The Evolution of Pharmaceutical Biotechnology – Science, Strategies, Products, and Regulations
Dr. Thomas Schreitmueller, Regulatory Policy, BiologicsF. Hoffmann – La Roche Ltd., Basel, Switzerland
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Table of content
Disease Challenges, Strategies and Developments
Biotech History, Process and Products
Biotech Regulations
Biosimilars
Pre-1950s 1950/60’s 1970/80’s 1990/00’s
Cells/Organisms
Understanding Disease MechanismsWhere did we come from, where are we going?
Today
DNA Structure Genetic Code Human Genome
Disease Mechanisms
# P
lau
sib
le T
arg
ets1000’s
10’s
100
Pathways
Basic Biological Mechanisms
Observational Biology
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 biomarkers
1 Spears et al., Trends Mol Med, 20012 Lazarou et al., JAMA, 1998
Personalised Healthcare is becoming a reality Molecular insights allow better treatment decisions
Identifying those patients optimizes care
MoleculardiagnosisPatients with breast
cancer: only the portion of patients that show over-expression of the HER2 gene and will benefit from Trastuzumab
Trastuzumab Changed the Natural History of HER2+mBCHER2-positive status has become a favorable prognostic factor
Pro
babili
ty o
f su
rviv
al (%
)
Time from
diagnosis
(months)
100
80
60
40
20
00 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
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
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
Biotech products manufacturing
DNA Vector
ATG
Stop
Working Cell Bank
AmplificationMaster Cell Bank
Biological product complexity: Examples of modifications: inherent or due to the manufacturing process
11Adapted from: Steven Kozlowski; FDA
K
pyro-E
G
D
O
D
G
OD
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
Protein Microheterogeneity
Small Molecule Drug
ProteinDrug
Carter, P.J. (2006) Nature Revs. Immunol. 6, 343-357
Glycosylation: important modification on MAbs
Enhancing antibody performance
NK
or MØ
Bi-specific antibodybinds to two different targetsand enhances specificity
Antibody inhibits or activates signaling
Naked Antibodiesbi-specific Antibodies
Bi-specific antibodybinds to two different targets in different cells
bi-specific Antibodiesdrugdrug
drugdrug
Antibody recruits immune effectorcell and induces cytotoxicity
ADCC enhanced Antibody
Antibody specifiesdelivery of drug
Armed Antibodies
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
PP
P
• Increased direct cell-death induction
• Enhanced antibody-dependentcell-mediated cytotoxicity (ADCC)
• Lower complement-dependent cytotoxicity (CDC) activity
In collaboration with Biogen IdecUmaña 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 mAb10 CT performed/ongoing
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
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
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INDEFINITE
Drug Discovery Preclinical Clinical Trials FDA/EMA Review
Scale-Up to Mfg. Post-MarketingSurveillance
ONE FDA/EMA-
APPROVED DRUG
0.5 – 2 YEARS6 – 7 YEARS3 – 6 YEARS
NUMBER OF VOLUNTEERS
PHASE 1
PHASE 2
PHASE 3
5250~ 5,000 – 10,000
COMPOUNDS
PR
E-D
ISC
OV
ER
Y
20–100 100–500 1,000–5,000
IND
SU
BM
ITT
ED
ND
A S
UB
MIT
TE
D
Sources: Drug Discovery and Development: Understanding the R&D Process, www.innovation.org
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
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
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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.”
Biosimilar vs. innovator clinical studies (oncology) Differences in requirements and study designs
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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*
Extrapolation Possible if justified Not allowed
* In some cases SoC may not exist
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.
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, FalkEhmann4, Niklas Ekman5, Esa Heinonen5,6,Kowid Ho7, Marcel H Hoefnagel8, RoelandMartijn van der Plas8, Sol Ruiz9, AntoniusJ van der Stappen8, Robin Thorpe10, KlaraTiitso4, Asterios S Tsiftsoglou11, CamilleVleminckx4, Guenter Waxenecker12, MatsWelin13, Martina Weise14 & Jean-HuguesTrouvin7,15on behalf of the Working Partyon Similar Biological (Biosimilar) MedicinalProducts (BMWP) and the Biologicals WorkingParty (BWP) of the Committee for MedicinalProducts for Human Use (CHMP)
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
An
alyt
ical
Sim
ilar
ity
Pre
-cli
nic
al S
imil
arit
y
Cli
nic
al S
imil
arit
y
Ph
arm
aco
vig
ilan
ce
B i o s i m i l a r i t y
Pro
per
Qu
alit
y S
yste
m
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Thank You !