MANUFACTURING ISSUES OF TWO
« BIOLOGICALS » AND
REGULATION
Youssou NDAO
Anne-Félice PELLET, Laure TIQUET,
Florent ZOONEKYND, Khadra BUBAKER
1
ACTUAL SITUATION
Top 10 Selling Biologics in 2011
Drug
Type
Revenue Cell line
Humira
Monoclonal antibody
8,24 b$
CHO
Enbrel
Fusion protein
7,89 b$
CHO
Remicade
Monoclonal antibody
7,19 b$
SP2/0
Rituxan
Monoclonal antibody
6,79 b$
CHO
Avastin
Monoclonal antibody
5,98 b$
CHO
Herceptin
Monoclonal antibody
5,94 b$
CHO
Insulin
5,45 b$
Esch. coli
Neulasta
Cytokine
3,95 b$
Esch. coli
Lucentis
Monoclonal antibody
3,77 b$
Esch. coli
Epogen
Erythropoiesis stimulating protein
3,73 b$
CHO
Lantus
Summary of product characteristics (www.ema.europa.eu/ & EvaluatePharma, June 2012
3
7
Mammalian
Cells
2
PROTEIN PRODUCTION PIPELINE
Target Selection
SALVAGE APPROACHES
Target Optimization
Gene Cloning
Selection of Expression Vector
Selection of Expression Host
Expression Analysis
Scaling up
Fermentation
Purification
Purification Optimization
Characterization
Concentration & Storage
http://www.sciencedirect.com/science/article/pii/S1046202311001605
3
GENE CLONING
Donor DNA
Recombinant Vector
with insert 1 or 2
Restriction frangments
Transformation
Replication,
Amplification
& cell division
Clone of donor
fragment 1
4
4
BUILDING THE MASTER CELL BANK
Collection of cells of uniform composition
derived from selected cell clone containing
the expression construct
MCB is cryopreserved in aliquots stored in
the liquid nitrogen
• Working Cell Bank derived from one or more vials of cells from
the MCB
• Cells from the MCB expanded by serial subculture up to a
passage number selected by the manufacturer and approved by
regulator
5
ICH Q5D: Derivation and characterization of cell substrates used for production of Biotechnological/Biological
CHARACTERIZATION OF MCB
• Manufacturers should perform Quality control tests for all cell
banks include:
Identity: expression construct
Sterility: Test for the presence of contaminating cell
lines, viruses, mycoplasma, and bacteria
Stability: coding region (for recombinant cell banks)
must be determined during cultivation and storage
6
ICH Q5D: Derivation and characterization of cell substrates used for production of Biotechnological/Biological
CELL PREPARATION FOR FREEZING
Refeed cells to ensure log
phase of growth
Label cryotubes with cell line,
cells/vial, date, MCB
Use trypan blue for viability
Count cells
Select a freezing media
Select a cryoprotective agent (DMSO or glycerol)
=> Place cryovials gradualy in freezer -40°C/-80°C, and in liquid
nitrogen (-196°C)
7
Cell preparation for freezing: Dana M. Hopkins Wm. Davies, Jr. Career & Technical HS, Rochester, NY
THAWING CELL BANK
Cells are damaged to
a certain degree
DMSO may be toxic to
cells after thawing
Cells should be thawed
rapidly (37°C) and then
diluted slowly into
warm growth medium
Removal of DMSO by
changing media quickly
(dilution)
8
www.corning.com/lifesciences
CELL CULTURE MEDIA
Over extended periods by serial passage is a high-risk approach
• Genotypic and phenotypic variation
• Risk of laboratory accidents
• contamination with microorganisms
• cross-contamination with other cells
Monitored
• Critical operating parameters
• Cell growth, viability
Appropriate procedures in place
• To detect contamination/decontaminate the equipment
9
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2958569/#R53
PROCESS CHARACTERIZATION AND
VALIDATION
Identification of :
Critical operational parameters
Key performance indicators
Use qualified analytical methods and raw materials
for consistency and accuracy
Product quality specifications are approved as part
of BLA
Three and five consecutive full-scale runs are
normally required for BLA (US & EU)
10
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2958569/#R53
PROCESS TECHNOLOGY TRANSFER
A “gap analysis” should be conducted
Limitations and potential risks
Facility and equipment modifications and
qualification activities should be completed
prior to full-scale production runs
Pre- and post-change product not identical, but:
. Biological activity highly comparable,
. Changes have no impact upon the safety or
efficacy of the product
11
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2958569/#R53
12
http://www.sciencedirect.com
CHARACTERIZATION OF PRODUCT
Peptide Mapping
• Evidence for the identity to confirm desired product
structure for lot release purposes
Carbohydrate structure
• For glycoproteins, the carbohydrate content (neutral
sugars, amino sugars, and sialic acids)
• Glycosylation site(s) of the polypeptide chain is
analyzed
13
ICH Q6B: Test procedures and acceptance criteria for Biotechnological/Biological products
STORAGE FACILITIES
Auditing process to ensure that maintenance
and documentation are kept up to date
Process changes and degradation products
during storage
Heterogeneity patterns in the material used during preclinical and
clinical development
Stability profile to proof that changes will be
detected
14
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2958569/#R53
PROBLEMATIC OF POSTTRANSCRIPTIONAL MODIFICATION
95082
82391
100000
Putative PTMs by Category
19478
Frequency
10000
5756
5058
4448
2642
2237
2204
1888
1490
1219
1176
1032
846
1000
100
10
1
Post-Translational Modification
15
Proteome-wide post-translational modification statistics: frequency analysis and curation of the swiss-prot Database. George A. Khoury, Richard C. Baliban & Christodoulos A. Floudas.
PROBLEMATIC OF POSTTRANSCRIPTIONAL MODIFICATION
95082
82391
100000
Putative PTMs by Category
19478
Frequency
10000
5756
5058
4448
2642
2237
2204
1888
1490
1219
1176
1032
846
1000
100
10
1
N-glycosylation
Post-Translational Modification
16
Proteome-wide post-translational modification statistics: frequency analysis and curation of the swiss-prot Database. George A. Khoury, Richard C. Baliban & Christodoulos A. Floudas.
N-GLYCOSYLATION IN HUMAN
KINETICS
Oligosaccharyl
transferase
NIH Public Access, Metabolism, Cell Surface Organization, and Disease James W. Dennis, Ivan R. Nabi, and Michael Demetriou
17
N-GLYCOSYLATION IN HUMAN
Glycosylation = Dynamic
Tri-antennary
complex
Leu
Asn
Gly
Ser
…
Arg
Ile
Cys
Thr
Asn
Glu
Ser
18
NIH Public Access, Metabolism, Cell Surface Organization, and Disease James W. Dennis, Ivan R. Nabi, and Michael Demetriou
N-GLYCOSYLATION IN HUMAN
Glycosylation = Dynamic
Tri-antennary
complex
Leu
Asn
Gly
Ser
…
Arg
Ile
Cys
Thr
Asn
Glu
High-Mannose
type
Ser
No glycan
NIH Public Access, Metabolism, Cell Surface Organization, and Disease James W. Dennis, Ivan R. Nabi, and Michael Demetriou
19
N-GLYCOSYLATION IN HUMAN
Example of human IgG
20
High Throughput Isolation and Glycosylation Analysis of IgG–Variability and Heritability of the IgG Glycome in Three Isolated Human Populations, The American Society for Biochemistry and Molecular Biology, Inc. 2011
EXAMPLE OF N-GLYCOSYLATION
PROBLEMATIC IN CHO
Ex : IgG
- Increase serum clearance
- Reduced ADCC
21
Optimal and consistent protein glycosylation in mammalian cell culture, P Hossler, SF Khattak, ZJ Li - Glycobiology, 2009 - Soc Glycobiology
EXAMPLE OF N-GLYCOSYLATION
PROBLEMATIC IN CHO
T1/2
Low
temperature
Overexpression of
CMP-SAT
Glycerol
22
Optimal and consistent protein glycosylation in mammalian cell culture, P Hossler, SF Khattak, ZJ Li - Glycobiology, 2009 - Soc Glycobiology
EXAMPLE OF N-GLYCOSYLATION
PROBLEMATIC IN CHO
Example of recombinant EPO
CLINICAL TRIALS
Activity 1
Activity 2
Activity 3
Activity 4
Half-life 1
Half-life 2
Half-life 3
Half-life 4
…
=
Product efficacy
23
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3449730/pdf/10616_2004_Article_267657.pdf
DEGRADATION PRODUCTS
• Desired product:
– Protein which has the expected structure
– Protein expected from the DNA sequence
– Anticipated post-translational modification (glycoforms),
Degradation products may be either:
• Product-related substance
• Degradation products
24
II – ETUDES DE CAS
Perjeta
Pertuzumab®
Fabrazyme®
&
Replagal®
25
PERJETA® - Pertuzumab
26
®
PERJETA
- Pertuzumab
Recombinant
humanized IgG1
Indication : Her2-positive
metastatic breast cancer
Combination with Trastuzumab and
Docetaxel
Aggressive tumor and a poor prognosis
Clinical pharmacology and biopharmaceutics review of perjeta
http://www.ncbi.nlm.nih.gov.doc-distant.univ-lille2.fr/pmc/articles/PMC3462608/
27
MECHANISM OF ACTION
Her 2 binding
Inhibition of Her2
dimerisation
Inhibition of key intracellular
pathways which are critical to
cell proliferation and survival
28
Clinical pharmacology and biopharmaceutics review of perjeta
MECHANISM OF ACTION
Pertuzumab
• Subdomain II of HER2
Pertuzumab
Trastuzumab
• Subdomain IV of HER2
HER2
Trastuzumab
http://clincancerres.aacrjournals.org/content/17/15.cover-expansion
29
ADCC : Antibody-dependent cellmediated cytotoxicity
Macrophages
NK Cells
Neutrophils
FcγR
Tumor
cell
Lysis of the target cell
30
Comment améliorer les propriétés effectrices des anticorps monoclonaux thérapeutiques ? Christophe Carnoy
CLINICAL TRIALS / « CLEOPATRA »
12.4 months with Placebo VS 18.4 months with Pertuzumab
=> 6.1 months of improvement (p < 0.001)
Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.
31
COST OF TREATMENT
Perjeta®
$5,900
per month
Herceptin®
$71,000
per year
$4,500
per month
$54,000
per year
$125,000 for 1 year
Pharmaceutical Approval Update Marvin M. Goldenberg, PhD, RPh, MS / Vol. 37 No. 9 • September 2012 • P&T
32
MANUFACTURING
Recombinant DNA
technology in CHO
FDA pre-approval
inspection
Failure rate for the Working
Cell Bank thaw during the 2012
manufacturing campaign
33
CENTER FOR DRUG EVALUATION AND RESEARCH
APPLICATION NUMBER:125409Orig1s000
CHEMISTRY REVIEW(S)
« We discovered that the Sponsor was experiencing
serious issues with the thaw and subsequent
propagation of cells from WCB »
34
35
http://www.bionique.com/mycoplasma-resources/technical-articles/certified-working-cell-bank.html
December 2011
Genentech filed
applications for approval
in US and EU
HISTORY
February 2012
FDA grants pertuzumab
“Priority Review”
June 8, 2012
FDA’s Approval
(Product launch about 2
weeks post-approval)
2011
December 7, 2011
Improvement PFS by
6.1 months (NEJM)
2012
May 2012
Submission in Japan
March 2012
FDA Pre-license drug
inspection
August 2012
Approval in Switzerland
Failure rate for WCB growth
PDL Biopharma Corporate Overview July 2012
Dec 13, 2012
Positive
opinion from
the CHMP
36
TO RECAP
37
RESTRICTIONS ON APPROVAL
Restriction from FDA :
Only campaign 2010 approved
Potential shortage
MANUFACTURING
ISSUES
Could have ramifications for the development and
approval of biosimilars
Genentech’s Perjeta Clears FDA despite Unresolved Manufacturing Issues Elsevier Business Intelligence: 'The Pink Sheet' - June 18, 2012
38
RECOMMENDATIONS ON
APPROVABILITY
Three concurrent plans to
resolve the cell growth issues
Manufacturing from the
Master Cell Bank
Manufacturing using a
modified process from
Working Cell Bank
Developing a new WCB
and manufacturing from
this new WCB
39
Center for drug evaluation an d research – 125409Orig1s000 Chemistry Review0
APPROVAL’S CONDITIONS
Letter from Division of Monoclonal
Antibodies (DMA)
13 Perjeta Commitments
40
1- Stability study of the drug
substance manufactured from specific
thaws 2012 pertuzumab campaign
Real time
Confirm the use-by-date
Stressed stability testing
Evaluate the intrinsic stability of the active molecule
Identify degradation products
Choose analytical methods
Predict the stability of a drug formulation
Shortened shelf life 
Risk of lack of biological effects
41
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/chem/stabt_stabe-fra.php#1.3
42
Stability studies : EMA’s guideline
“…proteins and/or polypeptides, maintenance of
molecular conformation and, hence of biological
activity, is dependent on noncovalent as well as
covalent forces.
The products are particularly sensitive to
environmental factors such as temperature
changes, oxidation, light, ionic content, and shear.
In order to ensure maintenance of biological
activity and to avoid degradation, stringent
conditions for their storage are usually
necessary.”
43
Guideline Quality of Biotechnological Products: Stability Testing of Biotechnological/BiologicalProducts
2- Stability studies of the Master Cell
Bank at more frequent intervals than
the currently proposed 10 years
Check the stability of the MCB
every 4 years
44
3- Reassess release and stability
specifications for pertuzumab drug
substance and drug product through
June 30, 2014
45
Process validation study to support
manufacture of pertuzumab from
4- Master Cell Bank
5- Working Cell Banks by a modified
process
6- A new Working Cell Bank
46
Process validation study
Objective : check that all manufacturing steps lead to a product in
compliance with standard of stability and reproducibility.
Drug substance manufacturing campaigns are
able to deliver consistent product with
comparable strength, quality, purity and
potency to that used in the phase 3 clinical trial
 Reproducibility : glycosylation profile,
ADCC activity, and purity
47
48
Process validation studies :
EMA’s guideline
“The evaluation/validation data provide essential
information on the reproducibility and robustness
of the process steps and are an important element
to guarantee consistency in the quality of the
product.”
49
“Effective process validation contributes
significantly to assuring drug quality
…
• Quality, safety, and efficacy are designed
or built into the product.
• Quality cannot be adequately assured
merely by in-process and finished-product
inspection or testing.
• Each step of a manufacturing process
is controlled to assure that the finished
product meets all quality attributes
including specifications.”
50
7- Study to establish a drug substance
release specification to control for
antibody-dependant cellular
cytotoxicity (ADCC) activity of
pertuzumab
ADCC boosted according to the glycoforms
Verify the expected activity
51
8- Study to assess the ability of a
CE-SDS assay to detect and quantitate
pertuzumab fragmentation
Check that the product is
stable once it is made
(no fragmentation)
Different / too low glycosylation
 Not protected enough in the culture media
 Fragmentation  Lack of efficacy
52
9- Tests for in vivo adventitious viruses
and genetic inconsistency using end of
production cells
Importance of ensuring the finished products well
kept free of « adventitious » agents.
Importance of genetic homogeneity of all last cells
used for the production
53
10- Re-qualify the bioburden test for
the bulk drug substance and inprocess bioburden samples
Control microbial contamination of
the drug and on the samples
recovered during manufacture
54
11- Revalidate the hold time for nonsterile cell culture media
Check the time during which a culture
medium is sterile
55
12- Comprehensive risk assessment
regarding the microbial control of the
cell culture process and action plan
based on the assessment
Find the critical points to prevent or
eliminate the risk of microbial
contamination in cell culture
56
13- Plan for responding to potential
pertuzumab shortages
Draft Plan Submission : 07/2012
Final Plan Submission : 09/2012
Communications to healthcare providers and patients
Mechanism for ensuring that patients who are already
receiving pertuzumab can continue to be treated
according to the product label
57
TO CONCLUDE
Issues
• Stability
• Thaw
• Cell growth
• Contamination
Risk by FDA
• Shortage
• Stock management
New clinical study?
58
REPLAGAL®
& FABRAZYME®
59
INDICATION
Indication : Fabry disease
= lysosomal storage disorder
Orphan disease => incidence of 1 per 60,000 to 1
per 35,000 live births (HAS) = 5,000 patients
worldwide, France ≈ 300, US ≈ 700
Deficiency of the enzyme α-galactosidase A
Accumulation of Gb3
Renal cells
Cardiac
cells
http://www.has-sante.fr/portail/upload/docs/application/pdf/2010-12/ald_17_pnds_fabry_vd.pdf
CNS
cells
Endothelial
cells
60
60
HUMAN α GALACTOSIDASE A
Active
site
61
http://www.replagal.co.uk/hcp/about-replagal/
SYNTHESIS OF α GALACTOSIDASE
A IN PHYSIOLOGICAL STATE
Glycosylation
62
http://www.ncbi.nlm.nih.gov/books/NBK11598/?report=printable
SITE OF ACTION OF
α GALACTOSIDASE A
Lysosome
63
http://www.lysosomalstorageresearch.ca/Fabry_eClinic/n-algasidase-alfa.html
FABRY DISEASE
Absence of
enzyme
Enzyme’s
activity
decreased
64
http://www.ncbi.nlm.nih.gov/books/NBK11598/?report=printable
FABRY DISEASE
No GLA
65
http://www.lysosomalstorageresearch.ca/Fabry_eClinic/n-algasidase-alfa.html
EFFECT OF GLYCOSYLATION ON
ACTIVITY OF α GALACTOSIDASE A
Stability => T1/2
Enzymatic transport
Modification of
the
biodistribution
and bioactivity
3D configuration
N192 et N215 sites of glycosylation (domain 1) mutate frequently =>
no binding to the M6P receptor => no adressing to the lysosome
66
http://www.ncbi.nlm.nih.gov/books/NBK11598/?report=printable
TWO TYPES OF FABRY DISEASE
Causes
Morbidity
Classical
Atypical variants
Absence of enzyme
Enzyme’s activity
decreased
• Renal failure
• Cardiomyopathy
• Cerebrovascular
incident
• Renal
• Cardiac
One of them only occur.
All these features
occur together or at least
two.
GL-3 accumulation in the kidney
vascular endothelium
http://www.ncbi.nlm.nih.gov/books/NBK11572/#A1092
http://wiki.medpedia.com/Fabry%27s_Disease
67
MORBIDITY RATE
80
70
60
50
40
30
20
10
0
Males
Females
68
http://www.ncbi.nlm.nih.gov/books/NBK11572/table/A1079/?report=objectonly
MECHANISMS OF FABRY DISEASE
http://flipper.diff.org/app/items/info/2968
69
ENZYME REPLACEMENT THERAPY
Recombinant human αgalactosidase A,
produced in a human cell
line by gene activation
Recombinant human αgalactosidase A, produced
in CHO cells by recombinant
techniques
70
ERT MECHANISM
71
http://www.ncbi.nlm.nih.gov/books/NBK11598/?report=printable
CHEMICAL & PHARMACOLOGICAL
CHARACTERISTICS
REPLAGAL®
FABRAZYME®
Manufacturing
Human cells
CHO cells
Frequence of occurrence
of IgG
55%
80%
IgE
No
Yes
Reaction at the injection
site
10%
50%
Duration of infusion
40 minutes
2-4 hours
Plasma half-life
42 to 117 min
15 to 45 min
Dosage
0,2 mg/Kg per 14 days
1 mg/Kg per 14 days
72
BIOCHEMINAL CHARACTERISATION
Replagal®
Oligomannose /
oligosaccharide ratio
Fabrazyme®
• Fucose : 3.0
• Fucose : 1.8
• Galactose : 12.2
• Galactose : 8.0
• N-acetyl glucosamine : • N-acetyl glucosamine :
22.5
18.4
Sialic Acid / Galactose
0.56
0.88
Mannose-6-phosphate
on oligomannose side
chain
1.8
3.1
Glycolisation sites
(Asparagine residues)
108 / 161 / 184
73
http://glycob.oxfordjournals.org/content/13/4/305.full#T2 - Table III
GLYCOSYLATION SITES
Replagal ®
% total glycoforms
Fabrazyme ®
% total glycoforms
15%
44%
25%
39%
Biphosphorylated
oligomannose 7
/
36%
Phosphorylated oligomannose 6
28
/
Major oligosaccharides species
in each binding sites
Asparagine 108
Trianttennary fucosylated
trisialylated (more complex
different sialilation)
Asparagine 161
Phosphorylated oligomannose 7
Asparagine 184
74
http://glycob.oxfordjournals.org/content/13/4/305.full#T2 - Table IV
FABRAZYME ® CLINICAL TRIALS
Protoccol No.
Study design
FB9702-01
Phase1/2 study
Open label nonrandomized dose
finding
Primary endpoint
Duration
(n)
Doses
•
•
•
10 weeks
10 weeks
10 weeks
10 days
10 days
(15)
Clinical pharmacodynamics
pharmacokinetic
safety parameters
•
•
•
•
•
0.3mg /kg/eow
1.0mgg/kg/eow
3.0mg/kg/eow
1.0mg/kg/q48h
3.0mg/kg/q48h
AGAL-1-002-98
Phase 3 double blind
placebo control
Morphological assessment of GL-3
inclusions of the kidney
•
1.0mg/kg/14q
20 weeks
(29)
AGAl-006-99
Phase ½ extension
Ongoing safety and efficacy
parameters of phase ½ open label
•
1.0mg/kg/14q
Until marketing
approval
AGAl-005-99
Phase 3 extension
Ongoing safety and efficacy
parameters of phase 3
•
1.0mg/kg/q14
Approx. 5 years
(58)
AGAl-007-99
Morphological assessment of GL-3
inclusions of the endothelium
kidney
•
1.0mg/kg/q14d
20 weeks
(13)
AGAl-008-00
Time of clinically significant
progression of the renal, cardiac,
cerebral vascular, & death among
Fabry with advanced case.
EMA & brief document
•
•
Primary end point
Fabrazyme / Placebo criteria
35 months
1.0mg/kg/14q
75
REPLAGAL® CLINICAL TRIALS
Protoccol No.
Study design
TKT 001
Open label , dose escalation
safety Phase 1
Primary endpoint
Doses
Duration
(n)
Worsening pain value.
Area Under the curve.
Single dose
(10)
0.2mg/kg/
6 months
(26)
TKT 003
Randomized double blind
placebo controlled Phase 2
Chronic neuropathic pain,
renal function, kidney
pathology, plasma, urine
sediment, kidney GL-3
content, cardiac structure
& function
TKT 006
Open label maintenance
study for pts completing
TKT003
/
0.2mg/kg
1 year
(25)
TKT 011
Open label maintenance
study for pts completing TKT
006
/
/
1 year interim analysis
(24)
TKT 005
Randomized, double blind,
placebo controlled phase 2
CardiacGL-3 levels,
(2ary cardiac mass, renal
function, GL-3 plasma urine)
0.2mg/kg/eow
6 months
Open label
(15)
TKT 014
Open label safety and
efficacy trial in females
Safety on females
0.2mg/kg/eow
3-12 weeks
(15)
EMA & brief document
Primary end point
criteria
76
USA APPROVAL
Accelerated approval
Special Conditions
601.40
Scope
Biological
products
effectiven
ess and
safety for
treating
601.41
Scope
601.43
Scope
Approval
based on a
surrogate
endpoint
Withdrawal
procedures
77
EUROPEAN APPROVAL
REPLAGAL®
BLA under "Exceptional
Circumstances"
FABRAZYME®
August 2001
August 2001
Simultaneous approval
Commercialization in
Europe
February 2002
February 2002
End of "Exceptional
Circumstances" in Europe
No
February 2008
Orphan designation for the 2 drugs
78
TREATMENT COST
REPLAGAL®
FABRAZYME®
Bottle price
1910 €
3900 €
Unit dose
3.5 mg
35 mg
Dosage
0.2 mg/kg
1 mg/kg
Injection price
109.1 €/kg
111.4 €/kg
Annual cost of
treatment
183 360 €
~
191 968 €
79
FABRAZYME MANUFACTURING
AND VIRAL CONTAMINATION
Production sites
Viral contamination
Consequences
Acquisition by SANOFI
80
PRODUCTION SITES
2004
Fabrazyme : 1 x 2KL
Cerezyme: 3 x 2KL
2011 / 2012
Fabrazyme : 1 x 2KL
Cerezyme: 3 x 2KL
81
THE VIRAL CONTAMINATION (June 2009)
Which Virus?
The vesivirus 2117
Contagiousness of the
virus?
Not for human, but for used
to product drugs (CHO only)
Where?
In the production site of
Allston Landing, MA, US
How does it work?
It affects the quality and not
the quantity of enzymes
producted by those cells
82
EMA, Questions/réponses sur les difficultés d’approvisionnement de Cerezyme et de Fabrazyme, 14 août 2009
HOW THE VIRUS WAS DETECTED ?
83
CONSEQUENCES
• Regulatory consequences
• Financial consequences
• Supplying consequences
84
REGULATORY CONSEQUENCES
Regulatory inspection
EMEA/ ANVISA /PMDA/
FDA
Plant Decontamination
June –October 2009
October
2008
February
2009
June 2009
End 2012
March 2010
Q2 2010
Regulatory
inspection
FDA
483Form
FDA
Warning
Letter
Sign Consent
Decree
Viral
FDA
contamination Enforcement
Action
End Consent
Decree
85
FINANCIAL CONSEQUENCES
-1.8%
1800
1600
1400
29%
0.64
%
-13%
29%
1.3%
1200
1000
Preview
800
Published
600
400
200
0
2005
2006
2007
2008
2009
2010
86
http://www.zonebourse.com/GENZYME-CORPORATION-4875/agenda/
ACQUISITION BY SANOFI
Plavix
Taxotere
Appoved Nov. 1997 FDA
 6.6 Billion 2009
Approved July 1998 by EMEA
Approved on 1996 FDA
Approved on Noc 1995 by EMEA
• SANOFI decide to buy GENZYME with an offer of more
than 20 Billion $ on Feb 2011 6.9% sales growth
• Better idea to buy Genzyme
on the 1St Q 2011.
87
CONSEQUENCES ON SUPPLYING
88
Source: company press releases and SEC filings
CONSEQUENCES ON THE U.S. MARKET
89
REPLAGAL® –
BIOEQUIVALENCE
PROBLEMS AFTER A
SWITCH OF PROCESS
90
REPLAGAL® MANUFACTURING
91
http://www.replagal.co.uk/hcp/about-replagal/
REPLAGAL® BLA
2001 :
BLA accepted
by the EMA
in Europe
2003 :
BLA denied
by the FDA
in the US
92
92
6 YEARS AFTER REPLAGAL
REJECTION OF BLA IN THE U.S. …
Fabrazyme®
shortage in the US
(June 2009)
93
93
38
SUMMER 2009 : THE FDA MADE
AVAILABLE THE REPLAGAL®
UNDER A TREAMENT IND
Treatment IND = Investigational New Drugs
Clinical study of 140 patients (20% of US fabry’s patients)
Oct 2009 to June 2012
Opportunity for Shire to collect data
FDA - For Consumers
94
GENZYME‘S CRISIS WAS SHIRE'S
OPPORTUNITY
March 2010
2nd
submission
for BLA =>
denied
Summer 2009
US :
Substitution by
Replagal
June 2009
27th March
2012
FDA
Advisory
Committee
FABRAZYME SHORTAGE
December
2009
1st
submission for
BLA => denied
March 2012
November
2011
3rd
submission for
BLA
BioCentury on BioBusiness “Behind Shire's decision to abandon Replagal for Fabry's in U.S” By Steve Usdin, Monday, June 25, 2012
95
BUT IN MARCH 2012 …
« Surprise »
withdrawal of
Replagal BLA
96
96
« SURPRISE » WITHDRAWAL OF
REPLAGAL® BLA - EXPLANATIONS
Fabrazyme
reappearance
Contents of
the briefing
documents
Sent anonymously
to
97
BioCentury on BioBusiness “Behind Shire's decision to abandon Replagal for Fabry's in U.S” By Steve Usdin, Monday, June 25, 2012
CONTENTS OF THE BRIEFING
DOCUMENTS
FDA require additional clinical data
for safety and efficacity
Lack of data / clinical
studies
Equivalence old/new
product ?
Data from 46 countries +
IND studies
98
98
Biocentury, Behind Shire's decision to abandon Replagal for Fabry's in U.S, June 25, 2012
THE NEW MANUFACTURING
PROCESS FOR REPLAGAL®
99
1st CHANGE IN THE PROCESS
2007
Transition to a new
manufacturing system
April 2009
Bovine serum and animalderived protein
No animal-derived
components in culture
medium
Roller bottles
Bioreactor
AIM : Eliminate animal components able to lead
to contamination and increase the yields
BioCentury on BioBusiness “Behind Shire's decision to abandon Replagal for Fabry's in U.S” By Steve Usdin, Monday, June 25, 2012
100
1st CHANGE IN THE PROCESS
2007
Transition to a new
manufacturing system
EMA
Approved in April
2009
=> Alewife
manufacturing plant
in Cambridge, MA
TGA (Australia)
Approved in May
2010 => on the
condition Shire
conduct a study
assessing the new
version
April 2009
CADTH (Canada)
Approved in 2010
=> on the condition
Shire conduct a
study assessing the
new version
101
BioCentury on BioBusiness “Behind Shire's decision to abandon Replagal for Fabry's in U.S” By Steve Usdin, Monday, June 25, 2012
2nd CHANGE IN THE PROCESS
Sept 2010
Purification of Replagal at the
new facility in Lexington
June 2011
Aim : Increase manufacturing capacity
Approved by
EMA, June 2011
102
BioCentury on BioBusiness “Behind Shire's decision to abandon Replagal for Fabry's in U.S” By Steve Usdin, Monday, June 25, 2012
3 TYPES OF
®
REPLAGAL
PRODUCTS
1. Original product : roller bottles
process
Clinical trial
NO SAMPLES
2. Animal-free product, bioreactor
process
3. Animal free product, bioreactor
process + purification in Lexington
Non clinical
tests/ lack
of human
data
103
BioCentury on BioBusiness “Behind Shire's decision to abandon Replagal for Fabry's in U.S” By Steve Usdin, Monday, June 25, 2012
2 CHARACTERISTICS CRITICAL TO THE
EFFICACY OF ERT (non clinical TGA data)
M6P
Animal free product
Ac. Sialique
Animal free product +
purification in
Lexington
M6P
Ac. Sialique
TGA concluded : "small differences" in the two formulations
"do not lead to any biologically significant differences in either
pharmacodynamic or pharmacokinetic properties"
BioCentury on BioBusiness “Behind Shire's decision to abandon Replagal for Fabry's in U.S” By Steve Usdin, Monday, June 25, 2012
104
FDA POINT OF VIEW
Changes of chemical
characteristics
Changes of
pharmacological
characteristics
Batches produced after changes are different from the
original one
105
BioCentury on BioBusiness “Behind Shire's decision to abandon Replagal for Fabry's in U.S” By Steve Usdin, Monday, June 25, 2012
SHIRE DECISION
Additional
studies would
cause a
significant
delay
Approval
possible in a
distant future
Withdrawal of Replagal BLA
106
BioCentury on BioBusiness “Behind Shire's decision to abandon Replagal for Fabry's in U.S” By Steve Usdin, Monday, June 25, 2012
CURRENT SITUATION IN
THE U.S.
Patients dependent on a single
supplier for a life-sustaining drug
An access to Replagal would protect against
future supply disruptions
107
BioCentury on BioBusiness “Behind Shire's decision to abandon Replagal for Fabry's in U.S” By Steve Usdin, Monday, June 25, 2012
THE LACK OF A MEDICINE JOINS
THE LACK OF THERAPEUTIC
EVALUATION
108
NO COMPARISON STUDY
BETWEEN THE 2 ERT BUT …
Canadian trial (2007 – 2017)
370 fabry’s patients - 3 arms
Fabrazyme shortage , 29 patients switched
to Replagal => no significant differences
Tsuboi study
11 patients, data collected for 3 years after
a switch Fabrazyme/Replagal
=> no significant differences
109
CONCLUSION
Replagal and Fabrazyme
are a
significant therapeutic
advance as first ERT for
Fabry disease
The long-term
effectiveness needs to
be evaluate
The comparison
between the 2 ERT
needs to be done
110
BIOLOGICALS PRODUCTION
One Company
Reference
« Master Cell Bank »
Thaw
New plant
Viral Contamination
Controlled
Manufacturing process
Caracterized
Biological product
111
THE BIOSIMILAR
One Company
Reference
« Master Cell Bank »
Reproductibility
10y experience
Thaw
New plant
Viral Contamination
Controlled
Manufacturing process
« Similar product »
112
THANKS FOR
YOUR ATTENTION
113