Biosimilar mAbsClinical issues
Regulatory perspective
EMEA Workshop on Biosimilar Monoclonal Antibodies
Christian K Schneider, MDBMWP Chairman
European Medicines Agency (EMEA), UKPaul-Ehrlich-Institut, Germany
2Christian K Schneider
Mechanisms of action can be complex!
Example: TNFαantagonism
www.wikipedia.org
Apoptosis
Cellular proliferation
Differentiation
Inflammation
Tumourigenesis
Viral replicationTNFα
TNF-R1 (CD120a; p55/60)(most tissues; mTNFα and sTNFα)TNF-R2 (CD120b; p75/80)(only immune cells; only mTNFα)
(TNF-R1 signalling)
3Christian K Schneider
Heretic‘s FAQ(not necessarily my view…)
French illumination, 14th century(www.welt.de)
ReceptorLigand
extracellular intracellular
mAb
SIG
NA
LLIN
G
Can the mechanism of action beunderstood as a sole ligand-receptor interaction?(or its inhibition by a mAb?)Is it important what comes „after“?Does the mechanism of actionhave to be known?
4Christian K Schneider
Licensed mAbs: Efficacy and safety
Example anti-TNFα antibodies*): How to designa biosimilar development programme?
Licensed indications:» Rheumatoid arthritis» Adult Crohn‘s disease» Paediatric Crohn‘s disease» Ulcerative colitis» Ankylosing spondylitis» Psoriatic arthritis» Psoriasis
Therapeutic equivalence?Non-inferiority?
All indications?Extrapolation of efficacy?Extrapolation of safety??
What endpoints?(Activity or Benefit?)(Phase II or Phase III endpoints?)
*) example chosen since well suitable to explain regulatory issues
5Christian K Schneider
Extrapolation of indicationsGuideline on Similar Biological Medicinal Products containing Biotechnology-Derived Proteins as Active Substance: Non-Clinical and Clinical Issues:
» „In case the originally authorised medicinal product has more thanone indication, the efficacy and safety of the medicinal productclaimed to be similar has to be justified or, if necessary, demonstrated separately for each of the claimed indications.“
» „In certain cases it may be possible to extrapolate therapeuticsimilarity shown in one indication to other indications of thereference medicinal product.“
» „Justification will depend on e.g., clinical experience, availableliterature data, whether or not the same mechanisms of action or thesame receptor(s) are involved in all indications.“
» Distribution, density, avidity and other characteristics of thesereceptors per indication?
» „Possible safety issues in different subpopulations should also beaddressed.“
6Christian K Schneider
Mechanisms of action can be complex!
Example: TNFαantagonism
www.wikipedia.org
Apoptosis
Cellular proliferation
Differentiation
Inflammation
Tumourigenesis
Viral replicationTNFα
TNF-R1 (CD120a; p55/60)(most tissues; mTNFα and sTNFα)TNF-R2 (CD120b; p75/80)(only immune cells; only mTNFα)
(TNF-R1 signalling)
7Christian K Schneider
Spectrum of Uncertainty
Peptides Protein Glycosylated mAbs Blood products ATMP
Primary Structure
Post Trans Mod
Higher structure
Impurities
Can these ever be biosimilar?
How similar is biosimilar?
Can these be bioidentical?
Source: Cecil Nick, Parexel
8Christian K Schneider
Spectrum of Uncertainty
Peptides Protein Glycosylated mAbs Blood products ATMPs
Primary Structure
Higher structure
Glycosyl-ation
Related Impurities
Process Impurities
Can these ever be biosimilar?
PD
Surrogate e.p.
Low variability
/short term e.p.
High variability
/long term e.p. Acceptable
Endpoints Complexity of Product
Extent of Difference
Can these be bioidentical?
Source: Cecil Nick, Parexel
9Christian K Schneider
ExtrapolationExtrapolation of indications:» What if mechanism of action is poorly understood? (e.g. interferons)» What if clinical endpoints for other indication(s) are not sensitive
enough?
Recent „milestones“:» Guideline on biosimilar LMWH (extrapolation)» Reflection paper on biosimilar alpha-interferons („PD fingerprinting“)
10Christian K Schneider
Case-by-case puzzle?
Clinicalendpoint
INDICATION #1Comparative
safetyINDICATION #1
Comparative physico-chemical and biological characterization
SurrogateMarker
INDICATION #4
SurrogateMarker
INDICATION #2
SurrogateMarker
INDICATION #3
KnownClass effects
Non-clinicalComparative
toxicity
CombinedMethod 1+2
Potencyassay
Method 3Method 4
Comparative physico-chemical and biological characterization
CombinedMethod 1+2
Bio-assay
#1
Bio-assay
#2
SurrogateEndpoint
Comparativesafety
PDmarker
#1
PDmarker
#2
PDmarker
#3
PDmarker
#4
PDmarker
#5
PDmarker
#6
Non-clinicalComparative
toxicity
ComparativePK
ComparativePK
ComparativePKPD
marker
PDmarker
#7
PDmarker
#8
PDmarker
#9
Bio-assay
#3
mAb 1 mAb 2
11Christian K Schneider
Immunogenicity
12Christian K Schneider
Immunogenicity
mAbs are not for substitution of endogeneousproteins like recent biosimilars (EPO, G-CSF,…)Is the perception of risk different?» Antibodies against mAbs are mostly
anti-idiotype (not anti-isotype)» Endogeneous IgG abundant!
Is Immunogenicity the „highest“ safety concern?…but immunogenicity nevertheless important!
13Christian K Schneider
Practical issuesAcceptability of biosimilar mAbs, e.g. in theoncological setting?(or: To what extent is the „biosimilar“ philosophyknown to patients and physicians?)
How to practically deal with phase I PK/PD studies in patients:» Are usually single dose studies» Cross-over?» How to continue treatment? Switch to
reference?
14Christian K Schneider
The floor is yours!
