4/6/2018

Biosimilars: What Prescribers Need To Know

Diana Webber, DNP, APRN-CNP April 2018

Objectives

• Compare and contrast the terms biosimilar and biologic reference product regarding structure, manufacturing, regulatory pathway, and clinical properties. • Discuss potential safety concerns with biosimilars • Describe current FDA policy related to prescribing biosimilar agents. • Evaluate if biosimilar agents are appropriate for select patients based on risks/benefits, disease/treatment-related factors, and patient preferences.

Outline

A. Definition “biologic” drug product i. Comparison biologic with small-molecule chemical drug ii. Nomenclature biologic products B. Definition “biosimilar” drug product i. Comparison biosimilar to generic small-molecule drug ii. Comparison biosimilar to biologic reference product iii. General principles of biosimilarity C. Biosimilar safety i. Immunogenicity ii. Interchageability & Extrapolation D. FDA Policy and Prescriber Concerns i. Approval process ii. Nomenclature iii. Prescriber Concerns E. Prescribing Scenario

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Quiz Time!

1. Small-molecule chemical drugs and biologics are used to treat a variety of diseases. Do you think that there is a significant difference between a small-molecule drug and a biologic agent? A. YES B. NO

2. In which ways do biosimilars and generic chemical drugs resemble each other? A. Both involve complex manufacturing processes, and it is impossible to ensure identical copies B. Both are stable products, not sensitive to external conditions C. Both products are non-immunogenic D. Biosimilars do not resemble generic chemical drugs

Definition “Biologic”

• Biological product • Biopharmaceutical examples: – Botox – Herceptin – Enbrel – Insulin analogs • Biologics 20-35% of new drugs in pipeline • Source materials • Recombinant DNA

https://www.ecfr.gov/cgi-bin/text- idx?SID=a3931adb89f6a292d67a7c48340f5b1a&mc=true&node=se21.7.600_13&rgn=div8

Development of a Biologic product

Identification and isolation of the gene of interest: https://www.youtube.com/watch?v=a Yhf-FXpoYs

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Chemical vs Biologic Drug

Chemical versus Biologic Drug Chemical (e.g. aspirin) Biologic (e.g. monoclonal antibody) Low molecular weight High molecular weight Well-defined, homogeneous Complex, heterogeneous structure chemical structure Produced by chemical Produced in living cell culture; difficult synthesis; predictable to control process; impossible to chemical process; can make ensure identical copy identical copies Stable Unstable, sensitive to external conditions Mostly non-immunogenic Immunogenic

Li, et al. (2015); CCO (2017), clinicaloptions.com

Chemical vs Biologic Drug

Kozloski, 2011

Biosimilars

• Reverse-engineered copies of FDA- approved biologic agents no longer under patent protection • Biologic products designed to mimic existing, approved biologic agents • Similar but not identical to reference biologic agent • Not “generic” for reference drug

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Biosimilar Definition

• A biologic product that is –“highly similar to the reference product notwithstanding minor differences in clinically inactive components ” – “there are no clinically meaningful differences between the reference product and the biologic product in terms of the safety, purity, and potency of the product.”

Biologics Price Competition and Innovation (BCPI) Act of 2009

Biosimilar Not Generic

Property Generic Chemical Drug Biosimilar Structural complexity Small, simple, Large, complex, biologic reproducible molecule molecule Comparison to •Identical active •Same amino acid sequence Reference Agent ingredients •May differ in some •Same dosage, route of parameters administration, •Higher potential bioequivalence, strength, immunogenicity purity Manufacturing •Chemical synthesis •Created in living systems Process •Predictable set •Unique cell lines & chemical reactions production steps from reference product FDA-approval •Abbreviated New Drug •Biosimilar Biologics License Process Application Application (abbreviated) •Demonstrate •Demonstrate similar safety, bioequivalence purity, potency, efficacy

Li, et al. (2015); CCO (2017 )

Biosimilar Not Generic

Property Generic Chemical Drug Biosimilar Immunogenic Less likely; allergic Possible; requires testing potential reactions can occur and monitoring Interchangeability Allowed by FDA if standards Only when a FDA “higher with reference of purity and bioequivalence standard of agent have been met interchangeability” has been met Automatic Generally allowed, FDA guidance pending substitution depending on state law and prescriber preference Nomenclature Name is generally the same FDA proposes unique as the International Non- nomenclature that shows proprietary Name (INN) relationship but distinction from reference product Cost Much less than branded Varies: 15-90% less than product reference product; greater cost savings outside of U.S.

Rak Tkaczuk & Jacobs (2014); Kay, et al. (2018); Blackstone & Joseph (2013); ACR (2016)

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What Features Do Biosimilars Share With Their Reference Biologics?

Reference Host cell line Host cell line Biosimilar Biologic Manufacturing Manufacturing processes processes Amino acid sequence Protein structure Protein structure

Inactive ingredients Mechanism Inactive ingredients of action

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

https://www.clinicaloptions.com/Immunology/Treatment%20Updates/Biosimilar%20Perspectives.aspx

General Principles Biosimilarity

• Biosimilar must demonstrate no clinically significant difference from reference product – Robust analytical, toxicologic, PK/PD, and immunogenicity studies compared to reference product – Smaller comparative effectiveness clinical trials, 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/efficacy between approved biosimilar and reference product – Same mechanism of action – Same route of administration, dosage form, dosage strength Slide credit: clinicaloptions.com

General Principles Biosimilarity

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Critical Attributes for Biosimilarity

High-Quality Biosimilar Not a Biosimilar

Primary Similar Primary structur Acceptable differences structur e Difference with critical e Higher Higher or unknown impact order Biological order Biological structure function structure function Product purity Product purity

General Stability General Stability properties Particles properties Particles and and and and excipients aggregates excipients aggregates Process- Process- related related ° 95 attributes similar ° 87 attributes similar impurities impurities ° 2 acceptable ° 7 acceptable differences differences ° 0 critical differences ° 3 critical differences

FDA. Overview of biosimilar products. 2016. Slide credit: clinicaloptions.com

Lot-to-lot variability of critical quality attributes must be assessed and controlled to ensure consistent product quality

Terms Related to Safety

• Interchangeability: “designation that allows a biosimilar agent to be substituted for its reference product with prescriber input.” • Substitution: “interchange or replacement of a biosimilar agent with its reference product by someone other than the prescribing health professional.” • Switch: “therapeutic transition from a reference product to a biosimilar agent or vice versa, based on prescriber decision.”

Dorner & Kay (2015)

Biosimilar Safety

• Biosimilar has same risk profile as its reference product • Potential adverse reactions due to variations in manufacturing of reference biologic and biosimilar • Potential risk associated with interchageability and automatic switching by pharmacy • Potential risk associated with extrapolation of data

Khraishi, et al. (2016)

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“Switching”

NOR-SWITCH study (2017) – 52-week randomized, double-blind Phase 4 trial in pts with RA, SpA, CD, Ps, PsA, or UC; stable on infliximab for ≥ 6 mos – Primary endpoint: disease worsening during 52-wk follow-up – Infliximab (n=202); infliximab-dyyb (n=206) – Result: switching from infliximab to infliximab-dyyb non-inferior to continued treatment with infliximab Jӧrgensen, et al. (2017) EGALITY trial (2017)

Extrapolation

Examples: – Adalimumab (Humira): approved for RA, Ps, PsA, AS, CD, UC – Adalimumab-atta (Amjevita): same indications

– Rituximab (Rituxin): approved for non- Hodgkin lymphoma, CD-20 + CLL, moderate- severe RA – GP2013 (Rixathon- biosimilar rituximab): license application accepted by FDA 9/2017

Quiz Time!

1. According to FDA guidance, what types of studies serve as the beginning or “foundation” for the stepwise development of a biosimilar? A. Structure/function B. Toxicity C. Immunogenicity D. Clinical efficacy and safety 2. A biosimilar approved by the FDA may be substituted without the intervention of the provider who prescribed the reference product under what circumstances? A. Any biosimilar with FDA approval may be substituted for approved indications. B. If allowed by state substitution laws C. If approved as interchangeable by the FDA and allowed by state laws D. Substitution rules vary depending on therapeutic class

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FDA Approval Process

• 351(k) abbreviated approval pathway • Standards for approval – FDA goal: to establish biosimilarity with the reference product, not to independently establish safety and effectiveness. Biosimilar can rely on safety/efficacy data from the reference product

Stepwise Approach

The foundation for the approach is the Analytical Studies. Then a stepwise approach evaluates “residual uncertainty” at each step

FDA Approved Biosimilars

Drug Name Approval Class *Zarxio (filgrastim-sndz) 3/2015 Colony stim factor *Inflectra (infliximab-dyyb) 4/2016 TNF-inhibitor Erelzi (etanercept-szzs) 8/2016 TNF-inhibitor Amjevita (adalimumab-atta) 9/2016 TNF-inhibitor *Renflexis (infliximab-abda) 5/2017 TNF-inhibitor Cyltezo (adalimumab-adbm) 8/2017 TNF-inhibitor Mvasi (bevacizumab-awwb) 9/2017 VEGF-inhibitor Hemlibra (emicizumab-kxwh) 11/2017 mAb Ogivri (trastuzamab-dkst) 12/2017 HER2/neu-inhibitor Ixifi (infliximab-qbtx) 12/2017 TNF-inhibitor

FDA Approved Biosimilar Products as of 12-2017

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2018 Biosimilar HCPCS Codes

Biosimilar HCPCS Product Corresponding Code Brand names Required Modifier Q5101 Injection, Filgrastim (G-CSF), Zarxio ZA - Novartis/Sandoz Biosimilar, 1 microgram Q5102 Injection, infliximab, Inflectra ZB - Pfizer/Hospira biosimilar, 10 mg Q5102 Injection, ZC –Merck/Samsung infliximab, Renflexis Bioepis biosimilar, 10 mg

CMS Biosimilar Product-HCPCS Payment Codes

Nomenclature

• Same non-proprietary name as reference product (core name) but with a 4-letter suffix – Randomly generated – Devoid of meaning – Only lower-case letters – Attached to core name with a hyphen – Free of legal barriers that would restrict usage • Examples: infliximab (Remicade) – Infliximab-abda (Renflexis) – Infliximab-dyyb (Inflectra) – Infliximab-qbtx (Ixifi)

Prescriber Concerns

• Interchangeability/Substitution without consent of prescriber The Purple Book • Notification of patient and prescriber when substitution occurs • Cost: CMS biosimilar payment changes may encourage use in Medicare patient population CMS 2018 Revisions to Part B Payments (p.53348-53349): https://www.gpo.gov/fdsys/pkg/FR-2017-11-15/pdf/2017-23953.pdf • How to introduce biosimilars into your practice

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Introducing Biosimilars into Practice

Potential Scenarios: • Gradual introduction of biosimilars only in pts newly starting a biologic • Instant switching to biosimilars for pts currently receiving a biologic • Switching due to loss of response or adverse events with a biologic • Switching between the biosimilar and the reference drug on an alternating basis, depending on pharmacy supply and drug product availability

Scenario

• 44 y/o Caucasian female; seropositive RA x 8 years • Initial course of therapy aggressive. Good control x3 years on this combination of meds: – Methotrexate (non-biologic) – Hydroxychloroquine (non-biologic) – Etanercept (biologic TNF inhibitor) • Received letter from insurance provider recommending she switch to biosimilar TNF inhibitor • She would like to decrease her out-of-pocket insurance costs, but she is concerned about the safety and efficacy of the biosimilar • She asks you a few questions…

Patient Questions

• What is a biosimilar? • Do biosimilars work as well as the reference product? • What are the risks associated with biosimilar use? • If the etanercept is working, why should I change? • Do you recommend that I switch to the biosimilar?

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For More Information

• https://www.fda.gov/drugs/developmenta pprovalprocess/howdrugsaredevelopeda ndapproved/approvalapplications/therap euticbiologicapplications/biosimilars/

• Search: FDA Biosimilars safe effective treatment options

Questions?

References

• American College of Rheumatology (2016). Position statement: Biosimilars. Presented by Committee on Rheumatologic Care . https://www.rheumatology.org/Portals/0/Files/Biosimilars-Position- Statement.pdf • Biologics Price Competition and Innovation Act of 2009. United States Code, 111 th Congress. 2nd Session ed. United States, 2010: 804-821. • Blackstone, E.A., Joseph, P.F. (2013). The economics of biosimilars. American Health Drug Benefits, 6 (8), p. 469-478. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031732/ • Clinical Care Options (2017). Slidesets: Immunology- Biosimilars. Retrieved from clinicaloptions.com https://www.clinicaloptions.com/Immunology/Slidesets.aspx • Chow, S., Song, F., Bai, H. (2016). Analytical similarity assessment in biosimilar studies. The AAPS Journal, 18 (3), p. 670-677. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256601/

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References

• Dörner, T., Kay, J. (2015). Biosimilars in rheumatology: current perspectives and lessons learnt. Nature Reviews Rheumatology, 11 (12), p. 713-724. https://www.researchgate.net/profile/Jonathan_Kay/publication/2810 96426_Biosimilars_in_rheumatology_Current_perspectives_and_le ssons_learnt/links/56658c2308ae4931cd623f1a/Biosimilars-in- rheumatology-Current-perspectives-and-lessons-learnt.pdf • FDA (2017). Biosimilar product regulatory review and approval. Retrieved https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrug sareDevelopedandApproved/ApprovalApplications/TherapeuticBiolo gicApplications/Biosimilars/ucm580429.htm • Fluhmann, B., et al. (2015). Non-biological complex drugs (NBCDs) and their follow-on versions: time for an editorial section. Genetics and Biosimilars Initiative Journal, 4 (4): 167-70. Retrieved from http://gabi-journal.net/non-biological-complex-drugs-nbcds-and- their-follow-on-versions-time-for-an-editorial-section.html

References

• Hoffman, M., Barry, J. (2018). U.S. biosimilars: The hope and the hype. Back Bay Whitepaper U.S. Biosimilars 2018: Opportunities and Challenges. Retrieved from https://bblsa.com/documents/Back- Bay-US-Biosimilars-2018.pdf • Hollander, P., Spellman, C.W. (2016). Preparing for the wave of the future: Biosimilars. CME: The France Foundation. Retrieved from http://www.biosimilarscme.org/content/Preparing_for_the_Wave_of_ Biosimilars_ebook.pdf •Jӧrgensen, K.K., Olsen, I.C, Lorentzen, M., Bolstad, N., Haavardsholm, E. A., Lundin, K.E.A….Kvient, T.V. (2017). Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator, infliximab (NOR-SWITCH): A 52- week, randomized, double-blind, non-inferiority trial. The Lancet. Published online May 11, 2017 http://dx.doi.org/10.1016/S0140- 6736(17)30068-5

References

• Kay, J., Schoels, M.M., Dorner, T., Emery, P., Kvien, T. K., Smolen, J.S., Breedveld, F.C. (2018). Consensus-based recommendations for the use of biosimilars to treat rheumatologic diseases. Annals Rheumatological Disease, 77 , p. 165-174. https://connect.ouhsc.edu/content/annrheumdis/77/2/,DanaInfo=ard.b mj.com+165.full.pdf • Khraishi, M., Stead, D., Lukas, M., Scotte, F., Schmid, H. (2016). Biosimilars: A multidisciplinary perspective. Clinical Therapeutics, 38 (5), p. 1238-1249. https://www.sciencedirect.com/science/article/pii/S014929181630092 3 • Kozlowski, S. Woodcock, J., Midthun, K., Behrman Sherman, R. (2011). Developing the nation’s biosimilars program. New England Journal Medicine, 365, p. 385-388. http://www.nejm.org/doi/full/10.1056/NEJMp1107285

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References

• Li, E.C., Ramanan, S., Green, L. (2015). Pharmacist substitution of biologic products: Issues and considerations. Journal of Managed Care and Specialty Pharmacy, 21, 532-539. https://www.jmcp.org/doi/pdf/10.18553/jmcp.2015.21.7.532 • Lybecker, K.M. (2016). The biologics revolution in the production of drugs. Fraser Institute. https://www.fraserinstitute.org/sites/default/files/biologics- revolution-in-the-production-of-drugs.pdf • Rak Tkaczuk, K. H., Jacobs, I.A. (2014). Biosimiliars in oncology: From development to clinical practice. Seminars in Oncology, 41 (S3), S3-12. Retrieved http://www.seminoncol.org/article/S0093-7754(14)00056- 6/fulltext

References

• U.S. Department of Health and Human Services, FDA, CDER, CBER (2017). Non-proprietary naming of biological products: Guidance for industry. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegu latoryInformation/Guidances/UCM459987.pdf

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