Biosimilar Monoclonal- a reality

Transcription

1 Biosimilar Monoclonal- a reality 2 nd MENA Regulatory Conference on Bioequivalence, Biowaivers, BIOANALYSIS, DISSOLUTION AND BIOSIMILARS Jordan DATE September 15-17, 2015 PRESENTED BY Rodeina Challand

2 The value of biologics 2

3 The Challenge Chemical Aspirin 180 Da Cytokine EPO: Da Monoclonal antibody Da 3

4 Biosimilars- myth or reality? 4

5 Biologics: Can There Be Abbreviated Applications, Generics, or Follow-On Products? BioPharm International July 01, 2003 What are "generic biologics"? A "generic" drug is approved by reference to a strict definition of sameness to the innovator's product. Sameness, however, cannot be determined for biologics from different manufacturers because of the complex nature of the products and their manufacturing processes. Therefore, "generic biologics" produced by different manufacturers cannot exist Safe generic drugs have been approved with abbreviated data packages because it is possible to show that the generic product is chemically and pharmaceutically identical to the pioneer's product, to within very tight confidence limits. Therefore, it is scientifically reasonable to expect that the clinical properties of the pioneer's product will be shared by the generic. Because the follow-on biologic cannot be shown to be identical to the innovator product, this relationship does not hold for biologics. Pharma Exec Feb 2006 EMEA held a workshop in Paris in December (2005), where stakeholders from across the industry shared their views on the introduction of the guidelines. The first guidelines are expected to cover erythropoietin, insulin, somatotropin and granulocyte-colony stimulating factor. Guidelines for interferons are also on the drawing board 5

6 Monoclonal antibodies in EU Nature Biotechnoloy 26, (2008) Recent licensing of recombinant somatropins and several erythropoietins as biosimilars has prompted discussions as to whether the same regulatory path could also be applied to more complex biologics, such as monoclonal antibodies (mabs). Although physicochemical and biological methods for characterization of mabs are becoming increasingly sophisticated, the ability to compare a biosimilar mab to a reference mab on an analytical level remains limited and the design of a clinical development program for a biosimilar mab will likely prove a challenge. 6

7 History of biosimilar monoclonal antibodies regulation in EU The EMEA workshop on biosimilar monoclonal antibodies (mabs) discussed the feasibility of the scientific development and authorization of monoclonal antibodies. Is the regulatory approval of a biosimilar of such a complex molecule even be possible? How much do we need to know? How much similarity do we need? The stage was set for a point-counterpoint exchange on by the innovator and biosimilar industries. 159 people including health care professionals, academics, representatives from regulatory agencies in the European Union (EU), United States (US) and Canada. Proceedings presented in the below report MAbs Sep-Oct; 1(5): European Medicines Agency workshop on biosimilar monoclonal antibodies July 2, 2009, London, UK Slides presentations /11/event_detail_ jsp&mid=WC0b01ac058004d5c3 7

8 Historical Background The EU continues to lead worldwide in the development of new guidelines and is now taking biosimilar medicines to the next level by organising a workshop on biosimilar monoclonal antibodies (mabs). The applicability of the biosimilarity concept to mabs is indeed triggering great interest. Highly sophisticated analytical and validation tools are available today to assist in the characterisation of mabs. In addition, modern manufacturing technologies allow the consistent production of recombinant proteins with highly specific predefined quality characteristics. Our industry is definitely taking up this new challenge. 8

9 EMA Regulatory Guidance for a Monoclonal Biosimilar Product Concept paper on the development of a guideline on similar biological medicinal products containing monoclonal antibodies EMEA/CHMP/BMWP/632613/ October 2009 Whilst available guidances appear to provide sufficient guidance on quality of biosimilar mabs, there are several issues pertinent to non-clinical and clinical development that are not sufficiently covered by current guidances. Guideline on similar biological medicinal products containing monoclonal antibodies non-clinical and clinical issues EMA/CHMP/BMWP/403543/ May 2012 The non-clinical section addresses the pharmaco-toxicological requirements and the clinical section the requirements for pharmacokinetic, pharmacodynamic, efficacy and safety studies as well as pharmacovigilance aspects. 9

10 EMA Regulatory Guidance for a Monoclonal Biosimilar Product Concept paper on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use. EMEA/CHMP/BMWP/114720/2009 March 2009 The very large number of mabs in clinical development and undergoing regulatory scrutiny emphasises the critical need for provision of appropriate guidance Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use. EMA/CHMP/BMWP/86289/ May 2012 This guideline addresses issues impacting on immunogenicity of mabs, the clinical consequences of immunogenicity, assay related problems, assessing neutralizing antibodies induced by mabs and consideration of a risk-based approach for the evaluation of immunogenicity of mabs. 10

11 Remicade Product summary Infliximab is a chimeric human-murine monoclonal antibody that binds with high affinity to both soluble and transmembrane forms of TNF α but not to lymphotoxin α (TNF ß ) Indications: Rheumatoid arthritis Adult Crohn's disease Paediatric Crohn's disease Ulcerative colitis Paediatric ulcerative colitis Ankylosing spondylitis Psoriatic arthritis Psoriasis 11

12 Remicade Clinical Package to support registration Remicade The clinical trial programme consisted of 14 completed studies including one study in healthy volunteers A further application for extension of the indications to include ankylosing spondylitis was based primarily upon the randomised, double-blind, placebo-controlled clinical study and an additional 8 supportive studies 12

13 Summary of the submission of the Remsima dossier to the EMA Celltrion received scientific advices from the CHMP on 24 September 2009 and 17 December The scientific advices pertained to quality, non-clinical and clinical aspects of the dossier. Concept paper on the development of a guideline on similar biological medicinal products containing monoclonal antibodies EMEA/CHMP/BMWP/632613/2009 October 2009 Concept paper on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use. EMEA/CHMP/BMWP/114720/2009 March 2009 Submitted to CHMP 01 March 2012 through Centralised Procedure Note: The product was not licensed in any country at the time of submission of the application. Remsima was given a marketing authorisation in South Korea on 23 July Similar biological medicinal products containing monoclonal antibodies: non-clinical and clinical issues EMA/CHMP/BMWP/403543/2010 Publication date: June 2012 Immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use EMA/CHMP/BMWP/86289/2010 Publication date: June 2012 Positive opinion by the CHMP June 2013 Approval by CHMP Sep

14 Assessment of Remsima- CHMP The application took: 16 months to review 3 lists of consolidated questions were sent to Celltrion 6 internal meetings within the CHMP 1 oral explanation, by Celltrion, before the CHMP Complex lengthy assessment! 14

15 Remsima Approval A major Milestone in the Biosimilar Market This approval is important not only because it is the first mab biosimilar approved in a mature market, but also because it included indication extrapolation for all of indications The biosimilar was approved for the same range of autoimmune diseases as the branded product (i.e., extrapolation ), including rheumatoid arthritis (RA), ankylosing spondylitis (AS), Crohn s disease (CD), ulcerative colitis (UC), psoriatic arthritis (PsA), and psoriasis. 15

16 Remsima Quality Data Package Active Substance Manufacture Development genetics Fermentation process Purification process Process validation and/or evaluation Manufacturing process development Characterisation An extensive product characterisation exercise was conducted, using a range of state-ofthe-art orthogonal methodologies in order to elucidate the primary, secondary and higher order structure, post-translational modifications and associated micro-heterogeneity, glycosylation, charged isoforms, purity and biological activity associated with CT-P13 (Remsima)..an extensive comparability alongside the RMP, Remicade, was undertaken. 16

17 Remsima Quality Data Package Finished Medicinal Product Pharmaceutical Development Adventitious agents Manufacture of the product Product specification Stability of the product Comparability Exercise for Finished Medicinal Product A comprehensive and state-of-the art comparability exercise was performed Multiple batches of CT-P13 finished product and Remicade were used for each analysis. All batches of Remicade were sourced in the EU. In many of the analytical evaluations, CT-P13 active substance was also used 17

18 Comparability Biological Activity Testing 21 different test methods used to compare Fc Receptor related and F(ab )2 related biological activities. Benefit-risk balance All major physicochemical characteristics and biological activities of CT-P13 are comparable to those of Remicade except for a lower amount of afucosylation species, which translates in a lower binding affinity to FcγRIIIa receptor. This difference is not considered clinically relevant as it does not affect the activities of CT-P13 in the experimental models that are most relevant to the pathophysiological conditions. 18

19 Summary of the Clinical Development Programme for Remsima and the RMP Tabular overview of clinical studies Protocol CT-P (pilot study) Design Prospective Phase 1, randomised double-blind, parallel-group, multiple single-dose intravenous (i.v.) infusion, multicentre Study population RA patients with active disease while receiving MTX Planned: 20 Randomised: 19 CT-P13: 9 Remicade: 10 CT-P PK equivalence (Study name: PLANET AS) Start Oct 2010 End June 2012 Prospective Phase 1, randomised, double-blind, multicentre, multiple single-dose i.v. infusion, parallel-group AS patients with active disease Planned: 246 (ratio: 1:1) Randomised: 250 CT-P13: 125 Remicade: 125 CT-P Therapeutic equivalence (Study name: PLANET RA) Start Oct 2010 End July 2012 Primary: No 2011 Prospective Phase 3, randomised, double-blind, multicentre, multiple single-dose i.v. infusion, parallel-group RA patients with active disease while receiving MTX Planned: 584 (ratio: 1:1) Randomised: 606 CT-P13: 302 Remicade:

20 Post approval studies 1. Celltrion, Inc. Trial protocol: BE (Ongoing) HU (Ongoing) GB (Ongoing) IT (Ongoing) ES (Ongoing) RO (Ongoing) DK (Ongoing) NL (Ongoing) N=214 A Randomized, Double-Blind, Parallel-Group, Phase 3 Study to Demonstrate Noninferiority in Efficacy and to Assess the Safety of CT-P13 Compared to Remicade in Patients With Active Crohn s Disease 2. Mundipharma Pharmaceuticals B.V. Trial protocol: NL (Ongoing) N= 150 An open-label, multicentre, phase IV study to investigate the infliximab serum concentration of Remsima (infliximab biosimilar) after switching from Remicade (infliximab) in subjects with Crohn s Disease (CD), Ulcerative Colitis (UC) or Rheumatoid Arthritis (RA) in stable remission 3. Department of medical gastroenterology, Herlev Hospital Trial protocol: DK (Ongoing) N= 316 Discontinuation of infliximab therapy in patients with Crohn s disease during sustained complete remission: A Nordic multi-center, double blinded, randomized, placebo controlled study 20

21 Norwegian-Switch Study Organization providing support: Norwegian Ministry of Health and Care Services 21

22 Canadian (Health Canada) Assessment A difference in opinion Summary basis of decision As with the CHMP Celltrion applied for all the originator product indications however The principles for extrapolation discussed above, and outlined in the SEB guidance document, were taken into account in the review of this submission, and extrapolation of data from the settings of rheumatoid arthritis and AS to adult and pediatric inflammatory bowel diseases (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.. it was concluded that ADCC cannot be ruled out as a mechanism of action in the inflammatory bowel diseases (IBD)...extrapolation from the settings of rheumatoid arthritis and ankylosing spondylitis to IBD cannot be recommended due to the absence of clinical studies in IBD. 22

23 United States Assessment of Remsima POSTPONED: March 17, 2015: Arthritis Advisory Committee Meeting Announcement UPDATED INFORMATION (as of 2/25/2015): The Food and Drug Administration (FDA) is postponing the meeting of the Arthritis Advisory Committee scheduled for March 17, The postponement is due to information requests pending with the sponsor of the application. A future meeting date will be announced in the Federal Register. 23

24 Global Status approval 50 countries 24

25 Biosimilars for Key Therapeutic Monoclonal Antibody products (2015) Disclaimer: numbers are only rough generation from various sources and not definitive 25

26 The future.. McKinsey & Company estimates that 40% of biosimilars in development are mabs That percentage will only increase as fewer first-generation biosimilars are introduced The competitive focus keeps turning to mabs In March 2012, 73 biosimilar mabs were under development, with 59 at the preclinical stage, five in Phase I or II, and nine in Phase III. 26

27 Conclusion Biosimilar monoclonals are real Biosimilar Monoclonals are here Here to stay And much more on the way.. 27

28 Thank you 28