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Biotherapeutic Products
Biotechnology derived products have been successful for therapy of various diseases
Hormones, enzymes, coagulation factors, cytokines Fusion proteins, monoclonal antibodies
Despite their benefits, therapeutic proteins have the potential to induce an immune response due either to their
Foreign nature if of exogenous origin
or
Due to recognition as non-self
Protein
Indication
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Unwanted Immunogenicity
Proteins Patients Non immunogenic (G-CSF, IFN-g)
Neutralize biologic effects and compromise further therapy (factor VIII, IFNa2a, GM-CSF)
Alter PK/PD
Cross-react with native protein and induce adverse symptoms (Epo, MGDF)
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Patient related
Age, gender, genetic make-up, ethnic sensitivity (IFN-2a more immunogenic in Chinese vs Caucasian hepatitis patients 39% vs 14%), immune status, disease
Production Process
Complex manufacturing process
New manufacturer (copy product) Manufacturing and/or purification process different, no access to knowhow of the process/history of product; limited to public domain information Step-Wise Process Changes Expression system/vector Fermentation/ cell culture process Purification process Formulation and filling Drug Product
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Complexity of Proteins
Biosimilars in the EU
Comparability studies are needed to demonstrate the similar nature, in terms of quality, safety and efficacy, of the new similar biological medicinal product and the reference product authorized in the EU
Emphasis has been given to immunogenicity Any subtle change introduced in the manufacturing process of a given product can have enormous implications for immunogenicity
Unwanted Immunogenicity
Current Position
Testing for unwanted immunogenicity is integral to product development (clinical & post-marketing phase) for ensuring: Clinical safety of a biotherapeutic Product comparability When a biosimilar product is developed
EMA Guidance
Guideline on Immunogenicity Assessment of BiotechnologyDerived Therapeutic Proteins EMA/CHMP/BMWP/14327/2006 Guideline on Immunogenicity Assessment of monoclonal antibodies (in consultation) EMA/CHMP/BMWP/86289/2010
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Consultation
mAbs
In Preparation
Revised IFN-b, FSH
Recent
LMWH
IFN-a
Unwanted Immunogenicity
Prediction of immunogenicity
In silico and T cell methods are promising but information on the true clinical utility of these approaches in a prospective manner is lacking
Determination of immunogenicity
Human clinical data neededcannot be replaced by use of animal or in vitro or in silico tools
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Neutralization assays: for distinguishing neutralizing & non-neutralizing antibodies. - Cell-based assay - Non-cell-based ligand binding assay
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+ve samples
Bioassay
Characterization
Assess correlation of characterized antibodies with clinical responses to biologic therapeutic Assays for clinical markers and assessment of clinical response in patients
This applies to all assays as shown in strategy slide Strategy needs to be established on a case-by-case basis product, patients, expected clinical parameters
In chronic use sequential sampling for a year In view of variability of antibody responses, adequate numbers of patients needed
However, unwanted immunogenicity may occur at a level, which is not detected in studies pre-approval so assessment post-approval, as part of pharmacovigilance surveillance is needed
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Comparative Immunogenicity
Studies need to be designed to demonstrate whether the immunogenicity of the products is the same or significantly different This may affect the design of the studies & their interpretation A homogeneous and clinically relevant patient population should be selected. Head-to-head studies using same assays & sampling strategy needed The consequences of immunogenicity must also be compared Post-approval assessment may be necessary, usually as part of pharmacovigilance surveillance
Immunogenicity of Biosimilars
The immunogenicity of the marketed product does not influence the need for comparative immunogenicity studies However, if the imunogenicity profiles of marketed and biosimilar products are significantly different, they may be considered DISSIMILAR
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Ab Incidence 0/51 (0.0%) 3/98 (3.4%) 2/314 (0.6%) * 0/305 (0.0%) 0/323 (0.0%) 7/356 (2.0%) 0% 3/183 (1.6%) 31/111 (27.9%) **
Reference Genotropin Humatrope Erypo Erypo Erypo Neupogen Neupogen Neupogen Roferon-A
Ab Incidence 1/44 (2.3%) 1/49 (2.0%) 3/164 (1.8%) * 0/304 (0.0%) 0/230 (0.0%) 2/134 (1.5%) 0% 0/95 (0.0%) 38/99 (38.4%) **
Pure red-cell aplasia (PRCA) and anti-EPO antibodies in patients treated with EPO (EPREX) 2002 - 13 cases in chronic renal failure patients, rapid development of severe transfusion dependence within months of therapy, resistant to other EPO products Pre 1998 2/3 cases 1998 to June05 260+cases worldwide
Casadevall N, et al. N Engl J Med. 2002;346(7):469-475.
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Avonex 2% to 6%; Rebif 12% to 28%; Betaferon 25% to 45% Loss of efficacy; abs cross-reactive and impact on disease management and QOL Monoclonal antibodies Ab incidence dependent on product, disease, age; loss of efficacy noted in some cases. Antibody Incidence % 61 8 0 65 1.9 29-63
Product Remicade
Type Anti-TNF
Rituxan
Anti-CD20
Campath
Anti-CD52
Immunogenicity Guideline
Recommendations for routine monitoring of changes in clinical response and linking immunologic findings to clinical events Immunogenicity as part of all clinical trials ( indication
specific differences possible)
Evaluate all patients ( and not in a symptom-driven manner) Standardize sampling schedule as much as possible
Specifically analyse adverse events for linkage to an unwanted immune response (ie, also in a symptom drivenmanner)
Provide guidance on how prescriber should handle patient in case unwanted immune response occurs (increase dose/discontinue, etc)
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