Biosimilars today and tomorrow - Pharma Marketing Club ... · 4/23/2012 · a pharma company...

a Novartis company

Biosimilars today and tomorrow Dr. Jörg Windisch, Head Global Technical Development PMCA Impuls Vienna, April 23, 2012

2 | Text footer (change in > View > Header and Footer) | March 2011

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

22

1

The “Biologics Boondoggle”

2


...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


…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)


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


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


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


... 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


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


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


C1





Blocking / Inhibiting RB


C1






C1





Blocking / Inhibiting Soluble Target

Effector cells (NK cells)


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


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


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

http://www.pfizer.com/�


Successful commercialization of biosimilars requires interaction with broad group of customers

Patients

Physicians

Hospitals

Payors / PBMs

Governments / MoHs

KOLs Pharmacists

Wholesalers / distributors


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


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


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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