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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 users.path. ox .uk.com 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 users.path. ox .uk.com 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 users.path. ox .uk.com 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