Biosimilar Guidance Luxury or Necessity?

Dr. Thomas Schreitmueller, Regulatory Policy and Strategy Biologics

F. Hoffmann La Roche Ltd., Basel, Switzerland
2
Table of content
Biosimilars Regulations
Raptiva
Myozyme
Alpheon
Pegaferon
Epoetin alfa: Binocrit, Epoetin alfa Hexal, Abseamed
Conclusions
3
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 regulations
and 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, Clinical
Investigation of Recombinant Factor VIII and IX Products, Immunogenicity Assessment
of Biotechnology-derived Therapeutic Proteins, Comparability of Biotechnology-Derived
Medicinal Products after a change in the Manufacturing Process - Non-Clinical and
Clinical Issues
44
55
Biological product complexity:
Examples of modifications: inherent or due to the
manufacturing 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, G2
Sialylation
Modifications may result in approximately 10
8
potential variants
6
Protein Microheterogeneity
Small Molecule
Drug
Protein
Drug
7
Biotech products are very complex, sensitive,
heterogenious mixtures of protein molecules.
Each molecular entity of that mixture is characterized
by specific physical, chemical and biological
properties.
Any change in the composition of that mixture is
potentially going to affect patients safety and chance
of cure.
Biotech products
88
Biosimilars:
Different process, different product
Biosimilar that is different from the
originator
Even if a biosimilar uses the same human gene as its innovator, It will
differ in other parts of the manufacturing process
Same gene as
innovator
Fermentation
Cloning into
DNA vector
Transfer into
host cell
Bacterial or
mammalian cell
produces protein
Human
gene
Formulation
DNA
vector
Differences in the process
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EU biosimilar guidelines & products
Guideline
Guideline on Similar Biological Medicinal Products
Guideline on Quality Issues
Guideline on
Non-clinical/Clinical Issues
GH
Insulin 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 to
reference product
Filgrastim Hexal
Zarzio
LMWH
IFN-alfa
Nivestim
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Biosimilars in EU
The Problem of Interchangeability/Substitution
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Biosimilars in EU
Interchangeability/Substitution: The English Way
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Biosimilars Global Regulations
13
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 same
reference 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 have
appropriate 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
15
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)
AUC
inf
27.9 36.9 1.324
AUC
t
26.9 35.6 1.324
C
max
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)
P
e
r
c
e
n
t
a
g
e

o
f

S
u
b
j
e
c
t
s
improved 75%
Trend for lower PASI* Response to Raptiva (Efalizumab) despite
higher peripheral Drug Concentrations
Changes that were believed not to affect the properties of the protein resulted
in 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
18
Case Study:
Complexity of Biological Product 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 from
the 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:
Complexity of Biological Product Manufacture
Myozyme

: FDA rejects Genzymes own scaled-up version

Mack G. Nature Biotechnology 2008; 26:592.
30% bioavailability
2881% hepatic uptake
2065% 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
21
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
23
Pegaferon
Name : Pegaferon
Batch: 07-B
MFD: 06 / 2007
Exp. Date 06 / 2009
The following clipping sites were characterized by ESI-MS and MALDI-MS/MS

90
QQLNDLEACVIQGVGVTETPLMK
112

12.4 kD
CDLPQTHSLGSRRTLMLLAQMRKISLFSCLKDRHDFG
FPQEEFGNQFQKAETIPVLHEMIQQIFNLFSTKDSSAA
WDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMK
EDSILAVRKYFQRITLYLKEKKYSPCAWEVVRAEIMRSF
SLSTNLQESLRSKE
Reduced Gel
7.1 kD
CDLPQTHSLGSRRTLMLLAQMRKISLFSCLKDRHDFG
FPQEEFGNQFQKAETIPVLHEMIQQIFNLFSTKDSSAA
WDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMK
EDSILAVRKYFQRITLYLKEKKYSPCAWEVVRAEIMR
SFSLSTNLQESLRSKE
6.0
14.4
3.5
21.5
55.4
66.3
SDS-PAGE Silver Stain reduced
Extended Characterization
25
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K
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NH
2
164
131
133
134
112
31
49
83
70
23
121
111
59
Pegylated IFN alfa-2a
26
IE-HPLC (Routine Analysis Drug Substance)
Separation of different PEG-IFN isomers in Pegaferon
1
2
3
4
5
6
7
8
9
10
11
The qualitative and quantitative positional isomer composition in
Pegaferon 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 Manigold
1Cardiothoracic 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
29
Products approved according to the EU guidelines:
What does similar mean? Similar enough?
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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 kidney
disease 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 safety
concerns, 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 only
be 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
32
Conclusions
Biologics are large and complex molecules
The manufacturing process confers unique properties on a
biologic product
Biosimilars are not identical to the original molecule
Immunogenic reactions can occur to biologics and are
unpredictable
Pharmacovigilance is required
Regulations
All biosimilars must undergo stepwise and head-to-head comparisons
with the originators
Countries adopting EMA and/or WHO guidance will have a robust
biosimilar approval pathway
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Thank You !