Download Biosimilar therapies: Use as indicated, in place of our current biologics

Biosimilars: Use as Indicated in
Place of our Current Biologic
Therapies
Brian G. Feagan MD
Professor of Medicine, Epidemiology and
Biostatistics, Western University
Director, Robarts Clinical Trials Inc.
Robarts Research Institute
It’s the Economy _ _ _ _ _ !
• We have unlimited ability to consume
resources for health care
• This is not sustainable
• Classic tension between individual and
societal benefit
Why Biopharmaceuticals are Different
• High molecular weight
• Complex three-dimensional structure
• Produced by living organisms, therefore often
heterogeneous
• Difficult to characterize completely by physicochemical analytical methods or bioassays
• Prone to eliciting an immune response
Biosimilars are not generic biopharmaceuticals
Crommelin DJA, et al. Int J Pharm 2003;266:3-16.
Complexity of Protein Structure
Taken from Horton HR, et al. Principles of Biochemistry. 3rd ed. 2002.
Proprietary Cell Lines
Production
Purification
Formulation
Handling/storage
Biologic activity
Safety
Efficacy
Kuhlmann & Covic. Nephrol Dial Transplant. 2006;21(suppl 5):v4–v8.
Chow et al. Statist Med 2013; 32:370–81.
Production cell lines
• Proprietary
• Not available to the
producers of SEBs
Manufacturing
process
• Changes in the active
pharmaceutical ingredient
can affect downstream safety
and efficacy
Front. Immunol., 20 October 2014 | http://dx.doi.org/10.3389/fimmu.2014.00520
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Pharmacokinetics and Immunogenicity
Target-Mediated Clearance
Anti-idiotypic
Antibody Formation
Aggregation/
Dimerization/
Thermal stability
(folding)
Fragmentation
-S S-S S-
FcγR- Mediated
Clearance
FcRn Binding
And IgG Recycling
Neutralizing Antibody Formation
Glycosylation – May Affect
Clearance and Half-Life
Glycation in
presence of
carbohydrate
excipients
All of these factors directly or indirectly contribute to or
are influenced by protein heterogeneities and can impact
PK and/or immunogenicity
Two Major Concerns
• Immunogenicity with multiple switching
(interchangeability)
• Extrapolation across indications ( Health
Canada – ADCC )
Schellekens H. Nat Rev Drug Discov 2002;1:457-62.
Major Concern 1: Immunogenicity
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Immunogenicity: The Issues
• It is impossible to predict all biological or clinical
properties of biopharmaceuticals by physical chemical
characterization
• The human immune system is highly efficient in detecting
differences between biopharmaceuticals and
endogenous proteins
• In vitro detection is assay dependent
Schellekens H. Nat Rev Drug Discov 2002;1:457-62.
Factors Influencing Immunogenicity
• Product-related factors
– Sequence variation
– Glycosylation
– Host cells
– Contaminants and process-related impurities
– Formulation
– Handling and storage
Changes in the manufacturing process, and inadequate
handling and storage of a drug, may alter its immunogenicity
Schellekens H. Nat Rev Drug Discov 2002;1:457-62.
Factors Influencing Immunogenicity
(cont.)
• Patient factors
– Route of administration: SC > IM > IV
– Dose and treatment duration
– Concomitant diseases and/or medication
– Genetic factors
• Unknown factors
Although important factors have been identified,
there are still several unknowns
Schellekens H. Nat Rev Drug Discov 2002;1:457-62.
Immunogenicity: Effects
• Immune responses to biopharmaceuticals can vary
from no perceptible effect to significant clinical
effects:
– Generalized immune effects (allergy, anaphylaxis)
– Neutralization of exogenous protein (loss or
enhancement of drug efficacy)
– Neutralization of the endogenous protein (serious
adverse event)
Schellekens H. Nat Rev Drug Discov 2002;1:457-62.
Manufacturing Drift
Regulatory
Agencies
• Evaluates
comparability
before and
after process
changes
• Helps ensure
that patient
outcomes will not
be affected.1
Reference
Biologic
Independent manufacturing
change (1)
Independent manufacturing
change (2)
SEB
Independent manufacturing
change (1)
Independent manufacturing
change (2)
Source: adapted from Dr. Amy Rosenberg (FDA)
Example of Variability Within
Specification Range
USL/LSL = Upper and Lower
Specification Limit
Any Criteria
UCL/LCL = Upper and
Lower Control Limits
on all critical
attributes and
parameters that are
internally trended
x
Batches out of trend (but
within specification) are
investigated for potential
future drift
Drift would be exhibited as falling outside of the
specification limits unexpectedly
Adapted from Ramanan & Grampp. BioDrugs
2014;28:363; Declerk. GaBi Journal 2012;1:13;
European Commission. A Consensus Information
Document 2013.
19
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Two Major Concerns
• Immunogenicity with multiple switching
(interchangeability)
• Extrapolation across indications ( Health
Canada – ADCC )
Schellekens H. Nat Rev Drug Discov 2002;1:457-62.
“Crohn's disease, ulcerative colitis) was not recommended.
This arose from the observed differences in the level of
afucosylation, FcγRIIIa receptor binding, and some in vitro
Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
assays. The Chemistry and Manufacturing review team
concluded that differences in the ability of the two products
to induce ADCC could not be ruled out”
www.hc.ca
Antibody-Dependent Cell-Mediated
Cytotoxicity (ADCC)
http://coursewareobjects.elsevier.com/objects/pathophysiology/mccance6e_v1/mod06/06l0119.html
TNF-α Antagonists In IBD
Chimeric
monoclonal
antibody
Human
monoclonal
antibody
Humanized
Fab′
fragment
Adalimumab
Certolizumab
pegol
Fc
IgG1
Infliximab
Are All TNF Antagonists the Same?
•
Mechanism of action of
TNF antagonists are not
fully defined
•
Important differences exist
between molecules that
may influence efficacy
•
Nesbitt evaluated 4
agents in vitro effects
•
All neutralized TNF equally
well
•
Large differences in
apoptosis and cytokine
expression
Nesbitt IBD 2007
Etanercept for Active Crohn’s Disease:
Response at Week 4
50
% Clinical Response
45
P= 0.763
40
35
30
25
20
15
10
5
0
Placebo
Sandborn WJ et al. Gastroenterology. 2001;121(5):1088-94
Etanercept
Conclusions
• Biosimilars are here to stay
• Potentially large cost savings
• Interchangeability \Immunogenicity is a critical
issue
• Data regarding the immunogenicity of differences in
CHO residues are needed- switch study
•
This experiment has probably already happened
•• The Health Canada decision to disallow extrapolation to
IBD is not based on strong science
•
Use as indicated in place of our current biologic
therapies
“There are risks and costs to a program of action….
But they are far less than the long-range risks
and costs of comfortable inaction”
• John F. Kennedy