Moscow / Thomas Kirchlechner, May 2013 Challenges of biosimilar product development and experience gained IFPMA/AIPM Biotherapeutic Medicines Regulatory Workshop Moscow, 15-16 May 2013 Dr. Thomas Kirchlechner Sandoz Biopharmaceuticals Development, Austria
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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
2 Moscow / Thomas Kirchlechner, May 2013
Agenda
Introduction to biosimilars
Future of biosimilars
How are biosimilars developed?
Sandoz experience
3 Moscow / Thomas Kirchlechner, May 2013
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
®
®
®
4 Moscow / Thomas Kirchlechner, May 2013
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.
5 Moscow / Thomas Kirchlechner, May 2013
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
• 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
6 Moscow / Thomas Kirchlechner, May 2013
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…
7 Moscow / Thomas Kirchlechner, May 2013
…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)
.
8 Moscow / Thomas Kirchlechner, May 2013
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
9 Moscow / Thomas Kirchlechner, May 2013
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
10 Moscow / Thomas Kirchlechner, May 2013
Agenda
Introduction to biosimilars
Future of biosimilars
How are biosimilars developed?
Sandoz experience
11 Moscow / Thomas Kirchlechner, May 2013
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
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
17 Moscow / Thomas Kirchlechner, May 2013
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)
18 Moscow / Thomas Kirchlechner, May 2013
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
19 Moscow / Thomas Kirchlechner, May 2013
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
20 Moscow / Thomas Kirchlechner, May 2013
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).
■ Culture history (genetic stability, process stability..)
■ Individual DSP steps
■ Hold times
■ Storage (buffer, container, conditions..)
1
2
21 Moscow / Thomas Kirchlechner, May 2013
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. %]
22 Moscow / Thomas Kirchlechner, May 2013
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
23 Moscow / Thomas Kirchlechner, May 2013
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
24 Moscow / Thomas Kirchlechner, May 2013
Biosimilars must match originators across multiple quality attributes
For monoclonal antibodies typically > 40 different methodologies are applied, analyzing more than 100 different quality attributes
25 Moscow / Thomas Kirchlechner, May 2013
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)