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

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

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

 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 EP PK Omnitrope 5,8 mg/vial X Omnitrope 5,0 mg/1,5 ml X Genotropin. - Study EP 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

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 CTA products under development

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 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 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

- 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

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

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

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 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 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 THANK YOU!