1. Laura Gomes Castanheira ANVISA- Brazil Anvisa’s expereience with the review of Omnitrope and clinical trials authorizations of products under development

2. 2 Omnitrope -Comparability exercise: Omnitrope (Sandoz) x Genotropin (Pfizer) 28 batches Different markets: Europe, USA, Japan Same manufacturer site: Sweden

3. 3 Omnitrope -Comparability exercise: -Primary structure – peptide mapping (mass and UV) - Higher order structure (secundary, tertiary)– Circular Dichroism Spectroscopy ; RMN-H 1 -1D Spectroscopy; UV Pectroscopy. - Mass –MALDI-TOF e LC-ESI. - Hidrofobicity – Cromatography (RP-HPLC). - Charge– Isoeletric Focusing (IEF); Capillary Eletrophoresis (CZE). - Size– Size Exclusion Cromatography (SEC) e SDS-PAGE. - Biological Activity – Cell Propliferation Assay. - Impurity – RP-HPLC; CZE; IEF e SEC. High similarity between Genotropin and Omnitrope

4.  Clinical Part 5 PK/PD studies- 120 health volunteers: - Study EP2K-99-PhISUSA – PK Omnitrope 5,8 mg/vial sc injection X placebo - Study EP2K-99-PHIUSA - PK Omnitrope 5,8 mg/vial sc injection X Genotropin. - Study EP2K-00-PHI AQ - PK Omnitrope 5,8 mg/vial sc injection X Omnitrope 5,0 mg/1,5 ml. - Study EP00-104 - PK Omnitrope 5,8 mg/vial X Omnitrope 5,0 mg/1,5 ml X Genotropin. - Study EP00-105 - PK Omnitrope 5,8 mg/vial X Omnitrope 10,0 mg/1,5 ml X Genotropin. PD criterias: serum concentration- IGF-1, IGFBP-3 time and NEFA PK: C max, T max e AUC. Omnitrope

5. OMNITROPE  Clinical Part 5 Phase III studies, 190 children 3 consective studies (EP2K-99-PhIII, EP2K-00-PhIIIFo e EP2K- 00-PhIII AQ ) Liophilized Omnitrope, liquid Omnitrope and Genotropin, same coorte, 89 patients Study EP2K-00-PhIIIb-E liquid Omnitrope, 50 patients Study EP2K-02-PhIII-Lyophilized Omnitrope- 51 patients

6. 6 CTA products under development

7. Biological product Individual route of development Comparability development Complete dossier Comparative Phase III Comparability exercise Quality, Safety, Efficacy Non innovative biological product Biosimilar Regulatory Paths

8. 8 Product X Individual Development Path CMC part: -Characterization using the assays described bellow. Assays: Eletrophoretic profile; Isoeletric focalization; SEC-HPLC and DLS; RP- HPLC; Circular dichroism; Nucelotide sequencing; Peptide maping; Sialic acid quantification; TNF receptor- ELISA; TNF receptor and human IgG portion- Western blot; Kinetic Assay TNF binding; Biologic assay- mice fibroblasts (ED50) Comparative and non comparative assays.

9. 9 Product X Individual Development Path Non clinical studies: 1 non comparative repeated toxicity studies using rats 1 non comparative acute subcutaneous injection toxicity study using rats 1 chronic subcutaneous injection toxicity study in monkeys 1 PK study in monkeys All the non clinical studies were non comparative but followed the same design and presented similar results already described for reference biological product in scientific literature

10. - Clinical studies in Asia: Phase I: Single dose study: safety and tolerability- 36 health male volunteers 6 weeks study:non comparative single dose PK profile- 30 patients with rheumatoid arthritis. Immunogenicity Phase II: Dose-response, safety and efficacy: double blind – 24 weeks- 300 patients. Comparative to MTX Dosed selected for the Product X was the same defined to RBP Phase III study:safety and efficacy Opened study- around 400 patients Product X x MTX Primary endpoint: ACR 20. Adverse events. Immunogenicity (6 months) *Important to observe that immunogenicity reactions incidence is 5% and it normally starts before 6 months of treatment Case Study II

11. Clinical trials approved in ANVISA: Phase I PK study health volunteers – around 30 patients C max, T max e AUC. Phase III study -Safety and efficacy study, double blind randomized non inferiority study, compared to RBP licensed in Brazil, moderate and severe RA patients - Around 300 patients -ACR 20 primary endpoint - Immunogenicity Case Study II

12. - Clinical indications claimed: Severe Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Juvenile Idiopathic Arthritis Only Severe Rheumatoid Arthritis will be approved Case Study II

13. 13 AcMo Y Comparability path CMC part: - Determination of critical Quality attributes and similarity ranges – - Characterization using the assays described bellow. Assays: Eletrophoretic profile; Isoeletric focalization; SEC-HPLC and DLS; RP- HPLC; Circular dichroism; Nucelotide sequencing; Peptide maping; Sialic acid quantification; Glycosilation profile; purity; binding assays, potency assays (in vivo/in vitro). Comparative assays using at least 8 batches of product Y and RBP

14. 14 AcMo Y Comparability path Non clinical studies: In vitro similarity:binding assays Dose repeated toxicity: cynomolgus monkeys. PK/PD: cynomolgus monkeys Comparative to RBP. High similarity betwenn AcMo Y and RBP

15. 15 AcMo Y Comparability path Clinical studies: Phase I study Patients (non Hodgkin lynphoma ) Cmax, Tmax, AUC Phase III study Double blind randomized comparative with RBP study – non Hodgking lymphoma patients Immunogenicity

16. 16 THANK YOU!