Expert Answers to Frequently Asked Questions About Biosimilars This program is supported by an educational grant from Pfizer

About These Slides Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients When using our slides, please retain the source attribution: These slides may not be published, posted online, or used in commercial presentations without permission. Please contact permissions@clinicaloptions.com for details Slide credit: clinicaloptions.com Disclaimer: The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

Faculty Sanjiv S. Agarwala, MD Professor of Medicine, Temple University Chief, Medical Oncology & Hematology St Luke’s Cancer Center Bethlehem, Pennsylvania Alan J. Kivitz, MD, CPI President Altoona Arthritis and Osteoporosis Center Altoona Center for Clinical Research Duncansville, Pennsylvania This slide lists the faculty who were involved in the production of these slides.

Faculty Robert M. Rifkin, MD, FACP Clinical Associate Professor of Medicine Division of Medical Oncology Department of Internal Medicine University of Colorado, Denver Aurora, Colorado  Medical Director, Biosimilars McKesson Specialty Health The US Oncology Network The Woodlands, Texas Kenneth G. Saag, MD, MSc Jane Knight Lowe Professor Division of Clinical Immunology and Rheumatology Vice Chair, Department of Medicine Director, Center for Education and Research on Therapeutics Center for Outcomes, Effectiveness Research and Education Center of Research Translation in Gout and Hyperuricemia University of Alabama at Birmingham Birmingham, Alabama This slide lists the faculty who were involved in the production of these slides.

Faculty Disclosures Sanjiv S. Agarwala, MD, has no real or apparent conflicts of interest to report. Alan J. Kivitz, MD, CPI, has disclosed that he has received consulting fees from AbbVie, Celgene, Genentech, Janssen, Merck, Novartis, Pfizer, Regeneron, Sanofi Genzyme, and UCB. Robert M. Rifkin, MD, FACP, has disclosed that he receives a salary from McKesson Specialty Health and has served on advisory boards for Amgen, Coherus, EMD Serono, and Pfizer. Kenneth G. Saag, MD, MSc, has disclosed that he has received consulting fees from Abbott, Amgen, Ardea Biosciences/AstraZeneca, Bayer, Bristol- Myers Squibb, Merck, and Roche/Genentech. This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

What Are Biosimilars? Biologic products designed to mimic existing, approved biologic agents Not identical to reference biologic FDA approval process outlined in Affordable Care Act[1] Biosimilars must demonstrate no clinically meaningful differences in safety and efficacy from reference biologic Minor variations in clinically inactive components permitted Simplification of development process anticipated to reduce production costs and encourage competition[2] Slide credit: clinicaloptions.com 1. FDA. Information on biosimilars. 2016. 2. Cornes P. Target Oncol. 2012;7:57-67.

How Do Biosimilars vs Small Molecule Generics Compare? Characteristic Biosimilar Generic Structure Large, complex biologic molecule Small, simple, reproducible molecule Comparison to reference agent Same amino acid sequence May differ in posttranslational modifications, protein folding, impurities, excipients[1] Higher potential for immunogenicity[1] Identical active ingredients Same dosage, route of administration, indications, bioequivalence, strength, purity, quality[2] Manufacturing process[3] Created in living systems Unique cell lines and set of production steps Chemical synthesis Predictable set of chemical reactions FDA approval process Biosimilar Biologics License Application[4] Demonstrate similar safety, purity, potency, and efficacy[5] Abbreviated New Drug Application[5] Demonstrate bioequivalence[1] 1. Li E, et al. J Manag Care Spec Pharm. 2015;21:532-539. 2. FDA. What are generic drugs? 2015. 3. Jeske W, et al. Drug Healthc Patient Saf. 2013;5:133-141. 4. FDA. Information for industry (biosimilars). 2017. 5. FDA. Information on biosimilars. 2016. Slide credit: clinicaloptions.com

What Features Do Biosimilars Share With Their Reference Biologics? Host cell line Host cell line Manufacturing processes Manufacturing processes Amino acid sequence Protein structure Protein structure Mechanism of action Inactive ingredients Inactive ingredients Proven efficacy, safety Proven similarity to reference biologic Li E, et al. J Manag Care Spec Pharm. 2015;21:532-539. Weise M, et al. Blood. 2012;120:5111-5117. Lucio SD, et al. Am J Health Syst Pharm. 2013;70:2004-2017. FDA. Information on biosimilars. 2016. Slide credit: clinicaloptions.com

What Is the Naming Convention for Biosimilars? Adalimumab-atto Etanercept-szzs Filgrastim-sndz Infliximab-abda Infliximab-dyyb Core name FDA-designated suffix No recognizable meaning 4 letters Lowercase Slide credit: clinicaloptions.com FDA. Nonproprietary naming of biological products: guidance for industry. 2017.

Manufacturing of Biosimilars, Reference Biologics, and Small Molecule Generics Small molecule generics: synthesized in chemistry labs by a well-defined set of chemical reactions; less expensive than synthesis of biologics and biosimilars[1,2] Biosimilars and reference biologics: created in living systems by multiple steps, including cell clone selection and bulk protein production, purification, and validation[1] Changes to manufacturing processes require FDA approval[2,3] Biosimilars use unique cell lines and distinct manufacturing processes, thus must undergo extensive analytic evaluation to demonstrate there is no clinically meaningful difference with reference biologic[1] 1. Jeske W, et al. Drug Healthc Patient Saf. 2013;5:133-141. 2. Mellstedt H, et al. Ann Oncol. 2008;19:411-419. 3. Schellekens H. NDT Plus. 2009;2(suppl 1):i27-i36. Slide credit: clinicaloptions.com

Can We Assure Comparable Safety and Efficacy of Biosimilars to Their Reference Biologics? Biosimilars are designed to replicate purity, potency of reference biologics, which is anticipated to translate into clinical comparability[1] After thorough assessment of this comparability by regulatory bodies,[2] approval of biosimilar is: Based on preclinical/clinical studies of pharmacology, efficacy, safety, immunogenicity[2] For specific indications only; extrapolation to other indications must be justified Subject to postmarketing surveillance to identify any unique safety signals 1. Schellekens H, et al. Lancet Oncol. 2016;17:e502-e509. 2. FDA. Scientific considerations in demonstrating biosimilarity to a reference product. 2015. Slide credit: clinicaloptions.com

What Is the Regulatory and Approval Pathway for Biosimilars in the US? Abbreviated licensure pathway Sequential, risk-based approach Demonstration that the biosimilar and reference biologic have no clinically meaningful differences in terms of safety, purity, and potency Efficacy/Safety of Proposed Biosimilar vs Reference Biologic Supports Biosimilarity? Superior No Equivalent or noninferior Yes Inferior FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. 2015. Slide credit: clinicaloptions.com

What Is the Regulatory and Approval Pathway for Biosimilars in the US? Analytical studies of structure and function At each step, FDA evaluates totality of evidence to determine if further studies are required to eliminate residual uncertainty between biosimilar and reference biologic Animal studies including assessment of toxicity Clinical studies of PK/PD and immunogenicity PD, pharmacodynamics; PK, pharmacokinetics. (If uncertainty remains) Comparative clinical studies to determine equivalence FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. 2015. Slide credit: clinicaloptions.com

Clinical Trials of New Biologics vs Biosimilars Clinical trials aim to independently establish efficacy, safety of biologic[1] Emphasis on large, late-phase clinical trials Biosimilars Clinical trials aim to demonstrate similarity to an already-approved reference biologic[2] Stronger emphasis on analytical data[3] Often compared with reference biologics from both US and Europe 1. Kingham R, et al. In: Wang W, et al. Biological drug products: development and strategies, first edition. 2014. 2. Alten R, et al. Semin Arthritis Rheum. 2015;44(6 suppl):S2-S8. 3. FDA. Scientific considerations in demonstrating biosimilarity to a reference product. 2015. Slide credit: clinicaloptions.com

How Do Clinical Development Pathways for New Biologics vs Biosimilars Compare? Study Phase New Biologic – 351(a)[1] Biosimilar – 351(k)[2,3] Preclinical and animal toxicology studies Defines pharmacologic, toxicologic effects prior to human studies Structural/functional analyses Animal studies including assessment of toxicity Phase I and II Dose and schedule determined; immunogenicity assessed Clinical activity and safety evaluated in given pt population Human PK, PD, immunogenicity compared to reference biologic Phase III Assessed in large population to confirm therapeutic benefit If requested by FDA because of residual uncertainty, typically designed to demonstrate equivalence or noninferiority to reference biologic At each step, FDA determines if further studies are needed All studies required by FDA PD, pharmacodynamics; PK, pharmacokinetics. 1. Kingham R, et al. In: Wang W, et al. Biological drug products: development and strategies, first edition. 2014. 2. Alten R, et al. Semin Arthritis Rheum. 2015;44(6 suppl):S2-S8. FDA. 3. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. 2015. Slide credit: clinicaloptions.com

Are Biosimilars and Their Reference Biologics Interchangeable? Within the area of biosimilars, interchangeability is the ability to switch to a biosimilar from its reference biologic without prescriber consent[1] FDA requires additional criteria for interchangeability designation, including demonstration of no loss of safety or efficacy when biosimilar switched or alternated with, not just compared with, US licensed reference biologic[2] Example switch study design: Study design is flexible, but should include: ≥ 3 switches assures at least 2 exposure periods for each product US-licensed reference biologic mimics clinical practice in US Reference Biologic (US Licensed) Study population should be pts, not healthy subjects, but does not need to be the same population used in study showing biosimilarity B, biosimilar; RB, reference biologic. Biosimilar RB B RB B 1. Ebbers HC, et al. GaBI Journal. 2014;3:88-93. 2. FDA. Considerations in Demonstrating Interchangeability With a Reference Product: Guidance for Industry. 2017. Slide credit: clinicaloptions.com

What Biosimilars Are Currently Available in the US? Drug Class Approval Date Indications Comparative Phase III Clinical Trial Data Leading to Approval Filgrastim-sndz[1] Recombinant G-CSF 2015 Prevention of severe neutropenia PIONEER: noninferiority to prevent neutropenia in breast cancer pts on myelosuppressive chemotherapy[2] Infliximab-dyyb[3,4] TNF-α inhibitor 2016 Crohn’s, ulcerative colitis, RA, AS, PsA, plaque psoriasis PLANETRA: equivalent ACR20 in RA pts[5] PLANETAS*: equivalent ASAS20 in AS pts[6] Infliximab-abda[7] 2017 Equivalent ACR20 in RA pts[8,9] Etanercept-szzs[3,4] 2016; ongoing patent litigation RA, AS, PsA, plaque psoriasis, polyarticular JIA EGALITY: equivalent PASI75 in pts with plaque psoriasis[10] Adalimumab-atto[11] Crohn’s, ulcerative colitis, RA, AS, PsA, plaque psoriasis, JIA Equivalent ACR20 in RA pts[12] Equivalent PASI improvement in pts with psoriasis[13] ACR20, American College of Rheumatology 20% improvement criteria; AS, ankylosing spondylitis; ASAS20, Assessment in SpondyloArthritis International Society 20% improvement criteria; G-CSF, granulocyte-colony stimulating factor; JIA, juvenile idiopathic arthritis; PASI, Psoriasis Area and Severity Index; PsA, psoriatic arthritis; RA, rheumatoid arthritis; TNF, tumor necrosis factor. References 1. Rugo HS, et al. Cancer Treat Rev. 2016;46:73-79. 2. Blackwell K, et al. Ann Oncol. 2015;26:1948-1953. 3. Rutherford AI, et al. Expert Rev Clin Immunol. 2016;12:697-699. 4. Ianculescu I, et al. Curr Opin Rheumatol. 2016;28:303-309. 5. Yoo DH, et al. Ann Rheum Dis. 2013;72:1613-1620. 6. Park W, et al. Ann Rheum Dis. 2013;72:1605-1612. 7. Infliximab-abda [package insert]. 2017. 8. Choe JY, et al. ACR/ARHP 2015. Abstract 2056. 9. Choe JY, et al. Ann Rheum Dis. 2017;76:58-64. 10. Griffiths CE, et al. Br J Dermatol. 2017;176:928-938. 11. Panesar K. US Pharm. 2016;41:26-29. 12. Cohen SB, et al. ACR/ARHP 2015. Abstract 2054. 13. Papp K, et al. J Am Acad Dermatol. 2017;[Epub ahead of print]. *Comparative phase I study. Slide credit: clinicaloptions.com References in slidenotes.

Extrapolation of Indications Beyond Study Populations Biosimilar Study Pt Population Additional Indications Extrapolated to by FDA Oncology Filgrastim-sndz[1] Neutropenia in breast cancer treatment Neutropenia in BMT and in treatment of nonmyeloid malignancies, AML; severe chronic neutropenia; leukapheresis[2] Immunology/Rheumatology Infliximab-dyyb[3-6] AS, RA Crohn’s, ulcerative colitis, PsA, plaque psoriasis[7] Infliximab-abda[8,9] RA Crohn’s, ulcerative colitis, AS, PsA, plaque psoriasis[10] Etanercept-szzs[11] Plaque psoriasis RA, AS, PsA, polyarticular JIA[12] Adalimumab-atto[13,14] RA, plaque psoriasis Crohn’s, ulcerative colitis, AS, PsA, polyarticular JIA[15] AML, acute myeloid leukemia; BMT, bone marrow transplantation; AS, ankylosing spondylitis; JIA, juvenile idiopathic arthritis; PsA, psoriatic arthritis; RA, rheumatoid arthritis. References 1. Blackwell K, et al. Ann Oncol. 2015;26:1948-1953. 2. FDA. Summary review of filgrastim-sndz BLA application. 2015. 3. Park W, et al. Ann Rheum Dis. 2013;72:1605-1612. 4. Park W, et al. Arthritis Res Ther. 2016;18:25. 5. Yoo DH, et al. Ann Rheum Dis. 2013;72:1613-1620. 6. Yoo DH, et al. Arthritis Res Ther. 2016;18:82. 7. FDA. AAC brief of infliximab-dyyb BLA application. 2016. 8. Choe JY, et al. ACR/ARHP 2015. Abstract 2056. 9. Choe JY, et al. Ann Rheum Dis. 2017;76:58-64. 10. Infliximab-abda [package insert]. 2017. 11. Griffiths CEM, et al. Br J Dermatol. 2017;176:928-938. 12. FDA. Summary review of etanercept-szzs BLA application. 2016. 13. Cohen SB, et al. ACR/ARHP 2015. Abstract 2054. 14. Papp K, et al. J Am Acad Dermatol. 2017;[Epub ahead of print]. 15. FDA. Summary review of adalimumab-atto BLA application. 2016. Slide credit: clinicaloptions.com References in slidenotes.

Safety Studies of Biosimilars Main Study Population Main Safety Studies Other Safety Studies Filgrastim-sndz[1] Neutropenia in breast cancer treatment Phase III PIONEER study (n = 218)[2] Pooled post approval studies in EU (n = 1302)[3] Prospective study in France (n = 184)[4] Pharmaco-epidemiologic MONITOR-GCSF study (n = 1447)[5] Infliximab-dyyb[6] AS, RA Phase I PLANETAS study in AS (n = 250)[7,8] Open-label switch extension (n = 174)[9] Phase III PLANETRA study in RA (n = 606)[10,11] Open-label switch extension (n = 302)[12] Observational meta-analysis in IBD (n = 552)[13] Infliximab-abda[14] RA Phase III study in RA (n = 584)[15,16] Double-blind switch extension (n = 396)[17] Pharmacokinetic study in healthy subjects (n = 159)[18] Etanercept-szzs[19] Plaque psoriasis Phase III EGALITY switch study in psoriasis (n = 531)[20] Pharmacokinetic studies in healthy males (n = 105)[21] Adalimumab-atto[22] RA, plaque psoriasis Phase III study in RA (n = 526)[23] Phase III study in psoriasis (n = 347)[24] Pharmacokinetic studies in healthy subjects (n = 203)[25] AS, ankylosing spondylitis; IBD, inflammatory bowel disease; JIA, juvenile idiopathic arthritis; PsA, psoriatic arthritis; RA, rheumatoid arthritis. References 1. Filgrastim-sndz [package insert]. 2015. 2. Blackwell K, et al. Ann Oncol. 2015;26:1948-1953. 3. Gascón P, et al. Support Care Cancer. 2013;21:2925-2932. 4. Nahon S, et al. Support Care Cancer. 2016;24:1991-1998. 5. Gascón P, et al. Support Care Cancer. 2016;24:911-925. 6. Infliximab-dyyb [package insert]. 2016. 7. Park W, et al. Ann Rheum Dis. 2013;72:1605-1612. 8. Park W, et al. Arthritis Res Ther. 2016;18:25. 9. Park W, et al. Ann Rheum Dis. 2017;76:346-354. 10. Yoo DH, et al. Ann Rheum Dis. 2013;72:1613-1620. 11. Yoo DH, et al. Arthritis Res Ther. 2016;18:82. 12. Yoo DH, et al. Ann Rheum Dis. 2017;76:355-363. 13. Komaki Y, et al. Aliment Pharmacol Ther. 2017;45:1043-1057. 14. Infliximab-abda [package insert]. 2017. 15. Choe JY, et al. ACR/ARHP 2015. Abstract 2056. 16. Choe JY, et al. Ann Rheum Dis. 2017;76:58-64. 17. Smolen JS, et al. ACR/ARHP 2016. Abstract 2596. 18. Shin D, et al. BioDrugs. 2015;29:381-388. 19. Etanercept-szzs [package insert]. 2016. 20. Griffiths CEM, et al. Br J Dermatol. 2017;176:928-938. 21. von Richter O, et al. Br J Clin Pharmacol. 2017;83:732-741. 22. Adalimumab-atto [package insert]. 2016. 23. Cohen SB, et al. ACR/ARHP 2015. Abstract 2054. 24. Papp K, et al. J Am Acad Dermatol. 2017;[Epub ahead of print]. 25. Kaur P, et al. Ann Rheum Dis. 2017;76:526-533. Slide credit: clinicaloptions.com References in slidenotes.

What Biosimilars Are Currently in the Pipeline in the US? Reference Biologic Drug Class ~ Patent Exp. Date Indication Biosimilars With Phase III Clinical Trials Trastuzumab[1-3] HER2 inhibitor 2019 Breast cancer CT-P6 equivalent efficacy, safety Myl1401O accepted for FDA review Multiple others registered/under way Rituximab[1-3] CD20 inhibitor 2016 Lymphoma; RA BCD-020 equivalent PK/PD, efficacy, safety in iNHL CT-P10 equivalent PK/PD, efficacy, safety, immunogenicity in RA RTXM83 equivalent PK, safety in DLBCL Bevacizumab[1-3] VEGF inhibitor CRC, lung, renal cancer BCD-021 equivalent efficacy, safety, immunogenicity in NSCLC Cetixumab[3] EGFR inhibitor CRC, head and neck cancer 1 under way Adalimumab[2-4] TNF-α inhibitor 2022* Autoimmune diseases BI695501 accepted for FDA review Infliximab[2-4] 2018* Multiple registered/under way Filgrastim[2,5] rG-CSF 2013 Neutropenia Gastrofil accepted for FDA review Registered trial for MK-4214 under way Pegfilgrastim[2,5] 2015 2 pegfilgrastim biosimilars accepted for FDA review, including CHS-1701 Epoetin alfa[2,5] r-EPO Anemia Retacrit submitted to FDA, multiple others registered/under way CRC, colorectal cancer; DLBCL, diffuse large B-cell lymphoma; EPO, erythropoietin; iNHL, indolent non-Hodgkin lymphoma; NSCLC, non-small-cell lung cancer; PD, pharmacodynamic; PK, pharmacokinetic; rG-CSF, recombinant granulocyte colony-stimulating factor; RA, rheumatoid arthritis; TNF, tumor necrosis factor. References: 1. Rugo HS, et al. Cancer Treat Rev. 2016;46:73-79. 2. Stevenson JG, et al. Ann of Pharmacotherapy. 2017;[Epub ahead of print]. 3. Panesar K. US Pharm. 2016;41:26-29. 4. Goel N, et al. Rheumatology. 2017;56:187-197. 5. Derbyshire M. GaBI Journal. 2015;4:178-179. *Ongoing patent litigation. Slide credit: clinicaloptions.com References in slidenotes.

Explaining Biosimilars to Pts: Potential Topics Use of biologics in the specific disease setting Definition of a biosimilar Totality of evidence required to demonstrate similar safety and efficacy of the biosimilar to its reference biologic Simplified explanations How the biosimilar is administered and any device that may be used Insurance coverage and out-of- pocket cost How decreased cost of biosimilars can lead to increased access to more expensive biologics Available pt support services Identity of the manufacturer May be familiar to pt and promote acceptance Slide credit: clinicaloptions.com Jacobs I, et al. Patient Prefer Adherence. 2016;10:937-948.

Reimbursement of Biosimilars by Payers: Medicare Medicare Part B: reimbursement slightly higher than ASP[1] Payment for biosimilars is based on ASP plus 6% of ASP of reference biologic Medicare Part D: new biosimilars treated like new branded drugs from formulary review and pt cost-sharing standpoint[2] Biosimilars ineligible for 50% coverage gap discount Biosimilar and reference biologic will not be considered different drugs for purposes of satisfying Part D formulary requirement for 2 distinct drugs per category/class ASP, average sale price. 1. Centers for Medicare & Medicaid Services. Part B biosimilar biological product payment and required modifiers. 2016. 2. Centers for Medicare & Medicaid Services. Part D requirements for biosimilar follow-on biological products. 2015. Slide credit: clinicaloptions.com

Reimbursement of Biosimilars by Payers: Commercial Commercial payer coverage will likely be based on: Cost differential Interchangeability designation Nature of FDA approval Therapeutic area Medical community Centers for Medicare & Medicaid Services Pt community Slide credit: clinicaloptions.com Felix AE, et al. GaBI Journal. 2014;2:108-115.

Go Online for More CCO Coverage of Biosimilars! CME-certified program with expert answers to frequently asked questions on biosimilars and their application in clinical practice clinicaloptions.com/immunology/biosimilars