Expert Answers to Frequently Asked Questions About Biosimilars

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Faculty Robert M. Rifkin, MD, FACP 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 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] FDA, US Food and Drug Administration. 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 biological 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[5] Manufacturing process[2] 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[3] Demonstrate similar safety, purity, potency, and efficacy[4] Abbreviated New Drug Application[5] Demonstrate bioequivalence[1] FDA, US Food and Drug Administration. 1. Li E, et al. J Manag Care Spec Pharm. 2015;21:532-539. 2. Jeske W, et al. Drug Healthc Patient Saf. 2013;5:133-141. 3. FDA. Information for industry (biosimilars). 2017. 4. FDA. Information on biosimilars. 2016. 5. FDA. What are generic drugs? 2015. 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 FDA, US Food and Drug Administration. 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

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] FDA, US Food and Drug Administration. 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 FDA, US Food and Drug Administration. 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 United States? 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 FDA, Federal Drug Administration; PD, pharmacodynamics; PK, pharmacokinetics. 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 United States? 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 FDA, Federal Drug Administration; 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 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. 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 FDA, US Food and Drug Administration; PD, pharmacodynamics; PK, pharmacokinetics. Kingham R, et al. In: Wang W, et al. Biological drug products: development and strategies, first edition. 2014. Alten R, et al. Semin Arthritis Rheum. 2015;44(6 suppl):S2-S8. FDA. 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; FDA, US Food and Drug Administration; 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 United States? Drug Class Approval Date Indications Comparative Phase III Clinical Trial Data Leading to Approval Oncology Filgrastim-sndz[1] Recombinant G-CSF 2015 Prevention of severe neutropenia PIONEER: noninferiority to prevent neutropenia in breast cancer pts on myelosuppressive chemotherapy[2] Immunology/Rheumatology Infliximab-dyyb[3,4] TNF-α inhibitor 2016 Crohn’s, ulcerative colitis, RA, AS, PsA, plaque psoriasis PLANTERA: equivalent ACR20 in RA pts[5] PLANETAS: equivalent ASAS20 in AS pts[6] Extrapolated to other indications Etanercept-szzs[3,4] 2016; ongoing patent litigation RA, AS, PsA, plaque psoriasis, polyarticular JIA EGALITY: equivalent PASI75 in pts with plaque psoriasis[7] Adalimumab-atto[8] Crohn’s, ulcerative colitis, RA, AS, PsA, plaque psoriasis, JIA Equivalent ACR20 in RA pts[9] Equivalent PASI improvement in pts with plaque psoriasis[10] ACR20, American College of Rheumatology 20% improvement criteria; AS, ankylosing spondylitis; ASAS20, Assessment in SpondyloArthritis International Society 20% improvement criteria FDA, US Food and Drug Administration; 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. Griffiths CE, et al. Br J Dermatol. 2016;[Epub ahead of print]. 8. Panesar K. US Pharm. 2016;41:26-29. 9. Cohen SB, et al. ACR/ARHP 2015. Abstract 2054. 10. Papp K, et al. EADV 2014. Slide credit: clinicaloptions.com References in slidenotes.

What Biosimilars Are Currently in the Pipeline in the United States? 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* SB2 accepted for FDA review 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; G-CSF, granulocyte colony-stimulating factor; FDA, US Food and Drug Administration; iNHL, indolent non-Hodgkin lymphoma; PD, pharmacodynamic; PK, pharmacokinetic; r, recombinant; RA, rheumatoid arthritis; TNF, tumor necrosis factor; EPO, erythropoietin. 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.

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 FDA, US Food and Drug Administration. Slide credit: clinicaloptions.com Felix AE, et al. GaBI Journal. 2014;2:108-115.

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