Post on 18-Dec-2021
a Novartis company
Biosimilars today and tomorrow Dr. Jörg Windisch, Head Global Technical Development PMCA Impuls Vienna, April 23, 2012
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Patient access is at risk because biosimilars are expensive...
“A breast cancer patient’s annual cost for Herceptin is $37,000…
People with rheumatoid arthritis or Crohn’s disease spend $50,000 a year
on Humira…
…and those who take Cerezyme to treat Gaucher disease….spend a staggering
$200,000 a year…
“…the top six biologics already consume 43% of the drug budget for Medicare
Part B”
Estimated daily treatment costs1 in USD per day
Small molecule drugs
Biopharma-ceuticals
1 Source: NY Times, March 2010
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The “Biologics Boondoggle”
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...and there are many By 2016, seven of the top 10 pharmaceuticals worldwide will be biologics1
Product Type 2016 Rev. (USD bn)
2010 Rev. (USD bn)
1. HUMIRA Biologic 10.0 6.7
2. AVASTIN Biologic 7.7 6.2
3. RITUXAN Biologic 7.6 6.1
4. ENBREL Biologic 7.1 7.3
5. CRESTOR Small molecule 7.5 6.0
6. SERETIDE/ADVAIR Respiratory / device 6.7 7.9
7. REMICADE Biologic 6.2 6.5
8. HERCEPTIN Biologic 6.3 5.2
9. REVLIMID Small molecule 6.1 2.5
10. LANTUS Biologic 5.3 4.7
1 Source: Evaluate Pharma, Sandoz analysis
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Biologics are more complex than small molecules…
Erythropoietin
simple biologic small chemical molecule
Calcitonin
complex biologic
Aspirin®
Molecular weight = 180 Daltons 0 amino acids
Molecular weight = 30,600 Daltons ~ 165 amino acids
- with host cell modifications (e.g. glycosylation)
- produced in mammalian cells
Molecular weight = 3,455 Daltons ~ 32 amino acids
- w/o host cell modifications - produced in yeast, bacteria
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…and are produced from living organisms
Modify host cells (e.g., bacteria, mammalian yeast) to produce recombinant proteins
Extract, refold, purify (downstream) – generate drug substance
Formulate to stable finished drug product (vial, syringe, cartridge)
Grow cells under controlled conditions (fermentation)
.
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Sandoz is a leader in developing and manufacturing biosimilars
Biologics development and manufacturing experience: 66 years of experience in pharmaceutical biotechnology 32 years of experience in rec. therapeutic proteins Extensive experience with novel biologics, from peptides
to mAbs In house development capabilities: Own labs for all key
activities, ~550 associates in development, plus Novartis In house manufacturing capabilities: Dedicated microbial
(E. coli, yeast) and cell culture facilities, 8 API lines up to 40.000 L; plus fill & finish lines
Biosimilars expertise: Pioneer – successfully developed 3 biosimilars WW 8-10 molecules in development, esp. mAbs, multiple
clinical trials ongoing (e.g. ph III rituximab, pegfilgrastim)
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Biosimilars are recognized around the world as safe and effective medicines
EU draft general
guidelines adopted
First biosimilar Somatropin approved and
launched in EU
2004 2005 2006 2007 2008 2009
First Epoetin approved and launched in EU
First Filgrastim approved in EU
Japan regulatory guidelines
First biosimilar approved and launched in
Japan & Canada
US regulatory pathway
“We are confident that if a product … gets an MA from the Commission... the product is as safe
and effective as any other product authorised by the Commission."
- Nicolas Rossignol, former administrator of EC pharma division1
1 Source: Speech at EGA Biosimilars conference 2008, quoted in Scrip
Draft EMA
mAb guidelines
7
2010
US regulatory pathway
US draft guidelines
2012
Final EMA mAb guidelines
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Biosimilar applications in Europe to date – the regulatory systems works reliably
Trade Name Common Name (INN)
Biosimilar Sponsor Reference Product
Decision Date Decision
Omnitrope® Somatropin Sandoz Genotropin Approve April 12, 2006
Valtropin® Somatropin BioPartners Humatrope Approve April 24, 2006
Biferonex® Interferon beta-1a BioPartners Avonex Reject Feb. 19, 2009
Alpheon® Interferon alfa-2a BioPartners Roferon-A Reject June 28, 2006
Binocrit® Epoetin alfa Sandoz Eprex Approve Aug. 28, 2007
Epoetin alfa Hexal® Epoetin alfa Hexal Eprex Approve Aug. 28, 2007
Abseamed® Epoetin alfa Medice Eprex Approve Aug. 28, 2007
Retacrit® Epoetin zeta Hospira Eprex Approve Dec. 18, 2007
Silapo® Epoetin zeta STADA Eprex Approve Dec. 18, 2007
Insulin Rapid Marvel® Insulin Marvel Humulin Withdraw Jan. 16, 2008
Insulin Long Marvel® Insulin Marvel Humulin Withdraw Jan. 16, 2008
Insulin 30/70 Marvel® Insulin Marvel Humulin Withdraw Jan. 16, 2008
Biograstim® Filgrastim CT Arzneimittel GmbH
Neupogen Approve Sep. 16, 2008
Filgrastim Ratiopharm® Filgrastim Ratiopharm GmbH Neupogen Approve Sep. 16, 2008
Ratiograstim® Filgrastim Ratiopharm GmbH Neupogen Approve Sep. 16, 2008
Tevagrastim® Filgrastim Teva Generics GmbH Neupogen Approve Sep. 16, 2008
Zarzio® Filgrastim Sandoz Neupogen Approve Feb. 6, 2009
Filgrastim Hexal® Filgrastim Hexal Neupogen Approve Feb. 6, 2009
Nivestim® Filgrastim Hospira Neupogen Approve Jun. 8, 2010
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Isoelectric focusing gels
Non-comparable “copy biologics” – not approved in highly regulated markets – are NOT biosimilars
Sample E IA IB IIA IIB IIIA IIIB IV V VII VIII E
Brockmeyer C & Seidl A et al. Eur J Hosp Pharm Pract 2009;15:34–40 Schellekens H et al. Eur J Hosp Pharm Pract 2004;3:43–7
Approved biosimilar in EU
Sample 1 2 3 4
NO difference to originator Non-comparable “copy biologic” ≠ biosimilar
NOT similar to Reference E
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Innovation required in both technical development and clinical development
Time & investment
Clinical development
• Significant expense (USD 75-250m)
• Long time to develop (7-10 years)
• Use of novel endpoints and populations to confirm biosimilarity (not de novo safety/efficacy)
• Clinical trial design to support extrapolation across indications and interchangeability
Key challenges
Technical development
• Achieving “highly similar” to match originator molecule profile
• Matching final dosage form of originator
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Example: Epoetin alfa - summary of clinical experience
CO
MPA
RAB
ILIT
Y
Physical characterisation
In vitro pharmacology and preclinical studies
Clinical safety
& efficacy
Comprehensive molecular analysis
Biological quality assessment
In vitro pharmacology and preclinical studies
PK / PD
Clinical
PAC
Demonstration of structure and purity at protein and carbohydrate levels
In vivo assay and in vitro testing demonstrates full biological functionality
4 week subchronic toxicity study PK/PD study
Local tolerance study
Comparable PK / PD shown in 6 phase I studies for s.c. and i.v.
Clinical safety and efficacy shown in 3 phase III studies
1700 pts treated in phase IV setting, more than 2200 in non-interventional trials
>122.000 patient years total
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Monoclonal antibodies are complex...
protein protein Protein
(no sugars)
mAb, ~150 kDa
Glycoprotein (with sugars)
Mammalian Bacteria, Yeast
calcitonin, ~3.5 kDa
epoetin ~30 kDa
somatropin ~22 kDa
Peptide
filgrastim ~19 kDa
Aspirin 0.18kDAa
1x 19x 105x 122x 170x 833x
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... but can be thoroughly characterized using state-of-the-art analytical science
Effector functions - Complement interaction - Fc Receptor interaction
CH 2
CH 3
Hea
vy c
hain
- S - S - - S - S -
Biological characteristics Physicochemical characteristics
N-terminal heterogeneity Pyroglutamate formation
Other modifications
Amino acid modifications Deamidation, Oxidation, Glycation,
Isomerization
Oligosaccharides Fucosylation, Sialylation, Galactosylation,...
C-terminal heterogeneity Lysine processing, Proline amidation
Fragmentation Cleavage in hinge region, Asp-Pro
Disulfide Bonds Free thiols, disulfide shuffling, thioether
-CO
O-
S S
S S
Fab
Fc
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Today’s analytical science provides full understanding of a mAb
Proteins can be well characterised at least up to the complexity of
monoclonal antibodies Primary structure determined from recombinant
DNA sequence and fully accessible to analytical verification
Set of orthogonal analytical methods available to characterize the identity and amount of
related variants with high sensitivity Glycosylation profile can be comprehensively
determined with regard to identity and content of individual glycans with high sensitivity
Accurate and relevant bioassays for pivotal biological functions available
Attributes: Primary structure
Mass Disulfide bridging Free cysteines Thioether bridging Higher order
structure N- and C-terminal
heterogeneity Glycosylation (isoforms, sialic acids, NGNA,
fucosylation, alpha gal, site specific) Glycation
Fragmentation Oxidation Deamidation Aggregation
Methods e.g.: MS (ESI, MALDI-
TOF/TOF, MS/MS) Peptide mapping
Ellman‘s CGE
SDS-PAGE CD
H-D exchange FT-IR HPLC HPAEC IEF
2AB NP-HPLC SE-HPLC FFF AUC DLS MALLS
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Orthogonal bioassays addressing multiple functions
Target cell Fc γ RIIIa
C1
PCD Programmed cell death ( apoptosis )
ADCC Antibody dependent cellular cytotoxicity
CDC complement dependent cytotoxicity
Membrane attack complex
Target cell Fc γ RIIIa
C1
PCD Programmed cell death ( apoptosis )
ADCC Antibody dependent cellular cytotoxicity
CDC complement dependent cytotoxicity
Membrane attack complex
Blocking / Inhibiting RB
Target cell Fc γ RIIIa
C1
PCD Programmed cell death ( apoptosis )
ADCC Antibody dependent cellular cytotoxicity
CDC complement dependent cytotoxicity
Membrane attack complex
Target cell Fc γ RIIIa
C1
PCD Programmed cell death ( apoptosis )
ADCC Antibody dependent cellular cytotoxicity
CDC complement dependent cytotoxicity
Membrane attack complex
Blocking / Inhibiting Soluble Target
Effector cells (NK cells)
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0,0
0,4
0,8
1,2
1,6
2,0
08.2007 12.2008 05.2010 09.2011Expiry Date
Unfucosylated G0[% of glycans]
60
80
100
120
140
08.2007 12.2008 05.2010 09.2011Expiry Date
ADCC Potency[% of reference]
Post-Shift
Pre-Shift
Pre-Shift
Post-Shift
Monitoring batches of an approved mAb revealed a shift in quality Shift in glycosylation
(structure) pattern results in different potency in cell-based assays (function) Indication of a change in
the manufacturing process Such shifts observed in
several original products Products found to be
equally safe and effective post-shift by regulators (EMA, FDA)
Variability in original biologics
Schiestl, M. et al., Nature Biotechnology 29, 310-312, 2011)
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Purification process development
Bioprocess development
Recombinant cell line development
Drug product development
Biosimilars must be systematically engineered to match the reference product
PK/PD
Preclinical
Biological characterization
Physicochemical characterization
Clinical
Reference product
Process development
Analytics
2. Confirmation of biosimilarity
Leveraging biological variability
1. Target directed development
Target range
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Target directed process development Example: Adjusting ADCC in clone selection
0 2 4 6 8
0
100
200
300
400
500
600
700
ADC
C (%
of R
efer
ence
)
bG0-F [rel. %]
Range of orginator on market too
narrow to deduce S/F-relationship
Variability observed during cell line development enables
elucidation of quantitative S/F-relationship
Parental Cell Line
Pools
Clones Cell Line X
Pool A
Clones Cell Line X
Pool A
Clones Cell Line X
Pool B
Final Clone Cell Line X
Pool B
0
2
4
6
8
10
Qua
lity
Attr
ibut
e [%
]
Screening of bioreactor conditions
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Pre-clinical and clinical development of biosimilar is a four-step process
Pre-clinical
Phase III (confirmatory)
Characteristics
Phase I (PK/PD)
Average time
Abbreviated pre-clinical program • Toxicology, efficacy/ safety in relevant species models
• Consider 3 R (replacement, reduction, refinement strategy to reduce animal studies
Demonstration of PK/PD equivalence in a sensitive population - can be healthy volunteers
Same posology is appropriate as confirmed by bioequivalence studies
• No phase II dose finding studies are needed
Demonstration of similarity in terms of efficacy and safety in ONE indication, but not patient benefit per se • “Sensitive“ primary endpoints may be different from those
used in originator trials, e.g. response rate vs. progression free survival or overall survival
• Sufficient for extrapolation across indications, if mechanism of action is similar
Post-approval trials Additional data to meet regulatory needs
6–12 months
9–12 months
2–4 years
Variable
1
4
2
3
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While Sandoz is well positioned in biosimilars, originators are entering the space
Technical expertise of a pharma company
Commercial expertise of generics company
1 2010 for US, Canada, Europe, Japan and Australia; based on IMS and company reports
Note: all trademarks in this presentation are the property of their respective owners
• #1 with ~50% share in biosimilar regulated
markets1
• Leading pipeline with 8-10 molecules
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Successful commercialization of biosimilars requires interaction with broad group of customers
Patients
Physicians
Hospitals
Payors / PBMs
Governments / MoHs
KOLs Pharmacists
Wholesalers / distributors
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However, a tailored commercial approach is required for biosimilars by product, market and channel
• Approach for commercial success varies significantly by product, country, and channel
• Need to focus resources on highest impact areas given typically lower investments than originators
• Successful commercial model can range from tender management to fully branded approach
Tender management
Key account management
Market access
Medical science liaisons
Patients kits/ training
Promotional activities (materials, reps)
Examples of Key Success Factors (KSFs1)
somatropin
1 Not a major KSF Major KSF
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UK example: Biosimilars expand access to G-CSF1
2010 2009 2008 2007
SOURCE: IMS, NHS
UK G-CSF volume growth Percent change vs. previous year
Sep. 2008 Biosimilars approved
• G-CSF prevents hospital re-admissions due to infections
• Many physicians have moved G-CSF back to 1st-line cancer
treatment due to lower biosimilars cost
• Sandoz’s Zarzio® (G-CSF) “Patient Support Kits” expand
patient access:
– Patients self-administer at home
– Substantial efficiency savings
1 Granulocyte colony stimulating factor
2011
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More than 15 years of experience with biosimilars
Development of biosimilars requires lots of expertise, time and money – these are not generics!
Approval of biosimilars is rigorously managed by EMA
No safety issues with marketed products after 6 years and millions of treatments
Biosimilar mAbs will reach the market soon, forming the next wave of more complex and very powerful products
Commercialization of biosimilars requires a tailored approach, closer to original products and much different from generics
There is a significant commercial opportunity and many originator companies are entering the biosimilars business
Biosimilars are expanding patient access already today
Summary
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