“The Evolution of Pharmaceutical Biotechnology – Science, Strategies, Products, and Regulations” Shows the latest developments in pharmaceutical biotechnology and provides a broad overview of biotherapeutic & biosimilar regulations globally and in the EU

1. The Evolution of Pharmaceutical Biotechnology –
Biotechnology –
Science, Strategies, Products, and Regulations
Regulations
Dr. Thomas Schreitmueller, Regulatory Policy, Biologics
F. Hoffmann – La Roche Ltd., Basel, Switzerland

2. 2
Table of content
Disease Challenges, Strategies and Developments
Biotech History, Process and Products
Biotech Regulations
Biosimilars

3. Pre-1950s 1950/60’s 1970/80’s 1990/00’s
Cells/Organisms
Understanding Disease Mechanisms
Where did we come from, where are we going?
Today
DNA Structure Genetic Code Human Genome
Disease Mechanisms
#PlausibleTargets
1000’s
10’s
100
Pathways
Basic Biological Mechanisms
Observational Biology

4. Understanding the disease is one thing -
Fitting treatments to patients another
Effectiveness of treatment can be improved . . .
• 20-75% of patients do not receive effective treatment1
• Thousands of deaths/yr from adverse drug reactions (e.g. US2)
. . . by tailoring treatments to selected patient groups defined by
biomarkers1 Spears et al., Trends Mol Med, 2001
2 Lazarou et al., JAMA, 1998

5. Personalised Healthcare is becoming a
reality
Molecular insights allow better treatment decisions
Identifying those
patients optimizes care
Molecular
diagnosisPatients with breast
cancer: only the portion
of patients that show
over-expression of the
HER2 gene and will
benefit from Trastuzumab

6. Trastuzumab Changed the Natural History of
HER2+mBC
HER2-positive status has become a favorable prognostic factor
Probabilityofsurvival(%)
Time
from
diagnosis
(months)
100
80
60
40
20
0
0 12 24 36 48 60
HER2-
positive
Herceptin n=191
HER2-
positive
No Herceptin n=118
HER2-
positive
Herceptin n=191
HER2-
positive
No Herceptin n=118
HER2-
negative
n=1,782

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Table of content
Disease Challenges, Strategies and Developments
Biotech History, Process and Products
Biotech Regulations
Biosimilars

8. Serum Therapy 1893
E. Bäumler, Auf der
Suche nach der
Zauberkugel,
Econ-Verlag 1971
•first Nobel prize
for medical
research in history
for the discovery of
“antibodies” 1901
Emil von Behring
immunizing a
“serum-horse”
Biotech Manufacturing Historical
Perspectives

9. 1978
The first biotech drug using recombinant technology was developed. Herbert Boyer
and others succeeded at genetically manipulating plasmids of E. coli bacteria to
produce insulin with the same amino sequence as seen in humans. (Insulin -
Genentech)
Herbert W Boyer and Robert A Swanson the founders of Genentech talking
about recombinant DNA.
Image: Courtesy of Genentech Inc
BioTechnology Developments

10. Biotech products manufacturing
DNA Vector
ATG
Stop
Working
Cell Bank
AmplificationMaster Cell Bank

11. Biological product complexity:
Examples of modifications: inherent or due to the
manufacturing process
11
Adapted from: Steven Kozlowski; FDA
K
pyro-E
G
D
O
D
G
O
D
pyro-E
• Pyroglutamyl peptides
K
• C-terminal Lysine
D
D
D • Deamidation
O
O
• Methionine oxidation
G
G
• Glycation
• High mannose, G0, G1, G1, G2
• Sialylation
Modifications may result in approximately 108 potential variants

12. Protein Microheterogeneity
Small Molecule
Drug
Protein
Drug

13. Carter, P.J. (2006) Nature Revs. Immunol. 6, 343-357
Glycosylation: important modification on
MAbs

14. Enhancing antibody performance
Bi-specific antibody
binds to two different target
and enhances specificity
Antibody inhibits
or activates signaling
Naked Antibodies
bi-specific Antibodies
Bi-specific antibody
binds to two different
targets in different cells
bi-specific Antibodies
drug
drug
Antibody recruits immune effector
cell and induces cytotoxicity
ADCC enhanced Antibody
Antibody specifies
delivery of drug
Armed Antibodies

15. Trastuzumab emtansine ADC
14 CT performed/ongoing
Emtansine
release
Inhibition of
microtubule
polymerization
15
Internalization
HER2
Adapted from LoRusso PM, et al. Clin Cancer Res 2011.
T-DM1
Lysosome
Nucleus
P
P
P

16. • Increased direct cell-death
induction
• Enhanced antibody-dependent
cell-mediated cytotoxicity
(ADCC)
• Lower complement-dependent
cytotoxicity (CDC) activity
In collaboration with Biogen Idec
Umaña et al, Blood 2006; 108, abstract 229, Umaña et al, Ann Oncology 2008, 19 (suppl 4), abstract 098
CD20
peptide
Type II
recognition
& elbow-hinge
residues
Carbohydrate glycoengineered (GlycoMabTM
technology):
Overexpression of GnTIII and ManII glycosylation genes
in Ab production cell lines leads to Ab glycoforms bearing
bisected, complex afucosylated oligosaccharides in Fc
region
Obinutuzumab: glycoengineered, anti-CD20 mAb
10 CT performed/ongoing

17. More than 500 clinical trials in over 50 cancers
investigating the use of Bevacizumab*
Bevazizumab has the largest clinical trial program
ever initiated in oncology
*www.clinicaltrials.gov April 2010

18. Valuable and Vulnerable Industry
• Developing a new medicine is lengthy, risky, and costly.
• New drug development takes an average of 10–15 years,
and costs approx. € 1.2 billion
18
INDEFINITE
Drug Discovery Preclinical Clinical Trials FDA/EMA
Review
Scale-Up to Mfg.
Post-Marketing
Surveillance
ONE
FDA/EMA-
APPROVED
DRUG
0.5 – 2
YEARS
6 – 7 YEARS3 – 6 YEARS
NUMBER OF VOLUNTEERS
PHASE
1
PHASE
2
PHASE
3
5250~ 5,000 – 10,000
COMPOUNDS
PRE-DISCOVERY
20–100 100–500 1,000–5,000
INDSUBMITTED
NDASUBMITTED
Sources: Drug Discovery and Development: Understanding the R&D Process, www.innovation.org

19. Biotech Pharmaceuticals –
Where do we stand today?
• Biotechnology has produced medical treatment for
hitherto serious incurable diseases.
• Hundreds of biologics drugs approved.
• Biotech drugs accounting approx. 17% of the world
pharma market.
• Approx. 50% new drugs are biotech drugs.
19
Source: IMS 2010

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Table of content
Disease Challenges, Strategies and Developments
Biotech History, Process and Products
Biotech Regulations
Biosimilars

22. How regulatory systems should evolve
globally ?
• Greater regulatory convergence of pharmaceutical regulations
is necessary facilitating R&D investment and to increase and
expedite patient access to new and innovative medicines
– Remove duplicative/different requirements between agencies,
which hinder global drug development and supply
– Develop a more innovative evaluation framework
• adaptive licensing
• inter agency reviews
– Mutually recognize GMP inspections

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Table of content
Disease Challenges, Strategies and Developments
Biotech History, Process and Products
Biotech Regulations
Biosimilars

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Biosimilars Global Regulations

25. 25
Thomas Palmberger, Pharmaceutical Development, Sandoz Bioharmaceuticals,
7-8 June 2011, Basel, Switzerland, 4th PDA Europe Workshop on Monoclonal Antibodies

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Biosimilar pathways – EMA biosimilar
antibody guideline
• The guideline is setting the stage for the overall stepwise
development approach having the goal “…ensuring that the
previously proven safety and efficacy of the drug is
conserved.”.
• The stepwise approach at the clinical side is outlined more clearly
focusing on the main principles to be considered when establishing
clinical similarity: “The guiding principle is to demonstrate
similar clinical efficacy and safety compared to the reference
medicinal product, not patient benefit per se, which has already
been shown for the reference medicinal product.”.
• This has to be achieved by planning all studies “…with the
intention to detect any potential differences between biosimilar
and reference medicinal product and to determine the relevance
of such differences, should they occur.”

28. Biosimilar vs. innovator clinical studies (oncology)
Differences in requirements and study designs
28
Aspects of
Development
Biosimilar Innovator
Patient Population Sensitive and
homogeneous (patients
are models)
Any
Clinical Design Comparative versus
innovator, normally
equivalence
Superiority vs standard of
care (SoC*)
Study Endpoints Sensitive
Clinically validated PD
markers
Clinical outcomes data or
accepted/established
surrogates (e.g. OS and
PFS)
Safety Similar safety profile to
innovator; no new
findings
Acceptable benefit/risk
profile versus SoC*
Immunogenicity Similar immunogenicity
profile to innovator
Acceptable risk/benefit
profile versus SoC*
* In some cases SoC may not exist

29. Demonstration of Clinical Similarity and Extrapolation
of Indications - A Challenge for Biosimilar Antibodies
• Comparative safety and efficacy trials in sensitive
populations are required to demonstrate clinical
equivalence to the reference product within pre-
defined margins.
• The sensitive patient population/indication for
the required similarity assessments with respect
to PK, PK/PD, Efficacy, Safety or Immunogenicity
may be a different one for each assessment.
• Extrapolation across indication will require extensive
scientific justification, additional efficacy, safety and
immunogenicity data may be needed as well as
specific risk mitigation strategies.

30. EMA: In support of the EU biosimilar framework
“Considering the complexity of
biomolecules, the limitations at
present in analytical
characterization and in clinical
trials (like defining sensitive and
feasible endpoints to detect
differences), it is necessary that
the biosimilar concept relies on
demonstrating comparability at all
three levels (that is, quality,
preclinical and clinical to ensure
as complete a picture as possible
on the features of such complex
molecules). A relaxation of these
requirements is not justified.”
Christian K Schneider1,2, John J Borg3, Falk
Ehmann4, Niklas Ekman5, Esa Heinonen5,6,
Kowid Ho7, Marcel H Hoefnagel8, Roeland
Martijn van der Plas8, Sol Ruiz9, Antonius
J van der Stappen8, Robin Thorpe10, Klara
Tiitso4, Asterios S Tsiftsoglou11, Camille
Vleminckx4, Guenter Waxenecker12, Mats
Welin13, Martina Weise14 & Jean-Hugues
Trouvin7,15on behalf of the Working Party
on Similar Biological (Biosimilar) Medicinal
Products (BMWP) and the Biologicals Working
Party (BWP) of the Committee for Medicinal
Products for Human Use (CHMP)

31. Based on science, the Concept of
Biosimilarity
is built on five indispensible pillars:
The use of existing copies of biotherapeutic products that
have not gone through an adequate development program
is not recommended due to potential safety implications.
S c i e n c e
AnalyticalSimilarity
Pre-clinicalSimilarity
ClinicalSimilarity
Pharmacovigilance
B i o s i m i l a r i t y
ProperQualitySystem

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