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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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)

8. Mechanism of action TNF-a : central cytokine in inflammatory response

9. 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

10. 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

11. Stages of rheumatoid arthritis
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.

12. 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

13. 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…

14. 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)

15. 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).

16. 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

17. 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

18. Dossier requirements for Biosimilars

19. Similar or Not ?
CMC
Pre-clinical
Clinical

20. 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

21. 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

22. Marketing Autorisation Holder
Manufacture
Marketing Autorisation Holder
Manufacturer

23. 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)

24. 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

25. 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

26. 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  

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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.

35. 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

36. Similar or Not ?
CMC
Pre-clinical
Clinical

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

38. Primary pharmacodynamic studies

39. 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

40. 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.

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

42. 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

43. 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

44. 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).

45. Pharmacokinetics

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

47. 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).

48. Toxicology

49. Toxicology Repeat dose toxicity
: 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.

50. Toxicology
Toxicocinetic

51. 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).

52. 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 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®

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

54. 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

55. Similar or Not ?
CMC
Pre-clinical
Clinical

56. Overview of clinical studies

57. PK STUDY

58. Clinical Studies

59. 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

60. 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

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

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

63. 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

64. 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 %

65. 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.

66. 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

67. Clinical study
Efficacy

68. Study SB4-G31-RA Recruitment Study initialization date = 11 June 2013
Week 24 cut-off date = 21 July 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

69. Study SB4-G31-RA
Main inclusion criteria
Male or female aged 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 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 …

70. 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)

71. 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

72. 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.

73. 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”

74. 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

75. 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

76. Results

77. Results

78. 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.

79. 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.

80. CLInical safety

81. 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

82. 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

83. 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

84. 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 

85. 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.

86. 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 

87. 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®

88. 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.

89. Similar or Not ?
CMC
Pre-clinical
Clinical

90. Post-Marketing

91. 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®

92. quick reference guide for benepali® - pre-filled pen

93. quick reference guide for benepali® - pre-filled syringe

94. 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

95. Patient alert Card

96. 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

97. Conclusion

98. 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