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Biosimilar Guidance Luxury or Necessity?
Dr. Thomas Schreitmueller, Regulatory Policy and Strategy Biologics
F. Hoffmann La Roche Ltd., Basel, Switzerland
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Table of content
Biosimilars Regulations
Raptiva
Myozyme
Alpheon
Pegaferon
Epoetin alfa: Binocrit, Epoetin alfa Hexal, Abseamed
Conclusions
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Global Regulatory Requirements Reflect the
Complexity of Biological Products
The Pharmaceutical industry is the second most regulated industry in the world
following aviation.
Manufacturers of biological products must comply with an extensive set of regulationsand guidance documents to insure quality and safety of biological products.
Regulations and Guidance for Development and Manufacture of Biological Products
US FDA
(9) Regulations/Proposed Rules;
(6) Points to Consider Documents; (22) Guidance Documents
EMA
(18) Guidelines
ICH
(10) Guidance Documents
Safety and Efficacy
ICH S6 Preclinical safety Evaluation of Biotechnology-Derived Pharmaceuticals
EMA: Clinical Investigation of the Pharmacokinetics of Therapeutic Proteins, ClinicalInvestigation of Recombinant Factor VIII and IX Products, Immunogenicity Assessmentof Biotechnology-derived Therapeutic Proteins, Comparability of Biotechnology-DerivedMedicinal Products after a change in the Manufacturing Process - Non-Clinical andClinical Issues
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Biological product complexity:Examples of modi f ications: inherent or due to the
manufactur ing process
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, G
Sialylation
Modifications may result in approximately 108 potential variants
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Protein Microheterogeneity
Small MoleculeDrug
ProteinDrug
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Biotech products are very complex, sensitive,heterogenious mixtures of protein molecules.
Each molecular entity of that mixture is characterized
by specific physical, chemical and biologicalproperties.
Any change in the composition of that mixture is
potentially going to affect patients safety and chance
of cure.
Biotech products
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Biosimilars:Different process, di f ferent pro duc t
Biosimilar that is different from the
originator
Even if a biosimilar uses the same human gene as its innovator, It willdiffer in other parts of the manufacturing process
Same gene as
innovator
FermentationCloning into
DNA vector
Transfer into
host cell
Bacterial ormammalian cell
produces protein
Human
gene
Formulation
DNA
vector
Differences in the process
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EU biosimilar guidelines & products
GuidelineGuideline on Similar Biological Medicinal Products
Guideline on Quality Issues
Guideline on
Non-clinical/Clinical Issues
GHInsulin G-CSF Epoetin
HX 575 (Binocrit,
Epoetin-alfa Hexal,
Abseamed)
Alpheon
rejected
(IFN-alfa)
Product-Class Specific Guidelines on Nonclinical/Clinical:
SB309 (Silapo, Retacrit)
Biograstim
Ratiograstim
Filgrastim
Ratiopharm
Tevagrastim
Proof of Similarity with
a reference product as
the basis for approval
Full dossier plus head-to-
head comparison to
reference product
Reduced dossier, head-to
head comparison toreference product
Filgrastim Hexal
Zarzio
LMWH
IFN-alfa
Nivestim
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Biosimilars in EUThe Problem of Interchangeability/Substitution
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Biosimilars in EUInterchangeability/Substitution: The English Way
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Biosimilars Global Regulations
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Key points from the WHO biosimilar guideline
Global high standard guidance based on scientific rationale due to
complexity of biologicals Based on demonstration of similarity at quality, safety and efficacy
Comparative quality, non-clinical and clinical studies to the samereference requested
Equivalence design in clinical studies preferred option, however,
non-inferiority designs may be considered if appropriately justified Extrapolation across indications possible if certain conditions are
fulfilled
National implementation of the WHO guideline supported
The guideline principles should be adopted as a whole
Pharmacovigilance is appropriately addressed but countries should haveappropriate PhV frameworks relevant for biologicals
The guidance does not address interchangeability/substitution
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Table of content
Biosimilars Regulations
Raptiva
Myozyme
Alpheon
Pegaferon
Epoetin alfa: Binocrit, Epoetin alfa Hexal, Abseamed
Conclusions
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The Raptiva (Efalizumab) Experience (1/2)
Raptiva (efalizumab) was originally manufactured by XOMA and used in the
Phase I/II trials and up to Phase III. Manufacturing was transferred to Genentech
(with full information).
Analytical and formulation differences expected to be inconsequential were
observed (changes in charge heterogeneity, increase in C-terminal processing,
higher levels of acidic forms, higher galactosylation)
In a bioequivalence study, some differences in PK parameters were observed:
However, because of the unpredictable nature of these PK changes an
additional Phase III study was performed to determine the safety and efficacy of the
Genentech material.
Xoma GNE Ratio (G:X)
AUCinf 27.9 36.9 1.324
AUCt 26.9 35.6 1.324
Cmax 3.59 4.22 1.175
Source: W.F. Bennett, Genentech
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The Raptiva (Efalizumab) Experience (2/2)
Source: W.F. Bennett, Genentech
26,6%
38.9%
2.4%0%5%
10%
15%
20%
25%
30%
35%40%
45%
Placebo
(n=170)
1.0
mg/kg/wk
XOMA
material
(n=162)
1.0
mg/kg/wk
GNE
material
(n=369)
Percentage
ofSubjects
improved75%
Trend for lower PASI* Response to Raptiva Efalizumab) despitehigher peripheral Drug Concentrations
Changes that were believed not to affect the properties of the protein resultedin clear differences in pharmacokinetics. Given the complexity of
therapeutic proteins, the impact of changes in pharmacokinetics (and probably
pharmacodynamics) on safety and efficacy cannot be reliably predicted.
Improved > 75%
*PASI = Psoriasis Area and
Severity Index
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Table of content
Biosimilars Regulations
Raptiva
Myozyme
Alpheon
Pegaferon
Epoetin alfa: Binocrit, Epoetin alfa Hexal, Abseamed
Conclusions
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Case Study:Comp lexi ty of B io logical Produc t Manufacture
Myozyme: FDA rejects Genzymes own scaled-up version
Mack G. Nature Biotechnology 2008; 26:592.
FDA reject Genzymes
application to scale up
production of Myozyme fromthe 160-litre facility to the
2,000-litre facility
The FDA was concerned about differences in the carbohydrate structure of the
products manufactured at each facility and therefore stipulated that the 2,000-litre
product required a new biologic license
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Case Study:Comp lexi ty of B io logical Produc t Manufacture
Myozyme: FDA rejects Genzymes own scaled-up version
Mack G. Nature Biotechnology 2008; 26:592.
30% bioavailability
2881% hepatic uptake2065% muscle uptake
Myozyme produced in the 2,000-litre-scale facility has lower bioavailability,
higher hepatic uptake and lower muscle (site of action) uptake compared with
Myozyme produced in the approved 160-litre-scale facility
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Table of content
Biosimilars Regulations
Raptiva
Myozyme
Alpheon
Pegaferon
Epoetin alfa: Binocrit, Epoetin alfa Hexal, Abseamed
Reditux
Biosimilars in the EU (Alpheon BioPartners)
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Biosimilars in the EU (Alpheon, BioPartners)
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Table of content
Biosimilars Regulations
Raptiva
Myozyme
Alpheon
Pegaferon
Epoetin alfa: Binocrit, Epoetin alfa Hexal, Abseamed
Conclusions
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Pegaferon
Name : Pegaferon
Batch: 07-B
MFD: 06 / 2007
Exp. Date 06 / 2009
SDS PAGE Sil St i d d
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The following clipping sites were characterized by ESI-MS and MALDI-MS/MS
90
QQLNDLEACVIQGVGVTETPLMK112
12.4 kDCDLPQTHSLGSRRTLMLLAQMRKISLFSCLKDRHDFG
FPQEEFGNQFQKAETIPVLHEMIQQIFNLFSTKDSSAA
WDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMK
EDSILAVRKYFQRITLYLKEKKYSPCAWEVVRAEIMRSF
SLSTNLQESLRSKE
Reduced Gel
7.1 kDCDLPQTHSLGSRRTLMLLAQMRKISLFSCLKDRHDFG
FPQEEFGNQFQKAETIPVLHEMIQQIFNLFSTKDSSAA
WDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMK
EDSILAVRKYFQRITLYLKEKKYSPCAWEVVRAEIMR
SFSLSTNLQESLRSKE
6.0
14.4
3.5
21.5
55.466.3
SDS-PAGE Silver Stain reduced
Extended Characterization
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EK
SR
LS
EQ
LN
TS
LS
F RS
A
M
IE
V
R
W
EV
PC
A
Y
S
Q RI
TL
Y
L
E
RVA
C
Y F
ET
P L
M E D S I L
CV
I
Q
G
V
G
V
T
D
FY
TL
N
D
LE
A
QQ Y
L E
D
L
PQ
T
HS
L G S R R T L M L L A
F
Q
L
S
I
R
M
D
E
T
L
L C
S
F
S
T
D
S
S
AAW
M
I
Q
Q
I
F
NL
E H
L
V
P
I
T
E
A
Q
F
Q
N
E
E
F
G
G
FPQ
H
D
F
LD
R
K
K
KK
K K
K
K
K
KNH
2
164
131
133
134
112
31
49
83
70
23
121
111
59
Pegylated IFN alfa-2a
IE-HPLC (Routine Analysis Drug Substance)
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IE-HPLC (Routine Analysis Drug Substance)
Separation of different PEG-IFN isomers in Pegaferon
1
2
3
4
5
6 7
89
1011
The qualitative and quantitative positional isomer composition inPegaferon is completely different as compared to Pegasys
Two additional positional isomers are present in Pegaferon not
being present in Pegasys
Isomer Profile of Pegaferon
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PEG-IFN pre-clinical safety results
PEG-INFas are currently used for the treatment of hepatitis C, but are
associated with lung toxicity. Here we show that INFa as well as
PEGINFas activate human lung cells to release IP10, ET-1 and eotaxin,
each of which are specifically associated with lung inflammation. Of the
INFs tested PEGINFa2a was the weakest as an inducer of inflammatory
mediators. Using human lung microvascular endothelial cells as a screen, we
found that by comparing responses of PEGINFa2a with selected isoforms, we
could separate the efficacy for anti-viral effects (Foser, Weyer et al. 2003)from those associated with induction of inflammatory mediators. This
study provides data relevant to INFa induced lung toxicity and describes a
screen by which safer isoforms of PEG-INFa may be identified.
INTERFERON (IFN) ALPHA PREPARATIONS ACTIVATE HUMAN LUNG
MICROVASCULAR ENDOTHELIAL CELLS TO RELEASE THE CHEMOKINE IP10
(AASLD)1Jane A Mitchell, 1Rekha Badiger 2Andreas Tietz, 1Catherin Aitkin,1Hime Gashaw, 2Heather J Hinton, 3Trevor T Hansel, 2Thomas Singer and 2Tobias Manigold1Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College, London, UK;
2Roche, Basel, Switzerland; 3Imperial Clinical Respiratory Research Unit (ICRRU),
St. Mary's Hospital, Paddington, London, UK
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Table of content
Biosimilars Regulations
Raptiva
Myozyme
Alpheon
Pegaferon
Epoetin alfa: Binocrit, Epoetin alfa Hexal, Abseamed
Conclusions
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Products approved according to the EU guidelines:
What does s imi lar mean? Simi lar enoug h?
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Biosimilars in EU
Epoetin alfa: Binocrit, Epoetin alfa Hexal, Abseamed
A one year safety study involving 300 patients suffering from chronic kidneydisease about to embark on dialysis, comparing EPO Hexal vs. Johnson &
Johnsons Erypo, has been suspended; this study was designed to assess the
safety of sub-cutaneous, rather than intravenous, EPO alfa administration
On 5 Aug 2009, Germanys BfArM (Bundesinstitut fr Arzneimittel und
Medizinprodukte) confirmed that the trial was suspended due to safetyconcerns, specifically a case of pure red cell aplasia (PRCA) in a patient
enrolled in a study in Germany, and a case of EPO neutralizing antibodies in a
patient enrolled in a study in Russia
In the statement, BfArM commented that after termination of this study,
BfArM explicitly states that Epo Alfa Hexal, Binocrit and Abseamed should onlybe administered via the intravenous route when prescribed for renal anemia
More investigations are taking place
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Table of content
Biosimilars Regulations
Raptiva
Myozyme
Alpheon
Pegaferon
Epoetin alfa: Binocrit, Epoetin alfa Hexal, Abseamed
Conclusions
Conclusions
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Conclusions
Biologics are large and complex molecules
The manufacturing process confers unique properties on abiologic product
Biosimilars are not identical to the original molecule
Immunogenic reactions can occur to biologics and areunpredictable
Pharmacovigilance is required
Regulations
All biosimilars must undergo stepwise and head-to-head comparisonswith the originators
Countries adopting EMA and/or WHO guidance will have a robust
biosimilar approval pathway
Thank You !
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Thank You !