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Dr. Khaled Al-Qaoud R&D manager
Jordan Company for Monoclonal Antibody Production (MonoJo)
www.monojo.com.jo
Jordan Pharmaceutical Association (JPA)
in Collaboration with
Jordan Company for Antibody Production
(MONOJO)
27. Feb, 2013
Biopharmaceuticals: A New Era in Human Health
REQUIREMENTS FOR DRUGS
www.monojo.com.jo
SAFE
EFFECTIVE
INEXPENSIVE
WHAT IS REQUIRED IS DRUGS THAT IS:
MILESTONES IN PHARMACEUTICAL INDUSTRY
www.monojo.com.jo
1895 Aspirin (Bayer)
1930 Sulphanilamide (Sulpha drugs)
1930 Large Scale Production of Insulin
1922 Discovery of Insulin
1940 Penicillin Production
1953 Structure of DNA
1973 Genetic Engineering
1975 Monoclonal Antibodies
AGE OF BIOPHARMACEUTICALS
>10,000 COMPANIES
100 INTERNATIONAL PLAYERS
5000 PHARMACEUTICAL PRODUCTS
$1.3T 2014
TOP 5 DRUGS ARE BIOPHARMACEUTICALS
50% OF TOP 100 ARE BIOPHARMACEUTICALS
1980 Recombinant Insulin
Biological therapeutics are taking the lead
www.monojo.com.jo
PROBABILITY OF SUCCESS TO MARKET FOR CHEMICAL
ENTITIES AND BIOTECHNOLOGY PRODUCTS
www.monojo.com.jo
0%
10%
20%
30%
40%
50%
60%
70%
80%
First human dose to
market
First patient dose to
market
First pivotal dose to
market
Submission to market
Pro
ba
bil
ity o
f s
uc
ce
ss
to
ma
rke
t
Biotech Chemical entities
90%
100%
Based on 485 new chemical entities and 61 biotechnology products in development within 32 companies.
NAS probability of success to market. Based on NASs entering a phase between 1997 - 1999 where a
decision was made by 31st December 2002
Fall in Chemical Drugs launched
www.monojo.com.jo 2003 LOWEST NUMBER OF NCE LAUNCHES IN 10 YEARS*
Nu
mb
er
of
NC
Es
la
un
ch
ed
42 42 43
51
45 45
41 37
36
30 31
0
10
20
30
40
50
60
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004
30 33
27 26
28
2005 2006 2007 2008 2009
Top 10 Drug Products by Sales in 2008
www.monojo.com.jo
Future Drug Sales Predictions Highlight Importance of Follow-on Biologics Legislation
Top 10 Drug Products by Sales in 2014
www.monojo.com.jo
DRUG DISCOVERY PROCESS AND
TIMEFRAMES
www.monojo.com.jo
DRUG
DISCOVERY PRE-CLINICAL CLINICAL TRIALS
FDA
REVIEW
LARGE SCALE
MANUFACTURING
PHASE IV
PHASE I
20-100
VOLUNTEERS PHASE III
1000-5000
VOLUNTEERS
PHASE II
100-500
VOLUNTEERS
FDA
APPROVED
DRUG
5 1.5 6 2 2
10,000 250 5 1
TIME
(YEARS)
COMPOUNDS
IND
ND
A
SYNTHESIS/
PURIFICATION
ANIMAL
TESTING
0-1000mg 1-1000g 1-1000kg AMOUNTS
$ $800-1,200M
NDE from Lab to Market
www.monojo.com.jo
www.monojo.com.jo
0
200
400
600
800
1000
1200
1400
1600
54
1976
231
1987 Year
$M
(in
year
20
00
do
llars
)
897
2000
2003
1550
1800
2000
2200
2010
2150
Average R&D costs per New Drug
Entity (NCE)
www.monojo.com.jo
Pharmaceutical Development
BIOPHARMACEUTICALS OUTGREW TOTAL PHARMA
SALES OVER LAST 10 YEARS, DRIVEN BY US MARKET
www.monojo.com.jo Year
0
10
20
30
40
50
60
19
94
19
95
1996
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
07
20
06
20
08
80
70
4.5%
9%
US 54%
Total
Biopharm
sales [$B]
What is a biological medicine ?
www.monojo.com.jo
• Is a medicine whose active
substance is made by or derived
from a living organism (through
Biotechnology as genetic
engineering).
• Example such as : insulin can be produced by an E. coli bacteria.
MILESTONES IN PHARMACEUTICAL INDUSTRY
www.monojo.com.jo
1895 Aspirin (Bayer)
1930 Sulphanilamide (Sulpha drugs)
1930 Large Scale Production of Insulin
1922 Discovery of Insulin
1940 Penicillin Production
1953 Structure of DNA
1973 Genetic Engineering
1975 Monoclonal Antibodies
AGE OF BIOPHARMACEUTICALS
>10,000 COMPANIES
100 INTERNATIONAL PLAYERS
5000 PHARMACEUTICAL PRODUCTS
$1.3T 2014
TOP 5 DRUGS ARE BIOPHARMACEUTICALS
50% OF TOP 100 ARE BIOPHARMACEUTICALS
1980 Recombinant Insulin
The Pharmacy of the Future as envisaged by a customer of Behring
www.monojo.com.jo
Biologic pipeline has major focus on cancer, infectious diseases, HIV/AIDS
www.monojo.com.jo
210
50
44
22
22
17
15
14
13
10
7
6
4
4
18
0 50 100 150 200 250
Other
Transplantation
Growth Disorders
Eye Conditions
Skin Disorders
Blood Disorders
Respiratory Disorders
Digestive
Diabetes/Related
Neurologic Disorders
Cardiovascular
AIDS/HIV Related
Autoimmune
Infectious Diseases
Cancer/Related
# of Biologic in Development by Disease Segment
www.monojo.com.jo
Recombinant Proteins and Monoclonal Antibodies
0
20
40
60
80
100
120
140
2003 2008 2015 2010
Global
sales(1)
[$B]
160
180 $167B
$92B
$39B
$25.5B
MAbs
Rec Proteins
THERAPY ANALYSIS, HISTORICAL AND FORECAST SALES GROWTH ($M), 2003–15
0
10,000
20,000
30,000
40,000
50,000
60,000
70,000
03 04 05 06 07 08 09 10 11 12 13 14 15
Oncology Immunology & inflammation Other
Central nervous system Respiratory Infectious diseases
Musculoskeletal Cardiovascular Endocrine, metabolic & genetic disorders
FDA APPROVED MONOCLONALS
FOR ONCOLOGY
THE AGE OF
BIOPHARMACEUTICALS
www.monojo.com.jo
RECOMBINANT DNA TECHNOLOGY HAS
4 MAJOR IMPACTS:
SOURCE AVAILABILITY
PRODUCT SAFETY
ALTERNATIVE TO DIRECT EXTRACTION FROM
INAPPROPRIATE/DANGEROUS SOURCE
MATERIAL
FACILITATES GENERATION OF IMPROVED
THERAPEUTIC DISPLAYING SOME CLINICAL
ADVANTAGE OVER NATIVE PROTEIN PRODUCT
www.monojo.com.jo
General Scheme for Biopharmaceutical Bulk Drug Substance Processes
Intracellular
(microbial
fermentation)
Bulk Formulation
Purification Purification
Isolation/Recovery Isolation/Recovery
Cell Disruption/Refold
Cell Harvesting Cell Removal
Bioreactor Conversion
Bulk Formulation
Working Cell Bank Extracellular
(microbial
fermentation
and mammalian
cell culture)
“Downstream”
Process
“Upstream”
Process
www.monojo.com.jo
....ATG Human Gene
Sequence STOP...
Cloning into
DNA Vector
Transfer into Host Cell
Expression
e.g., bacterial or mammalian cell
DNA Vector
ATG
Fermentation
Stop
Downstream
Purification
Biologic manufacturing is complex Biosimilars will always be different from the original
Courtesy of Georg-B. Kresse
Roche Pharma Research
EXPRESSION SYSTEMS
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E. coli
STREPTOMYCES
SACCHAROMYCES
INSECT CELLS
MAMMALIAN CELLS (CHO)
TRANSGENIC PLANTS/ANIMALS
ADVANTAGES AND DISADVANTAGES OF EXPRESSION IN E. coli
www.monojo.com.jo
WELL CHARACTERIZED MODEL
FOR PROKARYOTIC GENETICS
HIGH LEVELS OF EXPRESSION
(>45% TOTAL CELLULAR PROTEIN)
E. coli CELLS GROW ON SIMPLE/
INEXPENSIVE MEDIA
FERMENTATION TECHNOLOGY
WELL ESTABLISHED
HETEROLOGOUS PROTEINS
ACCUMULATE INTRACELLULARLY
INABILITY TO UNDERTAKE
POST-TRANSLATIONAL MODIFICATIONS
LIPOPOLYSACCHARIDE (ENDOTOXIN)
RECOMBINANT PROTEINS EXPRESSED IN SACCHAROMYCES CEREVISIAE
www.monojo.com.jo
ENGINEERED INSULIN
GM-CSF
rHBsAg
HIRUDIN
URATE OXIDASE
PLATELET-DERIVED
GROWTH FACTOR
(PDGF)
DIABETES
BONE MARROW TRANSPLANTATION
VACCINATION
ANTICOAGULANT
HYPERURICAEMIA
DIABETIC ULCERS
PROTEINS PRODUCED IN MILK OF TRANSGENIC ANIMALS
www.monojo.com.jo
Protein
tPA
Interleukin-2
Factor VIII
Factor IX
a1-Antitrypsin
Fibrinogen
Erythropoietin
Antithrombin III
Human a-Lactalbumin
Insulin-like Growth Factor
Protein C
Growth Hormone
Animal Species
Goat
Rabbit
Pig
Sheep
Goat
Sheep
Rabbit
Goat
Cow
Rabbit
Pig
Rabbit
Expression levels in milk (g/l)
6
0.0005
0.003
1
20
5
0.05
14
2.5
1
1
0.05
PROTEINS PRODUCED IN TRANSGENIC PLANTS
www.monojo.com.jo
Protein
Erythropoietin
HSA
Glucocerebrosidase
Interferon-a
Interferon-b
GM-CSF
Hirudin
Hepatitis B Antigen
Antibodes/Fragments
Expressed in
Tobacco
Potato
Tobacco
Rice
Tobacco
Tobacco
Canola
Tobacco
Tobacco
Expression levels
0.003% total soluble plant protein
0.02% soluble leaf protein
0.1% leaf weight
-
0.00002% fresh weight
250 ng/ml extract
1% seed weight
0.007% soluble leaf protein
Various
COST OF PLANT CULTIVATION IS LOW
HARVEST EQUIPMENT IS INEXPENSIVE/WELL ESTABLISHED
EASE OF SCALE-UP
PROTEINS EXPRESSED IN SEEDS ARE STABLE FOR YEARS
PLANT-BASED SYSTEMS ARE FREE OF HUMAN PATHOGENS
VARIABLE/LOW EXPRESSION LEVELS
POTENTIAL OCCURRENCE OF GENE SILENCING
(SEQUENCE SPECIFIC mRNA DEGRADATION)
NON-NATIVE HUMAN GLYCOSYLATION PATTERN
SEASONAL/GEOGRAPHICAL NATURE OF PLANT GROWTH
Why Recombinant Based Bio-products are challenging???
www.monojo.com.jo
High complexity of monoclonal antibodies Each monoclonal antibody is unique
www.monojo.com.jo
Interferon-alpha
Molecular weight
= 19,625 Daltons
~165 amino acids
Antibody (IgG)
Molecular weight
= 150,000 Daltons
~1,300 amino acids
Atorvastatin
(Lipitor)
Molecular weight
= 558 Daltons
0 amino acids
www.monojo.com.jo
The problem of formulating proteins
• Very large and unstable molecules
• Structure is held together
by weak, non-covalent forces
• Easily destroyed even
under relatively mild storage/handling conditions
+H3N
Amino end
Amino acid
subunits
helix
CH2 CH
O H
O
C HO
CH2
CH2 NH3+ C -O CH2
O
CH2 S S CH2
CH
CH3
CH3
H3C
H3C
Hydrophobic
interactions and
van der Waals
interactions
Polypeptide
backbone Hyrdogen
bond
Ionic bond
CH2
Disulfide bridge
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Why are biopharmaceuticals different?
• High molecular weight
• Complex three-dimensional structure
• Complex manufacturing process
• Produced by living organisms; therefore often heterogeneous
• Difficult to characterize completely by physico-chemical analytical methods or bioassays
• Dependence of biological activity on reproducibility of the production process, in-house standards
• Inherent risk of immunogenicity
Binding Image of an Antibody
Therapeutic Antibodies’ Mode of Action
ANTIBODY STRUCTURE VS FUNCTION
C1q binding
FcR Binding
Glycosylation
Evolution of Therapeutic Antibodies; 3 Main Eras
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Behring Era
Horse Sera
Kohler & Melstein Era
Mouse Monoclonals
Genetic Engineering Era
Humanized & Human
Humanized and Human Antibodies are the Mainstream of Therapeutic Antibodies
www.monojo.com.jo
Source of antibodies on the market (according to a “market analyst”)
Source Antigenicity % Human
Mouse +++ 0 %
Chimeric + 60-70%
Humanised - > 90%
Human - 100%
EVOLUTION OF MONOCLONAL ANTIBODY
1. TRANSGENIC
DNA SPLICING / GENE
KNOCK OUT
Therapeutic Antibodies by Type
TECHNOLOGY ANALYSIS, HISTORICAL AND FORECAST SALES GROWTH ($M), 2003–15
0
10,000
20,000
30,000
40,000
50,000
60,000
70,000
03 04 05 06 07 08 09 10 11 12 13 14 15
Humanized Human Chimeric Antibody fragment Humanized ADC Chimeric ADC
Murine RLC Trifunctional Murine Chimeric RLC Murine ADC
Therapeutic Antibodies on Market
www.monojo.com.jo
Humanized and Human anti-CD20 are in the pipeline
www.monojo.com.jo
Antibody therapeutic patent Expiry Date
www.monojo.com.jo Mo
no
clo
nal
An
tib
od
ies
www.monojo.com.jo
Biosimilars
What is a Biosimilar?
Similar product if compared to an original but is made according to Different process:
different construct, host, cell line, protocol and/or purification steps
additional pre-clinical tests or clinical trials required to show similarity
www.monojo.com.jo
Driving forces for biosimilars (Follow-on Biologics)
• The patents of several biopharmaceuticals have expired or they are about to expire
• Biologics responsible for 20 Billions USD annual sales will go off patent by 2015
• Pressure to reduce healthcare expenditure and increase patient access to treatment will drive the development of cheaper biosimilars
www.monojo.com.jo
www.monojo.com.jo
Biosimilars: Constraints & Drivers
• Regulatory
– No clear cut regulatory
• Technological
– Manufacturing complexity
– High setup & manufacturing costs
– Higher cost to prove comparability
• Market Factors
– Next generation biologics
– Limited discounting ability (discounting in the range 25% to 30%)
– Gaining acceptance by clinicians (brand based competition)
• Biologics segment size & growth
– Biologics performance exceeds that of overall market
– Biologics worth $18 bio. Will go off patent by 2011
• Increasing pressure to reduce healthcare expenditure
– Evolving regulatory mechanisms to recognise biosimilars (EU, Australia)
• Semi/unregulated markets as launch pad
CONSTRAINTS DRIVERS
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Data needed to prove similarity of follow-on biologics
• Analytic studies showing product is highly similar
• Animal studies (including toxicity)
• Clinical Studies showing safety, purity, and efficacy including immunogenicity
www.monojo.com.jo
The process is complex: Upstream and downstream
www.monojo.com.jo
www.monojo.com.jo
....ATG Human Gene
Sequence STOP...
Cloning into
DNA Vector
Transfer into Host Cell
Expression
e.g., bacterial or mammalian cell
DNA Vector
ATG
Fermentation
Stop
Downstream
Purification
(Probably) a different
DNA vector
A different
fermentation
process
A different
downstreaming
protocol
Different
in-process controls
Maybe the same
gene sequence
A different
recombinant
production cell
Biologic manufacturing is complex Biosimilars will always be different from the original
Courtesy of Georg-B. Kresse
Roche Pharma Research
www.monojo.com.jo
PRODUCTION & PURIFICATION SCHEME
Similarity and comparability are two distinct concepts
Only quality data combined with preclinical and clinical experience provide the full picture
www.monojo.com.jo Adapted from Koslowski S, Swann P. Advanced Drug Delivery Reviews 2006; 58: 707–722
In-p
rocess
co
ntr
ols
En
d-p
rod
uct
co
ntr
ols
Release tests
Extended
characterization
Process
www.monojo.com.jo 56
Sickle-Cell Disease: A Simple Change in Primary Structure
• Sickle-cell disease
– Results from a single amino acid substitution in the protein hemoglobin
www.monojo.com.jo
Fibers of abnormal
hemoglobin
deform cell into
sickle shape.
Primary
structure
Secondary
and tertiary
structures
Quaternary
structure
Hemoglobin A
10 m 10 m
Primary
structure
Secondary
and tertiary
structures
Quaternary
structure
Red blood
cell shape
Hemoglobin S
subunit subunit
1 2 3 4 5 6 7 3 4 5 6 7 2 1
Normal
hemoglobin Sickle-cell
hemoglobin . . . . . . Exposed
hydrophobic
region
Val Thr His Leu Pro Glul Glu Val His Leu Thr Pro Val Glu
ICH Q5E Document on Comparability
• Provides a harmonized approach for determining comparability however:
– Requirements for data are not consistent or transparent
• Glycosylation, N-terminal heterogeneity
• Process data
• Impurity data
• Non-clinical safety data
• pK/pD data and additional clinical data
– Application to investigational and approved products is not clear:
The Degree of Any Manufacturing Change
Determines How Much Data Will Be Required
59
Change filter
supplier
Move
equipment to
different part
of facility
Lower risk changes
Commonly implemented
Minimal Data Required
(Analytical Testing)
High risk changes
less common
Maximal Data Required
(incl. Clinical Testing)
Move
manufacturing
to new facility
Scale up
manufacturing
DEGREE OF MANUFACTURING CHANGE INCREASED RISK
New cell line
Change in process
technology
Formulation change
Biosimilars Manufacturing Changes
Commonly Implemented
EMEA Approach for Biosimilar Medicines: Guideline on Similar Biological Medicinal Products
(CHMP/437/04)
• Overall Approach
– Similar biological medicinal products are not generic medicinal products
– Comparability studies need to demonstrate the similar nature in terms of quality, safety, and efficacy
• Biosimilars will be different from the reference
– It is not expected that the quality attributes in the biosimilar and reference product will be identical
– The biosimilar product may exhibit a different safety profile (in terms of nature, seriousness, or incidence of adverse reactions)
Overview Of EMEA Guidelines
Guideline on Similar Biological Medicinal Products
Guideline on Similar Biological Medicinal Products
Containing Biotechnology-Derived Proteins as Active
Substance: Quality Issues
Overarching
Quality
Annexes
Nonclinical
& Clinical
Recombinant
Human
Erythropoietin
Recombinant
Human
G-CSF
Recombinant
Human
Insulin
Recombinant
Human Growth
Hormone
General:
Applies to all
Biosimilars
Specific:
Product data
requirements
Guideline on Similar Biological Medicinal Products
Containing Biotechnology-Derived Proteins as Active
Substance: Nonclinical & Clinical Issues
Nonclinical
& Clinical
TOPIC TITLE APPLICATION
Biosimilars
Erythropoietin (EPO)
www.monojo.com.jo
www.monojo.com.jo
Biochemical Assessment of Erythropoietin
high degree of isoform variability in rEPO products
www.monojo.com.jo
each of the two batches of Huan Er Bo, indicating
differences in the manufacturing process of the
product within the same company.
www.monojo.com.jo
Even what looks the same may be different
Absence of Evidence is not Evidence of Absence
IEF pattern and sialic acid content of the two EPO isoform preps are very similar – but bioactivity is different
huEPO-(1) huEPO-(2)
Isoform 2 Isoform 2
Sialic acid 14.0 14.2
in vivo
activity
(U/mg)
226,000 400,000
1
8
7
6 5 4 3 2
1
8
7
6 5 4 3 2
Courtesy of Georg-B. Kresse
Roche Pharma Research
The carbohydrate
structures of the
two EPO isoforms
differ
Carbohydrate
structures
huEPO-(1)
(isoform 2)
huEPO-(2)
(isoform 2)
Relative denaturation of EPO products to detect unfolding structure
www.monojo.com.jo
www.monojo.com.jo
Characteristic Method IPC DS DP ST
Methods
Identity Western Blot X X X X
Titer ELISA X
Standard Analytical Methods
In-Process Cell Culture
Cell count, viability, pH, C02, glucose
X
Appearance Visual examination X X X
pH Potentiometric X X X X Identity
Peptide Map X X X
Western Blot X X X X Quantity
Analytical Protein A X X X X
ELISA X
Purity
SDS-PAGE X X X X
RP-HPLC X X X X
Impurities
Host Cell DNA - qPCR X X
Host Cell Protein - ELISA X
Residual Protein A -ELISA X Protein Content
A280 X X X
BCA X
Endotoxin Kinetic Ph. Eur. X X X X
Bioburden Culture Ph. Eur. X X X X
Mycopiasma Unprocessed bulk harvest X
Viral testing Unprocessed bulk harvest X
Excipients to be determined X
IPC — In Process Control testing DS — Drug Substance release testing
DP — Drug Product release testing ST — Stability testing
www.monojo.com.jo
Biosimilars
Therapeutic Monoclonal antibodies
www.monojo.com.jo
Monoclonal antibodies Structurally much more complex than other proteins
• Complexity: considerably more complex than currently developed biosimilars
• Biological activity: glycosylation patterns are critical - small differences correlate to changes in biological activity
• Predictability: multi-functionality (both binding and immune effector functions) coupled with an often limited understanding of structure- function relationship will limit predictability of in vitro data
• Extrapolation: complexity and diversity of the mechanisms of action will be of particular challenge for indications and line extensions
www.monojo.com.jo
Monoclonal Antibody is a Glycated protein
N-Linked
Oligosaccharides
(sugars)
Reditux (anti CD20): an intended copy, not a proven biosimilar
• Same amino acid sequence
• Host cell protein content much higher
• Content of aggregates not comparable
• Glycosylation not comparable
• Effector function not comparable
• Charge distribution not comparable
• Clinical (PK/PD) published data - 17 patients
www.monojo.com.jo
Different manufacturing means: • Different drug
• Different safety/efficacy profile?
Changes in glycosylation of antibody will affect Potency
@Potency can be affected if the molecule: Has Fc function
Has glycosylation in the Fab region
@Effect on PK highly dependent on
sugar moieties High mannose can clear quicker in vivo
@Bioavailability depends on any charge differences
@Not easy to control from lot to lot
www.monojo.com.jo
Biosimilar or Biobetter
www.monojo.com.jo
Bio-better
• intended to be better or superior to the innovator product with marked differences in:
– clinical efficacy
– safety
– and/or convenience
• should go through the full development and approval process
www.monojo.com.jo
More details
• Modified by protein or glyco-engineering
• efficacious, require a lower dosing frequency
• most critically, reduce the risk of immunogenicity
• Even better, they have lower early-stage R&D costs
www.monojo.com.jo
Why going to bio-better
• modifying an existing therapeutic protein is significantly easier and less risky than developing a new one
www.monojo.com.jo
Biobetter in monoclonal therapeutics Adding benefits to key medicines; developing better ones
www.monojo.com.jo
T-DM1 as an example for next generation antibodies
www.monojo.com.jo
Follow-on Biologics will play a role in
shaping the future of Pharma industry
Main Future Big Players in Follow-on Biologics:
• Teva (large generics manufacturer) partnered Lunza Group
• Sandoz, generics arm of Novartis: increased capacity in Bio-manufacturing to ramp up its effort
• Bioventures of Merck: established in 2008 for the development of follow-on Biologics
• Pfizer: testing follow-on version of Enbrel (in phase 2 clinical trials)
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HIKMA CELLTRION PARTNERSHIP AGREEMENT
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CELLTRION Portfolio
www.monojo.com.jo
MidPharma-ISU ABXIS
Clotinab®
the first biosimilar of REOPRO® (Centocor)
• is a Fab fragment of a therapeutic antibody for GP IIb/IIIa receptor (human platelets)
• inhibits platelet aggregation.
• used for prevention of cardiac ischemic complications
www.monojo.com.jo
MONOJO
A
Hub for Biotech Innovation
www.monojo.com.jo
THANK YOU
