36. Adverse Events- mild Soreness and nodules 6 nodules in 99 patients 19 pts. With injection site soreness 2 pts. With transient fever High patient satisfaction- Scores went from 3.71 to under 1 (lower score is better) US Studies

37. US Study- Hermosa Beach Open label, uncontrolled, non-randomized Similar demographics and treatment schedule 1-6 treatments/patient Up to 6 cc per treatment Average time HIV+ 13 years Average time HAART- 9 years US Studies

38. Inclusion/Exclusion criteria Similar to Apex studies HIV+ Lipoatrophy Infections of face, Kaposi's sarcoma Treatment with interferon or steroids Uncontrolled DM, lactic acidosis US Studies

39. Endpoints To evaluate the quantifiable improvement in facial wasting after serial intradermal injections of New-Fill Safety- In repeated treatments Efficacy Durability of New-Fill Psychological impact on patients US Studies

40. Results Adverse events-mild 8 nodules in 87 patients High patient satisfaction Average increase TCT- 6mm @ 6 mos. Average mm initial7.44 Average mm-end of tx.13.92 Average mm- 6 mos.13.22 Average mm- increase 5.78 US Studies

41. Conclusion- Overall Safety In general, the majority of treatment related events are mild pain, bruising and swelling at the injection site. Device events are generally palpable subcutaneous nodules (up to 50%) No major AE’s reported

42. Conclusion- Overall Efficacy TCT analysis in VEGA study demonstrates increased TCT. Dermal thickness changes in the C&W study also demonstrate significant enhancement of dermal thickness Photographic evidence of sustained efficacy is shown

43. Quality of Life assessments show improvement from the baseline Conclusion- Overall Efficacy

44. No masking or use of validated severity scale Total Skin Thickness (TCT) was used as surrogate endpoint for improved appearance Statistically significant (p<0.001) increases in TCT observed in Vega and C&W Studies Treatment effect was independent of time on HAART, baseline CD4 counts, or baseline skin thickness Increase in skin thickness correlated pictorially with improved appearance Statistical Summary

45. Thank you

46. Panel Question-1 21 CFR 860.7(d)(1) states that there is a reasonable assurance that the device is safe when it can be determined that the probable benefits to health from use of the device for its intended uses, when accompanied by adequate instructions for use and warnings against unsafe use, outweigh any probable risks. Considering the data in the PMA, please comment on whether there is a reasonable assurance that the device is safe.

47. Panel Question- 2 21 CFR 860.7(e)(1) states that there is a reasonable assurance that a device is effective when it can be determined, based on valid scientific evidence, that in a significant portion of the target population, the use of the device for its intended uses and conditions of use, when accompanied by adequate directions for use and warnings against unsafe use, will produce clinically significant results. Considering the data in the PMA, is there reasonable assurance that the device is effective?

48. Panel Question- 3 Patients in the European studies (79) were followed-up for periods ranging from 24 weeks to 2 years, and those in the U.S. studies (286) were followed up to 2 years. If you agree that there is enough evidence in the PMA to support the safety and effectiveness of the device, do you feel that a post-approval study to assess the long term use of this device should be initiated, and if so, please advise FDA as to the type of data you feel should be collected, and the appropriate duration of follow-up.

49. Panel Question- 4 A large volume of this device (up to 11cc. per treatment) is required to achieve an optimal cosmetic effect, and precise placement of the material in the correct dermal plane (deep dermis or subcuticular layer) is important. Please advise FDA whether a physician training program is indicated for those wishing to use this device, and if so, what type of training would be appropriate.