What Is a Biosimilar?

Transcription

1 Learning Objectives Compare and contrast biosimilars to their reference product and generic therapies in terms of structure, manufacturing, regulatory pathway, and clinical properties Evaluate evolving policy related to prescribing, dispensing, and maintaining pharmacovigilance with biosimilars Determine whether biosimilars are appropriate for select patients with RA based on their benefits/limitations, diseaseand treatment-related factors, and patient preferences 1

2 What Is a Biosimilar? A biosimilar is a product that is highly similar to an FDA-approved biopharmaceutical (ie, reference product or biooriginator ) that will be out of patent in 10 years and has: Undergone rigorous analytical and clinical assessment, in comparison to its reference product Been approved by a regulatory agency according to a specific pathway for biosimilar evaluation A biosimilar is highly similar to its reference product in physicochemical characteristics, purity, potency, efficacy, and safety Beck A, et al. Anal Chem. 2012;84: ; Dörner T, et al. Nat Rev Rheumatol. 2015;11: Second-Generation (or Biobetter ) Structurally different from originally licensed biopharmaceutical Intended to improve performance while preserving mechanism of action Examples: Infliximab, adalimumab, golimumab Filgrastim and pegfilgrastim Not considered to be biosimilar Biosimilars Are Not Generic Drugs Small-molecule drugs that are less complex than biosimilars Manufacturing process is several orders of magnitude less complex Regulated under different legislation Beck A, et al. Anal Chem. 2012;84: ; Woodcock J, et al. Nat Rev Drug Discov. 2007;6:

3 Biosimilars approved by the US FDA to treat RA include: Infliximab-dyyb Etanercept-szzs Adalimumab-atto Biosimilar Current State of Biosimilars Market Reference Drug Class Company EU Approval Canada Approval Japan Approval Abseamed Eprex ESA Medice Arzneimittel Putter Aug-07 Binocrit Eprex ESA Sandoz (Novartis) Aug-07 Epoetin alfa Hexal Eprex/Erypo ESA Hexal (Novartis) Aug-07 Retacrit Eprex ESA Hospira Dec-07 Silapo Eprex ESA STADA Arzneimittel Dec-07 Epoetin alfa BS Espo ESA JCR Pharmaceuticals Jan-10 Biograstim Neupogen G-CSF CT Arzneimittel Sep-08 Ratiograstim Neupogen G-CSF Ratiopharm Sep-08 Tevagrastim/Filgrastim NK Neupogen G-CSF Teva/Nippon Kayaku Sep-08 Feb-13 US Approval Zarzio (EU)/Filgrastim BS Injection (Japan)/Zarxio (US) Neupogen G-CSF Sandoz (Novartis) Feb-09 Mar-14 Mar-15 Filgrastim Hexal Neupogen G-CSF Hexal (Novartis) Feb-09 Nivestim Neupogen G-CSF Hospira Jun-10 Grastofil Neupogen G-CSF Apotex/Stada Oct-13 Accofil Neupogen G-CSF Accord Healthcare Sep-14 Omnitrope Genotropin hgh Sandoz (Novartis) Apr-06 Apr-09 Jun-09 Remsima/Inflectra Remicade TNF inhibitor Celltrion//Nippon Kayaku Sep-13 Jan-14 Jul-14 Apr-16 Benepali Enbrel TNF inhibitor Samsung Bioepis Jan-16 Aug-16 Flixabi Remicade TNF inhibitor Samsung Bioepis May-16 Erelzi Enbrel TNF inhibitor Sandoz (Novartis) Aug-16 Amjevita Humira TNF inhibitor Amgen Sep-16 Ovaleap Gonal-f FSH Teva Sep-13 Bemfola Gonal-f FSH Finox Biotech Mar-14 Abasaglar (previously Abasria) Lantus Insulin glargine Eli Lilly/Boehringer Ingelheim Sep-14 Dec-14 Insulin glargine Lantus Insulin glargine Biocon/Fujifilm Pharma Mar

4 CT-P13 (infliximab-dvvb) First TNF inhibitor (biosimilar monoclonal antibody) approved US FDA granted approval April 5, 2016 Indicated for Crohn s disease, ulcerative colitis, RA, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis GP2015 (etanercept-szzs) US FDA granted approval August 30, 2016 Indicated for RA, polyarticular JIA, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis 4

5 ABP501 (adalimumab-atto) US FDA granted approval September 23, 2016 Indicated for RA, ankylosing spondylitis, cutaneous psoriasis, psoriatic arthritis, Crohn s disease, ulcerative colitis Goals of Stand-Alone and Biosimilar Development Are Different Stand-Alone Development Program, 351(a) Goal: To establish safety and efficacy of a new product Abbreviated Development Program, 351(k) Goal: To demonstrate biosimilarity (or interchangeability) Clinical Safety and Efficacy (Phases 1, 2, 3) Clinical Pharmacology Non-clinical Analytical Additional Clinical Studies Clinical Pharmacology Non-clinical Analytical Overview of the Regulatory Pathway and FDA s Guidance for the Development and Approval of Biosimilar Products in the US. MeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM pdf. Accessed September 7,

6 FDA Proposed Guidance on Naming USAN with an added random four-letter suffix, devoid of meaning, for all biologics (including reference products) with limited exceptions Filgrastim in the US (approved indications vary) Filgrastim (reference biologic) Tbo-filgrastim (not biosimilar [351(a)]) Filgrastim-sndz (biosimilar [351(k)] Benefits Ability to differentiate products for pharmacovigilance purposes Common core names will group similar biologics in electronic systems Having suffix for all products reduces perception that biosimilar is inferior to reference product Concerns Unless interchangeable biosimilar has the same suffix, it will inhibit interchange Potential for errors when using four-letter suffix devoid of meaning (alternative to represent manufacturer) More complex naming system increases likelihood that errors could occur, actually harming pharmacovigilance Need to change name of current biologics on market creates confusion aab7cd3f77b7%7d/physician-groups-support-proposed-fda-biosimilar-naming-convention-but-also-call-for-maker-id 6

7 Biosimilars Are Reverse Engineered Reference product 1 Reverse Engineering Biosimilar candidate Characterize reference product Identify CQAs of reference product Develop unique cell line and manufacturing process Characterize biosimilar candidate and identify CQAs Evaluate similarity to reference product 1. Kozlowski S Biotechnology Technology Summit; June 13, 2014; Rockville, MD Manufacturing Biosimilars: Sources of Variation Cloning and Protein Expression Target DNA Source DNA Possibly same gene sequence Cloning into DNA vector Possibly different vector Transfer into host cell Expression screening/ selection Different cellexpression system Protein Production, Purification, and Validation Cell expansion Different cell line, growth media, method of expansion Cell production in bioreactors Different cell line, growth media, bioreactor conditions Recovery through filtration or centrifugation Different operating conditions Purification through chromatography Different binding and elution conditions Characterization and stability Purified bulk drug Different methods, reagents, reference standards Adapted from Mellstedt H, et al. Ann Oncol. 2008;19:

8 Demonstrating Biosimilarity: General Principles Clinical efficacy and safety of reference biopharmaceutical have already been demonstrated Biosimilar must demonstrate no significant difference from its reference product Robust analytical, toxicologic, PK/PD, and immunogenicity studies in comparison to reference product Smaller comparative effectiveness clinical trial(s), which must be conducted in patients with a disease for which the reference product is licensed No need to demonstrate efficacy in all indications No differences in safety or efficacy are expected between an approved biosimilar and its reference product Gerrard T, et al. GaBi J. 2015;4: Biosimilars Development: A Stepwise Approach Preclinical Phase 1 Phase 3 In vitro studies Assess binding to target(s) Assess signal transduction and functional activity/ viability Determine if in vivo studies are needed Necessary only if factors of concern are identified, eg, new posttranslational modification structures In vivo studies Focus of study depends on the need for additional information PK/PD studies Single-dose crossover or parallel group designs preferred PD markers selected on the basis of their clinical relevance Affinity is a key determinant of the PK and PD profile of mabs and soluble receptor constructs 1.32 Close reproduction of conformational structure for biosimilar mabs and soluble receptor constructs is needed to ensure comparable biological effect 48 Safety and efficacy No clinically significant difference in efficacy to reference product Compare severity and frequency of adverse events, in particular for immunogenicity Dörner T, et al. Nat Rev Rheumatol. 2015;11:713-24; Dörner T, et al. Ann Rheum Dis. 2013;72:322-8; Braun J, et al. Arthritis Rheumatol. 2014;66:3538-9; 8

9 Extrapolation of Indications Extrapolation of data from a clinical trial of a biosimilar conducted in one disease to support approval for additional indications for which the reference product is already licensed Factors to be considered: Clinical experience with the reference product Mechanism(s) of action in each indication Target receptors Product structure and target/receptor interactions PK and biodistribution in different patient populations Differences in the safety/immunogenicity profile between indications Cannot extrapolate across indications in which reference product may have different mechanisms of action (eg, rituximab in RA and lymphoma) Weise M, et al. Blood. 2014;124: Switching vs Substitution Switch = transition Patient transitioned to biosimilar, after initial treatment with originator Single switch study Substitution = interchange BPCI Act of 2009 affords 1 year of exclusive marketing rights to first biosimilar approved as being interchangeable with reference product Interchange could be initiated without prescriber input Repeated switching study (although single switch study might fulfill statutory requirement) Dörner T, et al. Nat Rev Rheumatol. 2015;11:

10 BPCI Act of 2009: Interchangeability ComplianceRegulatoryInformation/UCM pdf. Efficacy and Safety of Approved Biosimilars Biosimilars have been shown to be as effective as reference products at early time points and in sustained studies No meaningful safety differences Emery P, et al. Ann Rheum Dis Jul 6. [epub ahead of print]; Yoo DH, et al. Ann Rheum Dis. 2013;72: ; Yoo DJ, et al. Arthritis Res Ther. 2016;18:82. 10

11 Acknowledgment of Commercial Support This activity is supported by an educational grant from Genentech. Contact Information Call (toll-free) Please visit us online at for additional activities provided by Med-IQ. To receive credit, click the Get Credit tab at the bottom of the Webcast for access to the evaluation, attestation, and post-test Unless otherwise indicated, photographed subjects who appear within the content of this activity or on artwork associated with this activity are models; they are not actual patients or doctors. 11

12 Abbreviations/Acronyms BPCI = Biologics Price Competition and Innovation CQAs = critical quality attributes DNA = deoxyribonucleic acid ESA = erythropoietin-stimulating agent EU = European Union G-CSF = granulocyte colony-stimulating factor FDA = Food and Drug Administration FSH = follicle-stimulating hormone HgH = human growth hormone JIA = juvenile idiopathic arthritis mabs = monoclonal antibodies PD = pharmacodynamic PK = pharmacokinetic RA = rheumatoid arthritis TNF = tumor necrosis factor US = United States USAN = United States Adopted Name 12