EMA Benepali® BARRY Binta BOUVET Audrey BRICAUD Manon DAVROUX Clémence DELPLANQUE Margot DROUGARD Sixtine HIA Cécile LEFEBVRE Laurine MAUGEST Mathilde MEROT Mathilde SAADAOUI Zeineb

Benepali® - Etanercept – SB4 19 January 2012 – 19 July 2012 – 19 December 2013 : Scientific Advice (CHMP). The Scientific Advice pertained to quality, non-clinical and clinical aspects of the dossier. 25 April 2014 : Eligibility to the centralised (EMA/CHMP) 3 December 2014 : Centralised procedure by Samsung Bioepis – within the Article 3(1) and point 1 of Annex of Regulation (EC) No 726/2004.) 24 December 2014 : Start of procedure 19 November 2015 : Positive opinion from the CHMP

Benepali® - Etanercept Tumour Necrosis Factor-alpha (TNF-a) inhibitor Immunosuppressant (ATC code : L04AB01) Single use pre-filled syringes & pre-filled pens 50 mg etanercept / mL Subcutaneous injection

Enbrel® Powder and Solvent for solution for injection 50 mg 25mg Powder and Solvent for solution for injection 10 mg 50 mg Powder for solution for injection 25mg 50 mg Solution for injection in pre-filled syringe 25mg Solution for injection in pre-filled pen 50 mg

Samsung Bioepis - Writing a new history in the field of pharmaceuticals Actively devoted in creating affordable and high-quality biopharmaceutical and biosimilar products. Oncology Diabetes http://www.samsungbioepis.com/

Enbrel® First Biosimilar of Enbrel® Loss of patent : approved in 1998 by FDA approved in 2000 by the European Commission Loss of patent : EU : February 2015 US : October 2012 But Amgen Annouced on 22 November 2011 that it had been granted a new US patent : November 2028 http://www.gabionline.net/Biosimilars/News/New-Amgen-Enbrel-patent-could-block-biosimilars-until-2028

Mechanism of action TNF-a : central cytokine in inflammatory response Macrophages Increased Inflammation (pro-inflammatory cytokines – chemokines) Increase cell infiltration (adhesion molecules) TNF Endothelium Increased angiogenesis (vascular endothelial growth factor VEGF) Hepatocytes Increased CRP in serum (acute phase response) Synoviocytes Articular cartilage degradation (metalloproteinase synthesis) http://pharmacologycorner.com/mechanism-of-action-indications-and-adverse-effects-of-etanercept-infliximab-and-adalimumab/

Mechanism of action TNF-a : central cytokine in inflammatory response http://www.medscape.com/viewarticle/452881_3

Indication Rheumatoid arthritis Psoriatic arthritis Plaque psoriasis Axial spondyloarthritis Ankylosing spondylitis Non-radiographic axial spondyloarthritis Reduce the rate of progression of joint damage as measured by X-ray and improve physical function Same indications as Enbrel except for Juvenile idiopathic arthritis and Paediatric plaque psoriasis

Rheumatoid arthritis (RA) In combination with methotrexate or alone (in case of intolerance to methotrexate) Treatment of moderate to severe active rheumatoid arthritis in adults The most common type of autoimmune arthritis In Europe and the United States, RA affects approximately 0.5 to 1.0% of the population The cause is not known Attacks tissues near joint (hand) and other body parts (eye, lung…) No cure, No single treatment works for all patients Peut survenir à tout âge

Stages of rheumatoid arthritis http://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Rheumatoid-Arthritis#sthash.mECFhLJr.dpuf The immune system attack the body and create inflammation (synovium). Production of cytokines TNF alpha and IL-1: stimulation of chrondrocytes, fibroblasts and osteoclasts. Enzymes can damage cartilage (the tissue that cushions between joints) and bone.

Disease-modifying antirheumatic drugs (DMARDs) Category of otherwise unrelated drugs defined by their use in RA to slow down disease progression Common DMARDs include: Methotrexate Leflunomide Hydroxychloroquine Sulfasalazine Background therapy: inconstant and exhaustible efficacy

TNF inhibitors in RA FDA-approved drugs of this type include : Etanercept (Enbrel) Adalimumab (Humira) Certolizumab (Cimzia) Golimumab (Simponi) Infliximab (Remicade) → biosimilar Remsima Other indications: Crohn’s disease, Ulcerative colitis…

Psoriatic arthritis/ Plaque psoriasis Treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying anti-rheumatic drug therapy has been inadequate. chronic arthritis (distal joints of the fingers and toes, and also the back and sacroiliac joints of the pelvis) 0.06 to 0.2% of the general population (UE) Treatment of adults with moderate to severe plaque psoriasis who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy, including ciclosporin, methotrexate or psoralen and ultraviolet-A light (PUVA). chronic inflammatory skin disease between 0.2 and 4.8% of the general population (UE)

Axial spondyloarthritis/ Ankylosing spondylitis/ Non-radiographic axial spondyloarthritis Treatment of adults with severe active ankylosing spondylitis and non- radiographic axial spondyloarthritiswho have had an inadequate response to conventional therapy. Type of arthritis that attacks the spine and, in some people, the joints of the arms and legs. It can also involve the skin, intestines and eyes AS is 3 X more common in men than in women and most commonly starts between the ages of 20 and 30 years. 0.1 to 1.4% of the general population (UE).

Similar biological application Under Article 10(4) of Directive 2001/83/EC on the basis of a complete dossier Comparability studies are needed to generate evidence substantiating the similar nature, in terms of quality, safety and efficacy The dossier requirements for similar biological medicinal products are found in Part II, Section 4 of the Annex I of Directive 2001/83/EC, as amended. In addition, the following guidelines should be taken into account: Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance – quality issues (EMA/CHMP/BWP/247713/2012) Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues EMEA/CHMP/BMWP/42832/2005 Rev) Administrative information Complete quality data Appropriate non-clinical & clinical data for a similar biological medicinal product http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf

Principle of BIOSIMILAR (based on Guideline on similar biological medicinal products) Biological medicinal product claimed to be “similar” to a reference medicinal product A biosimilar should be highly similar to the reference medicinal product in physicochemical and biological terms. Any observed differences have to be duly justified with regard to their potential impact on safety and efficacy. A stepwise approach is normally recommended throughout the development programme, starting with a comprehensive physicochemical and biological characterisation.  Standard generic approach - demonstration of bioequivalence with a reference medicinal product by appropriate bioavailability studies - which is applicable to most chemically-derived medicinal products is not sufficient to demonstrate similarity of biological/biotechnology-derived products due to their complexity

Dossier requirements for Biosimilars

Similar or Not ? CMC Pre-clinical Clinical

CMC Active substance Finished product biosimilarity Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance – quality issues (EMA/CHMP/BWP/247713/2012) CMC Active substance Finished product biosimilarity

Active substance - Etanercept Recombinant human tumor necrosis factor receptor (p75) Fc fusion protein (TNFR:Fc) Chimeric protein, created through the joining of two or more genes which originally coded for separate proteins. 934 amino acids Molecular weight of approximately 130 kDa Highly glycosylated fusion protein

Marketing Autorisation Holder Manufacture Marketing Autorisation Holder Manufacturer

Manufacturing process Thawing of a vial of the working cell bank (WCB), which is a Chinese Hamster Ovary (CHO) cell line transfected with Benepali expression vector. Serially expanding the culture in cell mass and volume, inoculation into the production bioreactor. Purification : chromatographic steps, virus inactivation and filtration steps and ultrafiltration/diafiltration steps. Genetic stability of the Benepali cell substrate : genetic and phenotypic analysis methods (ICH Guideline 5QB)

Characterisation - ICH Guideline Q6B. Assay Methode Molecular weight Mass spectrometry Amino acid analysis Peptide mapping   N- and C-terminal sequence analysis Liquid chromatography electrospray ionization mass spectrometry/ mass spectrometry N-linked glycosylation sites Met oxidation Disulphide bond analysis Mode of action relevant biological activities Binding assays to TNF-α

Finished product – formulation Active Substance Excipients Etanercept (50 mg/mL) Sodium chloride Phosphate monobasic monohydrate Sodium phosphate diabasic heptahydrate Water for injections Difference with Enbrel : exclusion of L-arginine hydrochloride Impact ? Formulation similar to Enbrel

Finished product – manufacture Thawing of the active substance Homogenization Sterile filtration Aseptic filling into : Pre filled syringe PFS Pre filled pen PFP (PFS is assembled into a pen device) Manufacturing of the full commercial scale process has been validated  

Finished product – stability According ICH guidelines Shelf life : 30 months at 5°C +/- 3°C without significant degradation or other negative impact on quality Enbrel® may be stored at < 25°C for a single period of up to 4 weeks The Applicant is recommended to submit stability data from 2 additional finished product batches to further support storage up to 4 weeks at < 25°C subsequent to long term storage at 5°C +/- 3°C

Finished product – adventitious agents According to ICH guideline Q5A/D Animal derived raw materials come from countries with the lowest possible BSE risk Virus safety testing on the MCB/WCB : free of adventitious virus Virus inactivation and chromatography steps have been validated

Biosimilarity Enbrel® - Benepali® Characterization study References : multiple batches of Enbrel® from the UE, US, Korea markets Test of multiple batches of clinical active substance, clinical finished product, PVR (Process Validation Run) active substance, and PVR finished product → Assess similarity of Benepali® PVR materials to Enbrel from the products of the three markets → Demonstrate comparability of the PVR to the clinical process Structure : primary, secondary and tertiary structure Post-translational modifications (PTMs) Charge Purity Glycosylation Biological activities Critical quality attributes (CQAs) based on the mode of action (MoA) of etanercept and results from structure-activity relationship (SAR) studies Critical quality attributes (CQAs) for assessment of similarity based on the mode of action (MoA) of etanercept and results from structure-activity relationship (SAR) studies

Biosimilarity UE Enbrel® - Benepali® (1) Structure : primary, secondary and tertiary structure Method Results Weight Mass spectrometry Similar Full amino acid sequence Compared to the amino acid sequence encoded by the proposed DNA sequence Identical Peptide mapping LC-ESI-MS/MS after subsequent digestion with different proteases Chromatograms : identical patterns (irrespective of protease used) Integrity N-terminal sequencing C-terminal sequence LC-ESI-MS/MS (liquid chromatography-electrospray ionization-tandem mass spectrometry) Two forms in both Size exclusion chromatography Dimer Hydrophobicity Hydrophobic interaction chromatography Difference  Structure-Activity Relationship  no impact LC-ESI-MS/MS : ionisation par électronébuliseur liquid chromatography-electrospray ionization-tandem mass spectrometry

Biosimilarity UE Enbrel® - Benepali® (2) 2. Post-translational modifications (PTMs) Method Results Met oxidation Deamidation level of Asn Disulphide bonds LC-MS LC-ESI-MS/MS Relative content of the oxidised form : similar Minor differences  effect on FcRn binding affinity : no Comparable Molar concentration of free sulfhydryl content and the %free sulfhydryl Minor differences But 58 Cys residues linked by disulphide bonds and practically no free Cys residue Relative level of the Lys variant Lower in Benepali : most of the Lys on the C-terminus of Benepali has been found cleaved → impact ? neonatal fc Asparagine Oxydation méthionine Methionine : antioxydant comme cytéine

Biosimilarity UE Enbrel® - Benepali® (3) 3. Charges Method Results Charge of the product (charge variant content) CEX-HPLC (Cation exchange high performance chromatography) %Main + %Acidic : higher %Basic (caused by the difference in the content of C-terminus with Lys) : lower → SAR study Difference in TNF-α binding activities ? Non clinical 4. Purity Determination of purity and manufacturing consistency Capillary Electrophoresis-Sodium Dodecyl Sulfate Comparable peak profile

Biosimilarity UE Enbrel® - Benepali® (4) 5. Glycosylation Method Results N-linked glycosylation sites LC-ESI-MS/MS Identical N-glycan structures Similar Quantity of N glycan structures HILIC-UPLC (Hydrophilic interaction ultra-performance liquid chromatography) Different : N-glycan profiles different - Fucosylated glycan higher associated with FcγRIIIa binding activity and ADCC  Impact ?  non clinical studies - Neutral galactosylated glycan : More variable, generally associated with CDC activity for monoclonal antibodies  impact ? non clinical studies O-linked glycosylated peptides reverse phase (RP)-UPLC coupled to ESI-MS/MS. O-glycan profile, sialic acid content similar Hydrophilic interaction ultra-performance liquid chromatography (HILIC-UPLC) Indice de fluidité Diffusion dynamique de la lumière

Biosimilarity UE Enbrel® - Benepali® (5) 6. Biological activities Method Results Binding affinities FcγRIa, FcγRIIa, FcγRIIb, FcγRIIIa, and FcRn binding assay, TNF-α binding from different species, apoptosis, C1q binding, CDC, and ADCC Similarity Others Method Results - Quantification and visualisation of sub-visible particles - Sub-visible aggregates MFI (Melt flow imaging) DLS (dynamic light scattering) Particule concentration lower Similar Forced-degradation stability active substance and finished product high temperatures (accelerated and stress conditions), forced degradation (freeze-thaw and oxidation) photostability studies Degradation profiles comparable  stored in a carton protected from light compare the degradation profiles of Benepali active substance and finished product with Enbrel. The comparative stability studies have involved high temperatures (accelerated and stress conditions), forced degradation (freeze-thaw and oxidation) and photostability studies.

Biosimilarity UE Enbrel® - Benepali® - conclusion Information about the active substance and finished product  acceptable quality. Sufficient evidence regarding the manufacturing processes has been provided. Active substance and the finished product : be reproducibly manufactured Specification limits and analytical methods are suitable to control the quality of the active substance and the finished product. The finished product was well characterised, but some differences  Impact ?  non clinical studies The stability program is considered satisfactory. The results generated during the stability studies support the proposed shelf life and storage conditions as defined in the SmPC

Similar or Not ? CMC Pre-clinical Clinical

Primary pharmacodynamic studies Pharmacokinetics Toxicology Non Clinical Studies Primary pharmacodynamic studies Pharmacokinetics Toxicology

Primary pharmacodynamic studies

In Vitro Studies Mechanism of Action Related Assays Investigated Fab-related biological activities: TNF-α, LT-α3 Binding Assays and a TNF-α Neutralisation Cell Based Assay To analyse the relative binding potency of SB4 or Enbrel® to TNF-α or LT-α3, Fluorescence Resonance Energy Transfer (FRET)-based assays were developed and qualified.  Did not show a statistically significant difference between SB4 and Enbrel

In Vitro Studies Non-Mechanism of Action Related Assays = Because clinical outcomes of etanercept are not related to Fc-related binding activities Predominant function of the Fc region in etanercept is to prolong the half-life rather than to impart Fc-mediated efficacy Binding affinity tested: FcγRIa-, FcγRIIa-, FcγRIIb-, FcγRIIIa (V-type)-, and FcRn-binding Effets non liés au mécanisme d’action: l’activité clinique de l’etanercept n’est pas lié aux liaisons aux récepteurs Fc, cette liaison est liée à la prolongation de la demi-vie du médicament. Les tests d’affinités de liaison effectuées portents sur les récepteurs Fc gamma Ia IIa IIb et IIIa et néonatal.

In Vitro Studies  Did not show a statistically significant difference between SB4 and Enbrel®

Additional functionnal Assay to compare SB4 with EU Enbrel® : - FcγRIIIa (F158 allotype), FcγRIIIb and C1q binding assays, - a complement-dependent cytotoxicity (CDC) assay, - an antibody dependent cell-mediated cytotoxicity (ADCC) assay, - an apoptosis activity assay. Autres tests effectués pour caractériser les fonctions ou propriétés de SB4 par rapport à Enbrel : Tests de liaisons aux Recepteur Fc gamma IIIa de l’allotype F158, le IIIb et le C1q Cytotoxicité dépendante du complément Cytotoxicité dépendante de l’anticorps Activité apoptotique

In vivo Model of Collagen-induced Arthritis Aims: demonstrate similar suppressive activity of SB4 and Enbrel® on TNF-α mediated pathology in a mouse (BALB/c) model of collagen antibody-induced arthritis (CAIA) SB4 and Enbrel® suppressed the development of arthritis which was determined by footpad volume changes  No significant differences were detected among treated groups in the majority of study endpoints Modèle in vivo de l’arthrite Buts : démontrer que l’activité suppressive de SB4 et enbrel sur les pathologies liées au TNF alpha sont similaires. Le score dépend de 5 paramètres : inflammation, pannus, dommage du cartilage, changements du périoste et résorption osseuse), sachant que 0 = normal et 5 = sévère

The Applicant did not present any data on Secondary pharmacology, Safety pharmacology, PD drug interactions. In line with the CHMP guidance on similar biological medicinal products containing monoclonal antibodies (EMA/CHMP/BMWP/403543/2010).

Pharmacokinetics

Pharmacokinetic Absorption RD-00407: Pharmacokinetics study of SB4 in Sprague-Dawley rats PK chez e rat

Pharmacokinetic The Applicant did not present any data on Distribution Metabolism and excretion PK drug interaction → In line with the CHMP guidance on similar biological medicinal products containing monoclonal antibodies (EMA/CHMP/BMWP/403543/2010).

Toxicology

Toxicology Repeat dose toxicity 2064-004: A 4-week repeat dose toxicity study of SB4 in Cynomolgus monkeys Aim: evaluate the potential subchronic toxicity, toxicokinetic and immunogenicity profiles of SB4 and Enbrel® Three-arm study Cynomolgus monkeys (n=3/gender/group) received 1 mg/kg (low dose, representing the human clinical dose) or 15 mg/kg (high dose) of SB4 or EU Enbrel (or US Enbrel®) in prefilled syringes, administered via bolus injection subcutaneously twice weekly on Days 1, 4, 8, 11, 15, 18, 22, and 25.

Toxicology Toxicocinetic

Toxicology The Applicant did not present any data on - Single dose toxicity - Genotoxicity – because repeat dose toxicity studies did not indicate any cause of concern - Carcinogenicity - Reproduction toxicity → In line with the CHMP guidance on similar biological medicinal products containing monoclonal antibodies (EMA/CHMP/BMWP/403543/2010), and the CHMP guidance on similar biological medicinal products (EMEA/CHMP/BMWP/42832/2005).

Toxicology Local tolerance - No separate studies CHMP guideline on similar biological medicinal products containing mAbs : Studies on local tolerance are usually not required. If excipients are introduced for which there is no or little experience with the intended clinical route, local tolerance may need to be evaluated. If other in vivo studies are performed, evaluation of local tolerance may be part of the design of that study instead of the performance of separate local tolerance studies. Histopathological assessments of local (injection site) tolerance in the 2064.004 study : were carried out in the 4-week repeat-dose toxicity study in Cynomolgus monkeys No toxicologically significant differences in injection site  Similarity between SB4 & Enbrel®

Toxicology Other toxicity studies - Immunogenicity assessment of SB4 in comparison with Enbrel® was included into the repeat-dose toxicity study in Cynomolgus monkeys (2064-004).

Toxicology Ecotoxicity/environmental risk assessment No environmental risk assessment was performed in line with the CHMP Guideline on the environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00)  Proteins are exempted from the need for an assessment of impact on the environment because they are unlikely to result in significant risk to the environment

Similar or Not ? CMC Pre-clinical Clinical

Overview of clinical studies

PK STUDY

Clinical Studies

PK studies Similarity in PK/ immunogenicity studies? SB4-G11-NHV Single dose PK study in healthy volunteers n=138 SB4-G31-RA Steady-state PK explorative subset Long-term study in RA patients n=79 as supportive

PK studies : SB4-G11-NHV in healthy volunteers Enrollment SB4 EU sourced Enbrel® US sourced Enbrel® Randomization 1:1 N=138 PK parameters to explore AUC, Tmax, Cmax, Vd, T1/2 Full PK profile Concordance with biosimilar guideline of CHMP Etude PK chez les patients sains = population la plus homogène Pour faire une étude comparative de PK Design en ligne avec les recos Résultats sur primary endpoint rentre bien dans le rang accepté prdefinié Étude descriptive de PK 28days washout Period 1 1 SC injection 50mg SB4 or EU sourced Cross-over Period 2 1 SC injection 50mg SB4 or EU sourced

PK studies : RESULTS Primary end-point = SD PK le plus representatif de la comparativité ( faite chez les volontaires sains) SD = Ecart type

PK studies : SB4-G31-RA PK study: 79 patients N= 41 SB4 N= 38 Etanercept EU

PK studies : SB4-G31-RA Following PK parameters W0- S24 : Concentration serum ( Ctrough) (2, 4, 8, 12, 16, 24) W8: AUC, Cmax, Cmin, degree of fluctuation, Tmax, CL/F, T1/2 Figure: Concentration-time curve at steady state

PK studies : SB4-G31-RA - rESULTS + 30 % + 26 % Results Mean exposure parameters were higher (+ 30% for AUCτ, 26% for Cmax and 42% for Cmin) following Benepali (SB4) than with EU Enbrel. The median Tmax was comparable (approximately 48 hours) The PK parameters showed considerable inter-subject variability (CV%), ranging from 35.1% to 71.5% following Benepali (SB4) and from 31.0% to 67.0% with EU Enbrel The PK parameters showed considerable inter-subject variability (CV%), ranging from 35.1% to 71.5% following Benepali (SB4) and from 31.0% to 67.0% with EU Enbrel. = 48h + 42 %

PK STUDY SUMMARY Absorption: No data for SB4 Distribution: data from healthy subjetcs : range between 10.3 and 11.2 l Elimination : calculated in healthy subjects : about 106 h ~ 4 days after s.c. administration Dose proportionality and time dependencies : no data administered at the recommended therapeutic of Enbrel® Special populations : No studies were performed Pharmacokinetic interaction studies : not required for a similar biological medicinal product.

Bioequivalent Biosimilar PK studies Conclusion Bioequivalent Biosimilar Extrapolation possible for other approved therapeutic indication of Enbrel® C-terminal Lys variation that is known not to impact PK profiles

Clinical study Efficacy

Study SB4-G31-RA Recruitment Study initialization date = 11 June 2013 Week 24 cut-off date = 21 July 2014 Study completion date = 28 November 2014 A total of 73 study centers across 10 countries Methods “A randomised, double-blind, parallel group, multicentre clinical study to evaluate the efficacy, safety, pharmacokinetics and immunogenicity of SB4 compared to Enbrel® in subjects with moderate to severe rheumatoid arthritis despite methotrexate therapy. “ Phase III study

Study SB4-G31-RA Main inclusion criteria Male or female aged 18-75 years old at the time of signing of the consent form Had been diagnosed as having RA according to the revised 1987 American College of Rheumatology (ACR) criteria for at least 6 months, but not exceeding 15 years prior to screening Had moderate to severe active disease despite MTX therapy Had been treated with MTX for at least 6 months prior to randomisation and be on stable dose of MTX 10-25 mg / week given orally or parentally for at least 4 weeks prior to screening Main exclusion criteria Had been treated previously with any biological agents including any TNF-α inhibitor …

4 weeks of safety follow-up Study design Randomization 1:1 Benepali (N=299) + MTX Week 24 (N=247) Up to Week 52 (N=224) 4 weeks of safety follow-up Enbrel (N=297) + MTX Week 24 (N=234) Up to Week 52 (N=216)

Efficacy Objectives and endpoints Primary objective : equivalence of ACR 20 at 24 weeks Primary criteria: ACR20 response rate at Week 24 equivalence on subjects with moderate to severe rheumatoid arthritis (RA) despite methotrexate (MTX) therapy ACR 20 : at least 20% improvement in tender and swollen joint counts Secondary objectives : evaluation of efficacy with other endpoints than ACR20, safety, tolerability, PK, immunogenicity compared to Enbrel® Secondary criteria : - ACR 50, ACR 70 at 24 and 52 weeks, ACR20 at 52 weeks - ACR-N - AUC of ACR-N - DAS28 score - EULAR Response - AUC DAS28 - Major clinical response - Change in Total Sharp Score nombre d'articulations sensibles et enflées

In accordance with CHMP/EMA guidelines and Enbrel previous studies : Study SB4-G31-RA Sample size and statistics The ACR20 responses to patients treated with Enbrel previous studies used (response rate at week) Calculation for equivalence margin and sample size : - Equivalence margin = 15 % - Sample size of 249 per arm (overall sample size of 498) = given 80% power accounting Overall 596 subjects randomised into the study = providing 87% power to the study Randomization blinding… In accordance with CHMP/EMA guidelines and Enbrel previous studies : - ACR20 response rate at week 24 as primary efficacy endpoint considered acceptable and representative of the clinical status in RA - Equivalence margin in the range of 10-15% agreed upon in Scientific Advice To preserve at least 50% of the effect of Enbrel over and above placebo, an equivalence limit of 15% was used for the primary analysis. for the 12% drop rate when the expected ACR20 response rate was assumed as 60% at Week 24 Overall 596 subjects randomised into the study due to the high number of subjects recruited during the last phase of the enrolment, which resulted in providing 87% power to the study.

Study SB4-G31-RA Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (18 December 2014 EMEA/CHMP/BMWP/42832/2005 Rev1) “it is recommended to generate the clinical data required for the biosimilar comparability exercise with the biosimilar product derived from the commercial manufacturing process and therefore representing the quality profile of the batches to become commercialized” “In the absence of surrogate markers for efficacy, it is usually necessary to demonstrate comparable clinical efficacy of the biosimilar and the reference medicinal product in adequately powered, randomised, parallel group comparative clinical trial(s), preferably double-blind, by using efficacy Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues EMEA/CHMP/BMWP/42832/2005 Rev1 Page 10/13 endpoints. The study population should generally be representative of approved therapeutic indication(s) of the reference product and be sensitive for detecting potential differences between the biosimilar and the reference” “extrapolation of clinical data to other indications of the reference product could be acceptable, but needs to be scientifically justified” It is expected that the safety and efficacy can be extrapolated when biosimilar comparability has been demonstrated by thorough physico-chemical and structural analyses as well as by in vitro functional tests complemented with clinical data (efficacy and safety and/or PK/PD data) in one therapeutic indication”

Study SB4-G31-RA Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues (30 May 2012 EMA/CHMP/BMWP/403543/2010) “Therefore, in general the most sensitive patient population and clinical endpoint is preferred to be able to detect product-related differences, if present and, at the same time, to reduce patient and disease-related factors to a minimum in order to increase precision and to simplify interpretation” “Comparability should be demonstrated in scientifically appropriately sensitive clinical models and study conditions (whether licensed or not), and the applicant should justify that the model is relevant as regards efficacy and safety, and sensitive to demonstrate comparability in the indication(s) applied for” Guidance for Clinical Development Programs for Drugs, Devices, and Biological Products for the Treatment of Rheumatoid Arthritis (RA) (01/01/1999/FDA) To support the claim of reduction in signs and symptoms, a clinical trial should be at least six months’ duration unless the product belongs to an already well-characterized pharmacologic class (e.g. NSAIDs) In particular, because methotrexate is used to treat many patients with RA, the potential for immunosuppression from combination therapy should be assessed

Study SB4-G31-RA Statistical methods Full Analysis Set = FAS = All subjects who were randomized at the Randomization Visit ≈ ITT Per-protocol Set 1 = PPS1 = PPS1 = All FAS subjects who completed the Week 24 visit and had an completely adherence Primary Variable Analysis Primary efficacy endpoint = Proportion of subjects meeting the ACR20 response criteria for RA at Week 24. H0 = Either (1) SB4 is inferior to Enbrel or (2) SB4 was superior to Enbrel® based on a pre-specified equivalence margin. H1 = Equivalence between the two treatment groups declared if the two-sided 95% (CI) of the difference in ACR20 response rate between SB4 and Enbrel® was entirely contained within the equivalence margin of [–15%, 15%]. Parametric ANCOVA method

Results

Results

Study SB4-G31-RA To go further : Sensitivity Analysis To explore the robustness of the ACR20 responses = Same analysis for the PPS1 and the FAS Additional analyses (logistic regression analysis) To go further : Discussion on clinical efficacy Choice of the clinical setting for the single pivotal equivalence trial = Rheumatoid arthritis patients not adequately controlled with methotrexate = in line with CHMP guidance Clinical model considered sufficiently sensitive = Approved therapeutic indications of Enbrel RA = Enable the detection of differences between biosimilar candidate and originator Validated and reasonably sensitive methods to study the disease activity of RA = Allow for the detection of any possible differences between the compared products Main inclusion/exclusion criteria comparable with the referenced trials and well balanced between study arms Enbrel in terms of proportion of ACR20 responders at week 24. The fact that upper and lower 95% CI bounds of difference in fact do not exceed 10% provided further assurance for Benepali (SB4) being similar to Enbrel, and would even accommodate a more stringent equivalence margin which had been proposed in the Scientific Advice procedure EMA/CHMP/SAWP/9771/2012.

Study SB4-G31-RA Conclusion Study SB4-G31-RA conducted in RA patients = provided robust evidence of equivalence between Benepali® and Enbrel® based on ACR20 response at Week 24, the primary endpoint, and this was supported by most secondary efficacy parameters and sensitivity analyses.

CLInical safety

PK studies Similarity in PK/ immunogenicity studies? SB4-G11-NHV Single dose Safety study in healthy volunteers n=138 SB4-G31-RA Safety + Immunogenicity Long-term study in RA patients n=569

Clinical Safety Safety information was derived from the clinical study SB4-G31-RA in RA patients as an appropriate study population for showing biosimilarity, and further supported by the clinical study SB4-G11-NHV in healthy subjects pooled safety analysis was not applicable (heterogeneity population) Results Any Adverse events

Clinical Safety Patient incidence of injection-site reactions (5.7%) at week 24 appeared lower than expected (36% in Enbrel SmPC) Contributed to the observed variation of risk were the lack of L-Arginine and the lack of latex in the needle shield in Benepali. Serious advers events/ adverse events of special interest The proportion of patients who experienced any SAEs was comparable between the Benepali® (SB4) and EU Enbrel treatment groups

Clinical Safety : immunogenicity assay Design Electrochemiluminescence assays, using SB4 as both capturing and detection antigen Single-dose Safety study: None of the 45 individuals in the SB4 arm ADAs 7 out of 45 in the Enbrel arm had antibodies, one with neutralising capacity Une perte d’efficacité et des problèmes de tolérance comme des réactions anaphylactiques ou des vascularites accompagnent le développement d’ADA. A côté des réactions immunitaires vis-à vis-des biothérapies, phénomène global qui concerne toute cette classe, certaines molécules comme les anti-TNF⍺ peuvent en plus entraîner une réponse auto-immune, qui se manifeste notamment par la production d’anticorps antinucléaires (ACAN). Le développement d’ACAN a été associé au lupus induit, et dans le psoriasis il pourrait être un marqueur d’échec au traitement par anti-TNF⍺. En se centrant sur le psoriasis, cet article fait le point sur les conséquences et les défis liés au développement d’anticorps anti-biothérapies et d’autoanticorps en thérapeutique humaine. Nab vérifie la neutralisation 

Clinical Safety : immunogenicity assay Design In Study SB4-G31-RA, blood samples tested for ADA. Analytique method Serum samples ( with ADA), neutralising antibody (Nab) assay to evaluate the effects of ADAs on the ability of etanercept to provide competitive inhibition of TNFα. In Study SB4-G31-RA, blood samples for the analysis of immunogenicity were collected at baseline and Weeks 2, 4, 8, 12, 16, 24, and 52 and tested for anti-drug antibodies (ADA). Serum samples in which ADA were detected would be reflexed to a neutralising antibody (Nab) assay to evaluate the effects of ADAs on the ability of etanercept to provide competitive inhibition of TNFα.

Clinical Safety Une perte d’efficacité et des problèmes de tolérance comme des réactions anaphylactiques ou des vascularites accompagnent le développement d’ADA. A côté des réactions immunitaires vis-à vis-des biothérapies, phénomène global qui concerne toute cette classe, certaines molécules comme les anti-TNF⍺ peuvent en plus entraîner une réponse auto-immune, qui se manifeste notamment par la production d’anticorps antinucléaires (ACAN). Le développement d’ACAN a été associé au lupus induit, et dans le psoriasis il pourrait être un marqueur d’échec au traitement par anti-TNF⍺. En se centrant sur le psoriasis, cet article fait le point sur les conséquences et les défis liés au développement d’anticorps anti-biothérapies et d’autoanticorps en thérapeutique humaine. Nab vérifie la neutralisation 

Clinical Safety The results of the ADA assays demonstrate that SB4 is not more immunogenic than Enbrel SB4 showed a favourable profile compared to Enbrel®

Immunogenicity RESULTS No correlation demonstrated between ADA & administration site reactions The ADA formation did not seem to cause a different efficacy profile, neither in ADA positive nor negative patients Not have a bearing in establishing biosimilarity between Benepali® and Enbrel® The potential impact of ADA status on administration site reactions was also investigated but did not demonstrate any correlation between the two. The ADA formation did not seem to cause a different efficacy profile, neither in ADA positive nor negative patients and therefore does not have a bearing in establishing biosimilarity between Benepali and Enbrel.

Similar or Not ? CMC Pre-clinical Clinical

Post-Marketing

Risk management plan Educational material Prescribe the product on the correct and safe use of the pre-filled pen/prefilled syringes Inform them that the product is not for paediatric use Patient Alert Card which is to be given to patients using Benepali®

quick reference guide for benepali® - pre-filled pen

quick reference guide for benepali® - pre-filled syringe

Risk management plan Educational material Prescribe the product on the correct and safe use of the pre-filled pen/prefilled syringes Inform them that the product is not for paediatric use Patient Alert Card which is to be given to patients using Benepali® The Patient Alert Card should contain the following key elements for patients treated with Benepali® The risk of opportunistic infections and tuberculosis (TB) The risk of Congestive Heart Failure (CHF) Benepali® is not for use in children

Patient alert Card

Studies in post-authorisation development plan Final results Objectives SB4-G31-RA 2016 open-label extension of the clinical trial (RA): safety The British Society for Rheumatology Biologics Register-rheumatoid arthritis (BSRBR-RA) 2027 national prospective study; to assess long-term toxicity from the use of these agents in routine practice Rheumatoid Arthritis Observation of Biologic Therapy A prospective, observational cohort study ; to evaluate the long-term effectiveness, safety, and costs associated with TNF in the treatment of RA vs treatment with non-biological DMARD Anti-rheumatic Therapies In Sweden (ARTIS) A national prospective, observational, uncontrolled cohort study; to evaluate the risk of selected adverse events in RA, JIA, and other rheumatic disease patients treated with etanercept. British Association of Dermatologists Biologic Interventions Register A nationwide registry in the UK to assess the long-term safety of biological treatments for psoriasis. 5 studies/ DMARM disease-modifying anti-rheumatic drugs

Conclusion

BENEPALI ® Guidelines Key concepts of biosimilar development programmes : specific guideline for monoclonal antibodies and similar biological medicinal products containing biotechnology devied proteins as active substance: quality issues Characterisation Key point in the development of a biosimilar product Equivalence Efficacy and safety studies Similar to Enbrel® : Same indications except pediatric Differents dose regimens Risk-management plan to confirm the long-term efficacy and safety of a biosimilar