1. 1 Cellular, Tissue and Gene Therapies Advisory Committee Meeting azfibrocel-T (previously Isolagen Therapy (IT)) BLA 125348 Proposed Indication: Treatment of moderate to severe nasolabial fold wrinkles October 9, 2009 U.S. Food and Drug Administration CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

2. 2 FDA Presenters Terrig Thomas, PhD - Product Manufacture Division of Cellular and Gene Therapies Office of Cellular, Tissue and Gene Therapies Agnes Lim, MD - Clinical Efficacy Yao-Yao Zhu, MD - Clinical Safety Division of Clinical Evaluation, Pharmacology and Toxicology Office of Cellular, Tissue and Gene Therapies Shiowjen Lee, PhD - Statistics Division of Biostatistics Office of Biostatistics and Epidemiology U.S. Food and Drug Administration CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

3. 3 azfibrocel-T Review Team Product Terrig Thomas, PhD Donald Fink, PhD Clinical Agnes Lim, MD Yao-Yao Zhu, MD Bruce Schneider, MD Changting Haudenschild, MD Statistics Shiowjen Lee, PhD Pharmacology/Toxicology Shamsul Hoque, PhD Project Management Lori Tull, RAC Labeling Lisa Stockbridge, PhD Bioresearch Monitoring Janet White, CSO Epidemiology Craig Zinderman, MD, MPH Aileen Buckler MD, MPH Alan Ou, MD, MPH Manufacturing and Product Quality Gang Wang, PhD, Randa Melhem, PhD CDER Consult Jane Liedtka, MD CDRH Consults Charles Durfor, PhD, Janette Alexander, MD U.S. Food and Drug Administration CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

4. 4 azfibrocel-T - Product Manufacturing azfibrocel-T is an autologous cell product composed primarily of a suspension of viable cultured fibroblasts expanded from a patient’s skin biopsy –Source material –Manufacturing Process overview –Cellular characteristics –Final product testing –Potency assay

5. 5 azfibrocel-T - Product Manufacturing Source Material – Post-Auricular Biopsy Biopsies are performed in the physician’s office Three 3mm punch biopsies are taken and placed in sterile medium Biopsies are shipped overnight to the manufacturing facility at 2-8°C

6. 6 azfibrocel-T - Product Manufacturing Cell Harvest Cryopreservation (testing completed) Thaw + wash cells Formulation of azfibrocel-T 1.0 – 2.0 x 10 7 cells/ml in DMEM w/o Phenol Red Cell Isolation from Biopsies Cell Expansion (2 – 3 passages) Ship to Physician (o/n 2-8°C) Morphology Cell count/viability Mycoplasma Endotoxin Sterility Cell count/viability Cell identity Gram Stain Endotoxin Sterility Potency QC TESTING ~ 90 days

7. 7 Morphology and Cellular Characteristics Fibroblasts proliferate more rapidly in vitro than other dermal cell types and represent ≥ 98% of the cells in azfibrocel-T Keratinocytes comprise up to 2% of azfibrocel-T

8. 8 Morphology and Cellular Characteristics Cell growth and morphology are monitored throughout the cell expansion phase to distinguish normal fibroblasts from transformed fibroblasts and other cell types –Any cultures exhibiting abnormal growth or morphological characteristics will be discarded –During the pivotal trials there were no reported occurrences of abnormal cell morphology during the manufacture of azfibrocel-T

9. 9 azfibrocel-T - Final Product Testing Each test method is proprietary and under review by the Agency TestResult SterilityAbsence of microorganisms MycoplasmaNegative PurityEndotoxin - below acceptance limit Identity≥ 98% Fibroblasts Potency Cell count (1.0 to 2.0 x 10 7 cells/ml) Viability (within defined limit) Collagen production (within defined limit)

10. 10 azfibrocel-T Potency Assay The mechanism of action of azfibrocel-T has not been defined The rationale for collagen production as part of the potency assay is based on the premise that: Collagen is a primary component of dermal connective tissue and the major extracellular matrix protein synthesized by fibroblasts Fibroblast survival and collagen biosynthesis are proposed to be important factors for azfibrocel-T improvement of nasolabial fold wrinkles

11. 11 Summary No specific questions on the manufacture of azfibrocel-T are being posed to the Committee Elements of the manufacturing process may be relevant to the clinical discussion of the safety and efficacy questions