14. dr. thomas kirchlechner - sandoz biopharmaceuticals development

1 Moscow / Thomas Kirchlechner, May 2013

Challenges of biosimilar product development and experience gainedIFPMA/AIPM Biotherapeutic Medicines Regulatory Workshop

Moscow, 15-16 May 2013

Dr. Thomas Kirchlechner

Sandoz Biopharmaceuticals Development, Austria


Agenda

Introduction to biosimilars

Future of biosimilars

How are biosimilars developed?

Sandoz experience


Biologics have revolutionized modern medicine – and will continue to do so

Today / future

Human genome

Stem-cell research

Gene therapy

1990s to today

Leading

biotech brands emerge

1950s

DNA moleculedecoded

Genetic code cracked

1960s

Basic biotechnology

enabled

1970s

Offer real hope for many unmet needs, particularly complex diseases

Bind to specific targets within the body – simply not possible with other medicines

Contribute significantly to improved survival rates, enhanced longevity, and better quality of life

Source: Company websites and annual reports Note: All trademarks, logos and pictures are the property of the respective owner

Commercial biotech firms

founded

1980s

®

®

®


By 2016, 7 of the top 10 pharmaceuticals worldwide will be biologics1

Product Type2016 Rev. (USD bn)

2011 Rev. (USD bn)

1. HUMIRA® Biologic 11.2 8.3

2. ENBREL® Biologic 7.5 7.9

3. RITUXAN® Biologic 7.4 7.1

4. AVASTIN® Biologic 7.2 6.0

5. REMICADE® Biologic 7.0 7.2

6. SERETIDE®/ADVAIR® Respiratory / device 6.8 8.1

7. HERCEPTIN® Biologic 6.3 5.9

8. REVLIMID® Small molecule 5.9 3.2

9. CRESTOR® Small molecule 5.8 7.1

10. LANTUS® Biologic 5.5 5.5

1 Source: Evaluate Pharma March 20 2012, vaccines excludedNote: All trademarks are the property of their respective owners.


What is a biosimilar (or follow-on biologic)?

• A biologic approved via a stringent regulatory pathway demonstrating comparability

Overview

• Successor to a biologic medicine that has lost exclusivity

• Not a simple generic due to complexity: size, structure and manufacturing

Regulatory definition

Comparabilityapproach

• Highly analogous structure (via robust analytical characterization)

• Comparable quality, safety and efficacy (via clinical trials)

Description

140

120

100

80

60

40

20

0

Min

mA

U

Zarzio®

Neupogen®

GCSF Peptide Mapping

Determination of Receptor Binding:Surface plasmon resonance spectroscopy

Rigorous analytical characterization

Association rate Dissociation rate

0 200 400 600 800 1000 1200 1400

rel.

resp

on

se (

RU

)

time (s)

80

60

40

20

0

-20

Association rate

0 200 400 600 800 1000 1200 1400

rel.

resp

on

se (

RU

)

time (s)

80

60

40

20

0

-20

Batch 1Batch 2Batch 3Batch 4Batch 5Batch 6Batch 7


protein proteinProtein(no sugars)

Monoclonal antibody ~150 kDa

Glycoprotein (with sugars)

MammalianBacteria, Yeast

calcitonin ~3.5 kDa

epoetin~30 kDa

somatropin~22 kDa

Peptide

filgrastim~19 kDa

Aspirin0.18kDa

1x 19x 105x 122x 170x 833x

Biologics are more complex than small molecules…


…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)

.


Access to biologics is a growing issue around the world

Almost one-quarter of 46 European countries do not provide access to biologics for arthritis1

Canadian children with juvenile idiopathic arthritis may not receive "standard" care because pediatric coverage for biologic drugs is limited and inconsistent3

Cancer patients twice as likely as general population to go bankrupt a year after their diagnosis2

Only 50% of severe RA patients receive biologics across EU5, US and Japan4

1 EULAR 2012: Annual Congress of the European League Against Rheumatism2 Cancer diagnosis as a risk factor for personal bankruptcy, ASCO 20113 Access to biologic therapies in Canada for children with juvenile idiopathic arthritis. J.Rheum, September 20124 Stakeholder Insight: Rheumatoid Arthritis DMHC2592/ Published 09/2010


Biosimilar guidelines and regulations are being developed worldwide

EU Biosimilars legal framework established

US Health Care Reform enacted March 2010, includes Biosimilars

Japan final guideline released on March 4,

2009

Australia has adopted EU guidelines, no separate pathway will be

established

Canada final guideline on SEBs released in March

2010

WHO released final guidance in April 2010

Taiwan

Malaysia

Argentinia

Columbia

Turkey

Venezuela

Mexico

Brazil

Saudi-Arabia

South Korea

Singapore


Agenda




Sandoz experience


Significant time, resources and expertise required for developing biosimilars

Time & Investment

Clinical Trials

• Significant expense (USD 75 - 250m)

• Long time to develop (7-8 years)

• Confirm comparable efficacy and safety

• Support extrapolation across indications & commercial success

• Speed of patient recruitment / trial execution

Key challenges

Technical Development

• Achieving molecule profile highly comparable tooriginator

• Developing high yielding manufacturing process


Purification process development

Bioprocess development

Recombinant cell line development

Drug product development

PK/PD

Preclinical

Biological characterization

Physicochemical characterization

Clinical

Reference product variability

Processdevelopment

Analytics

3. Confirmation of biosimilarityBiological variability

2. Target directed development

Target range

1. Target definition

Biosimilar mAbs must be systematically engineered to match the reference product


Pre-clinical and clinical development of biosimilars

Pre-clinical

Phase III (confirmatory)

Characteristics

Phase I (PK/PD)

Avg Time

Abbreviated pre-clinical program

Demonstration of PK/PD equivalence in a sensitive population - can be healthy volunteersNo phase II dose finding studies are needed

Demonstration of similar efficacy & safety, usually in one indication

Post approvaltrials

Continue to follow the product, generate additional data

6 – 12 months

9 – 12 months

2 – 4 yrs

Variable

1

4

2

3


Agenda




Sandoz experience


Structure: High resolution, orthogonality and redundancy in analytical characterization provide full understanding

Proteins can be well characterized 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


Originators have changed their biologics manufacturing processes multiple times after approval

Source: C Schneider, Ann Rheum Dis March 2013 Vol 72 No 3Number of changes in the manufacturing process after approval for monoclonal antibodies (mAbs)/cepts authorised in rheumatologicalindications (A). Products in order of date of approval in Europe (from MabThera, authorised on 2 June 1998 for the initial authorisation in oncology,to Benlysta, licensed on 13 July 2011)

Changes include e.g.

• Change in the supplier of a cell culture media

• New purification methods

• New manufacturing sites


0,0

0,4

0,8

1,2

1,6

2,0

08.2007 12.2008 05.2010 09.2011

Expiry Date

Unfucosylated G0[% of glycans]

60

80

100

120

140

08.2007 12.2008 05.2010 09.2011

Expiry 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

Sandoz observed such shifts in several original products

Originator variability is the basis for the biosimilarity goal posts...

Schiestl, M. et al., Nature Biotechnology 29, 310-312, 2011)


0 2 4 6 8

0

100

200

300

400

500

600

700

AD

CC

(%

of R

efer

ence

)

bG0-F [rel. %]

Variability of reference product

Variability observed during cell line development

Very narrow goalposts for

biosimilar

Biologically possible variability

...and these goal posts are very narrow


Originator manufacturing changes over time are the basis for biosimilarity goal posts

A biosimilar product can be as similar to its reference product,...

..as that reference product is to itself over its lifetime due to process changes

Originator Process OLD

Biosimilar

Goal posts for a given parameter

Originator Process NEW

Originator product changes are basis for biosimilars and justify:

– extrapolation across indications

– interchangeability

• Manufacturing process changes are tightly regulated (see ICH Q5E)• Change of quality attributes only acceptable if they do not alter

safety/efficacy• To demonstrate biosimilarity, it is therefore acceptable to use upper and

lower limit of pre- and post-shift material• However, biosimilar release specification should be as tight as current

reference product specification


Quality attributes can be influenced at all stages of cell line and process development...

Quality

Cell line

■ Host cell line.

■ Transfection/amplification pool

■ Genetic “set up” of production cell line (clone).

Process

■ Growth medium composition.

■ Culture conditions (pH, T, aeration,...)

■ USP type (batch, fed batch, perfusion,...)

■ USP regime (duration, fed type, perfusion rate..)

■ Culture history (genetic stability, process stability..)

■ Individual DSP steps

■ Hold times

■ Storage (buffer, container, conditions..)

1

2


Example for Quality by Design: Attention to detail is essential...

High resolution identification and quantification of major (G0,G1,G2) and minor glycan structures (down to a level of 0.1 rel.%)

Characterization of mAb glycosylation heterogeneity

Targeting ADCC activity and fucosylation by clone selection

2x

Originators Parental Cells

Pool 18 Pool 16 Clone 19

0

2

4

6

8

10

bG

0(-

F)

[%]

0 2 4 6 8

0

100

200

300

400

500

600

700

AD

CC

(%

of

Ref

eren

ce)

bG0-F [rel. %]


Source: Mike Doherty, Global Head Regulatory Affairs, Roche Pharmaceuticals, at Roche Investor Day 2010, March 18, 2010, see http://www.roche.com/investors/ir_agenda/rid_2010.htm?track=8 and www.roche.com/irp100318_md.pdf

...and follow-on biologics not fulfilling these high standards are not biosimilars and will not be approved in EU

Higher host cell protein content

Content of aggregates not comparable

Charge distribution not comparable

Glycosylation not comparable

ADCC effector function not comparable

Clinical data: Only PK/PD study in 17 patients


Isoelectric focusing gels

“Non-Comparable 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;15:34–40Schellekens 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 Alternative biologics ≠biosimilar

NOT similar to Reference E

Novartis/Sandoz does not represent all these approaches


Biosimilars must match originators across multiple quality attributes

Post translat. modif. e.g.:•NP-HPLC-(MS) N-glycans•AEX N-glycans•MALDI-TOF N-glycans•HPAEC-PAD N-glycans•MALDI-TOF O-glycans•HPAEC-PAD sialic acids•RP-HPLC sialic acids

Primary structure e.g.:•LC-MS intact mass•LC-MS subunits•Peptide mapping

Higher order structure e.g.:•NMR•CD spectroscopy•FT-IR

Impurities e.g.:•CEX, cIEF acidic/basic variants•LC glycation•Peptide mapping deamidation, •oxidation, mutation, glycation•SEC/FFF/AUC aggregation

Combination of attributes e.g.:•MVDA, mathematical algorithms

Biological activity e.g.:•Binding assay•ADCC assay•CDC assay

For monoclonal antibodies typically > 40 different methodologies are applied, analyzing more than 100 different quality attributes


Examples of clinical experience with biosimilars

Clinical studies started more than 12 years ago Product evaluated for 84 months in clinical phase III study ~ 35.000.000 patient days of safe use (2005-today)

~ 3.500.000 patient days of safe use (2009-today)

Evaluated in multiple studies with >5000 patients overall ~ 67.000.000 patient days of safe use (2007-today)

Somatropin (Human Growth Hormone):

Filgrastim (Granulocyte-Colony Stimulating Factor/G-CSF):

Epoetin alfa (Erythropoietin/Epo):


Agenda




Sandoz experience

27 Moscow / Thomas Kirchlechner, May 2013Source: IMS, NHS

UK G-CSF volume growth Percent change vs. previous year

Sept. 2008 biosimilars approved by EMA

G-CSF prevents hospital re-admission due to infection

More physicians start G-CSF treatment earlier (primary prophylaxis) due to more affordable cost

2010200920082007 2011

Biosimilar expand patient access already today


Today, biologics can be thoroughly understood both structurally and functionally

Biosimilars can be created with product attributes that fall within the variability of the original products – “highly similar”

Clinical trials confirm similarity - de novo proof of efficacy not necessary

Many years experience have shown that EMA approved biosimilars are as safe and effective as the original products

Biosimilars are broadening patient access and improving affordability already today

Conclusions

2013 © All rights reserved. All trademarks are the property of their respective owners.


Thank you!

14. dr. thomas kirchlechner - sandoz biopharmaceuticals development

Health & Medicine

moscow thomas kirchlechner

biologic therapies

lantus biologic

humira biologic

enbrel biologic

rituxan biologic

avastin biologic

remicade biologic