The comparability exercise Superiority physicochemical analysis Vs compara3ve clinical trials

Transcription

1 The comparability exercise Superiority physicochemical analysis Vs compara3ve clinical trials Joao Goncalves, PharmD, PhD Professor/Investigator Faculty of Pharmacy University of Lisbon 1

2 Biosimilars in EU A science- based exercise for the dawn of a new era Infliximab 2014

3 Totality of scien>fic evidence to characterize the biologic biosimilar an>body Phase III Clinical Studies Comparability & Biosimilarity Design Phase III Originator Biologic Drug Phase II Clinical Studies Phase I Clinical Studies Nonclinical Studies Molecule Characterization PK / PD (Phase I clinical studies) Nonclinical Studies Functional (biological) Characterization Physicochemical Characterization

4 Biosimilars focus on drug characterization and confirm data in the clinical studies Original Biosimilar Speed Confort Safety Emo>ons Engine Wheels and dampers Aibags Color

5 Are all an>- TNF mab the same? Structure (humaniza>on, human, stability) What the drug does to the body PD Mechanisms TNF binding; apoptosis; reverse signaling, Fc binding, ADCC/CDC What the body does to the drug PK and immunogenicity

6 Goals of biosimilar tes>ng Iden>fy differences inside a quality and efficacy range between a mab original and biosimilar. Use of state- of- the- art scien>fic knowledge and sensi>ve technology in every step of evalua>on.

7 Scale- up and post- approval changes of Remicade produc>on Manufacturing Changes are a normal process in all biologics Type IA (n=15) Type IB (n=7) Major changes Type II (n=47) /7/ /4/ /1/ /10/2006 6/7/2009 1/4/ /12/2014 Comparability protocols validated that these major (Type II) manufacturing changes did not impact the quality, safety and efficacy of the drug. Type IA Variation Minimal or no impact on the quality, safety, or efficacy of the medicinal product concerned Notification procedure Type IB Variation Variation which is neither Type IA nor Type II Notification procedure Type II Variation A significant impact on the quality, safety, or efficacy of a medicinal product Prior approval procedure European Medicines Agency. REMICADE procedural steps taken and scientific information after the authorisation _Procedural_steps_taken_and_scientific_information_after_authorisation /human/000240/wc pdf. Accessed October 12, 2014.

8 Micro- variability is in the nature of glycoproteins Schiestl et al, Nat Biotech 2011

9 The clinical relevance of molecular attributes is well understood Impact 1. Immunogenicity 2. Safety/Toxicity 3. Pharmacokine>cs 4. Efficacy Uncertainty Immunogenicity Safety/Toxicity Pharmacokine=cs Efficacy Aggregates Impuri>es Antibody purity Antibody glycosylation Antibody modifications Antibody Structure Antibody Glycosylation Antibody Glycosylation Mechanisms of action Rathore A, 2009, Trends in Biotechnology. Roadmap for implementa>on of quality by design (QbD) for biotechnology products

10 Varia>ons in produc>on are controlled cri>cal product afributes Comparability of Cri=cal Product AEributes Score of CPA Original an=body Original an=body new process Schiestl M et al. Biologicals. Published online December 24, doi: /j.biologicals

11 In vitro and in vivo models are more sensi>ve to assess MoA than Clinical studies

12 Comparability of a biologic altera>on New version IFX Extrapola=on Extrapola=on RA AS Comparability Quality Pre-clinical IBD IFX original

13 Coevolution of EMA Guidelines for Biologics and Biosimilar Biologics Biologics Manufacturing changes Produc>on and quality of cytokine products Aug 1990 Quality Jul 1995 Stability Jul 1996 Quality Mar 1998 June 1998 Quality Dec 2003 Clinical & non clinical June 2004 Jun 2005 Quality Nov 2007 April 2008 Immunogenicity Dec 2012 Immunogenicity Commifee Quality Clinical & non clinical Immunogenicity Immunogenicity clinical Biosimilar biologics Clinical & non Jun 2006 European Medicines Agency - Scientific guidelines - Biological guidelines (

14 Integration of data from multiple analytical and biological tests provides complete understanding Primary structure + Impurities + Biological activity Higher order structure + Posttranslational modifications Combined data from ~40 different methods provide information on multiple attributes (orthogonality) Every attribute is evaluated more than once (redundancy) Σ Combination of attributes Berkowitz SA, et al. Nat Rev Drug Discov 2012; 11(7):

15 Possible modification of antibodies Pyro- glutamate at N- terminus Higher order structure change DisulEide scrambling Aggregation (Soluble or Insoluble) Deamidation (Asn) Isomerization (Asp) Glycation (Primary amine) Glycosylation (Silalylation, Fucosylation, Galactosylation, High manose) Oxidation (Met) C- terminal lysine variants Amidation (Proline) Strictly confidential 15

16 The sensi>vity of analy>cal methods has increased enormously: Mass spectrometry example

17 The structure of a protein is essen>al to its func>on If the structure of the reference product and biosimilar do not match, they will not function in the same way

18 Analy>cal comparison of CT- P13 and Remicade The ter>ary structure of Inflectra and Remicade was confirmed to be iden>cal Higher order structure is comparable. Comparable folding of the proteins was demonstrated. Physicochemical characteriza>on of Remsima, mabs, 6:5, , DOI: /mabs.32221

19 Integration of data from multiple analytical and biological tests provides complete understanding Primary structure + Impurities + Biological activity Higher order structure + Posttranslational modifications Combined data from ~40 different methods provide information on multiple attributes (orthogonality) Every attribute is evaluated more than once (redundancy) Σ Combination of attributes Berkowitz SA, et al. Nat Rev Drug Discov 2012; 11(7):

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21 Binding to stnf and Neutraliza>on of mtnf Arthri>s IBD TNF- R NF- kb Y mtnf T- cell NK and T- cells in RA T- cells and monocytes/macrophages in IBD

22 Transmembrane TNFα may inhibit sustained ac>va>on of monocytes CT-P13 Celltrion, Data on file

23 Mechanism of Action of Anti-TNFα used differently in IBD and RA 23

24 Cellular ac=vity of mab dependent on FcyR binding Adapted from: Falk Nimmerjahn and Jeffrey V. Ravetch. Translating basic mechanisms of IgG effector activity into next generation cancer therapies. Cancer Immunity. 2012;12:13-20.

25 Comparison of oligosacharide profiles between CT-P13 and Remicade Hypothesis Remicade CT- P13 Physicochemical characteriza>on of Remsima, mabs, 6:5, , DOI: /mabs Houde et al, 2010; Therapeu>c monoclonal an>bodies, Wiley 2009

26 ADCC using whole blood to assess differences in CT-P13 fucosylation ADCC Bioactivities (% Specific Lysis) for CT-P13 and Remicade Containing Varying Amounts of Af ucosylated Molecular Variants Using Whole Blood from CD Patient #1 (V/F Genotype) 1. Data on file. Celltrion Inc.

27 Focus on the drug not pathology: Assess the totality of scientific data VARIABLE REGIONS (Fab) TNF-α BINDING Primary mechanism TNFα neutralisa=on binding to mtnfα and inhibi=on of cell signalling for prolifera=on. Variable CONSTANT REGIONS (Fc) FcyR and FcRn BINDING Secondary mechanism: ac=va=on of the immune responses which includes an=body- dependent cell cytotoxicity (ADCC), complement- dependent cytotoxicity, induc=on of regulatory macrophages, EMEA, Inflectra European Public Assessment Report, EMA/CHMP/394891/2013, J Goncalves 27 June - Dec Soon Kwan Jung, Kyoung Hoon Lee, Jae Won Jeon, Joon Won Lee, Byoung Oh Kwon, Yeon Jung Kim, Jin Soo Bae, Dong- Il Kim, Soo Young Lee 27 & Shin Jae Chang (2014) Physicochemical characteriza>on of Remsima, mabs, 6:5,

28 Clinical studies aim to confirm the efficacy of the biosimilar and respond to uncertan=es When analy=cs demonstrate that the ac=ve moie=es in two products are highly similar, then the only unknowns or residual uncertainty are PK and Immunogenicity

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30 Key PK comparability of CT-P13 vs Remicade in one-dose and multidose Multi-dose CT-P13 PK in AS The serum concentra=on profiles of infliximab were very similar between Remicade and CT- P13 One-dose CT-P13 PK in healthy volunteers CT- P13 5mg/kg Remicade 5mg/kg Pre- defined bioequivalence acceptance range = % 1. European Medicines Agency. Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies Non-clinical and Clinical Issues. EMA/CHMP/BMWP/403543/2010 accessed

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32 CT- P13 stability/aggrega=on and its impact to mab immunogenicity Charge Variants of CT- P13 vs Remicade Physicochemical characteriza>on of Remsima, mabs, 6:5, , DOI: /mabs.32221

33 An=bodies to Remicade recognize equally CT- P13 Antibody array ELISA can find new epitope exposure at levels as low as 0.1% within a mab population can be accurately detected and quantified. Epitope mapping (Fab region) Epitope mapping (Fc region) Absorbance at 450 nm Absorbance at 450 nm CT-P13 Lot #1 CT-P13 Lot #2 CT-P13 Lot #3 CT-P13 Lot #4 CT-P13 Lot #5 CT-P13 Lot #6 CT-P13 Lot #7 RMP Lot #1 RMP Lot #2 RMP Lot #3 RMP Lot #4 RMP Lot #5 RMP Lot #6 RMP Lot #7 0 Ab1 Ab2 Ab3 Ab4 Ab5 Ab6 Ab7 Ab7 Ab8 Ab9 Ab10 Ab11 0 Ab13 Ab14 Ab15 Ab16 Ab17 Ab18 Ab19 Ab20 Ab21 Ab22 Ab23 Ab24 Ab25 Ab26 Ab27 Ab28 Ab29 Ab30 Ab31 Ab32 Ab33 Ab34 Physicochemical characteriza>on of CT- P13, mabs, 6:5, , DOI: /mabs.32221

34 Extensive comparability exercise which demonstrated biosimilarity Post-marketing surveillance and ongoing safety monitoring Post-marketing Safety Comparable efficacy and safety profiles between Inflectra and Remicade (infliximab) in RA patients with active disease receiving methotrexate (MTX) Therapeutic Equivalence Trial Comparable PK at steady state for AUC τ & C max,ss demonstrated between Inflectra and Remicade in AS patients Pharmacokinetic Equivalence Trial In vivo and in vitro assays confirm biosimilarity in terms of PK, PD, and toxicity. Dose-ranging-finding study investigating TK and immunogenicity conducted Non-clinical Studies Comparability demonstrated with regards to protein structure and product quality EMA/CHMP/589422/2013; Inflectra Assessment Report MRC F Extensive molecular characterisation program

35 Scientific principles of drug comparability and clinical pharmacology support biosimilar indications We can rely on the progress made in regulatory science over 20 years to come to a consistent, fair, and science-based conclusion of biosimilarity. Comparability has been used as the basis for complete extrapolation between all indications as well as full interchangeability for each indication, irrespective of whether the mechanism of action is known or whether any clinical studies at all have been conducted on the post-change product. Analytical and PK/PD high similarity is the most robust scientific basis for comparing independently sourced biologics.

36 Thank You/Obrigado Thank Lisbon - Not a biosimilar of San Franscisco