1. Expert Perspectives on Biosimilar Agents
Supported by an independent educational grant from Boehringer Ingelheim Pharmaceuticals, Inc.

2. Disclosures
Andrew M. Evens, DO, MSc, FACP, has disclosed that he has received consulting fees from Seattle Genetics and Takeda, fees for non-CME/CE services from Celgene, and funds for research support from Seattle Genetics and Takeda. Jonathan Kay, MD, has disclosed that he has received consulting fees from Amgen, Boehringer Ingelheim, Bristol‐Myers Squibb, Janssen, Lilly, Merck, Pfizer, Roche, Samsung Bioepis, Sandoz, and UCB and funds for research support paid to his institution from AbbVie, Genentech, Lilly, Pfizer, and UCB. Alan C. Moss, MD, has disclosed that he has received consulting fees from Boehringer Ingelheim, Gilead Sciences, Janssen, Pfizer, and Seres.
This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

3. 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: Weise M, et al. Blood. 2012;120: Lucio SD, et al. Am J Health Syst Pharm. 2013;70: FDA. Information on biosimilars
Slide credit: clinicaloptions.com

4. What Biosimilars Are Not
Biosimilars are different than:
Generics
Intended copies (biomimics)
Biobetters
Second-generation biologics
Next-generation biologics
Slide credit: clinicaloptions.com
Olech E. Semin Arthritis Rheum. 2016;45:S1-S10.

5. Biosimilars Represent Paradigm Shift in Product Development
Reference Biologic[1]
Postmarketing Surveillance
Phase III Clinical
Phase II Clinical
Phase I Clinical
Preclinical
Molecular Characterization
Biosimilar[2]
Molecular Characterization
Preclinical
PK/PD
Immunogenicity
Clinical
Postmarketing Surveillance
Clinical Predictability
Contribution to
Clinical Predictability
Contribution to
PD, pharmacodynamics; PK, pharmacokinetics.
1. FDA. Drug development overview FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry
Slide credit: clinicaloptions.com
1. FDA. Drug development overview. June 12, FDA Guidance for Industry, Scientific Considerations

6. Higher Standards for Biosimilars Designated as Interchangeable
Within the area of biosimilars, interchangeability is the ability to switch to a biosimilar from its reference biologic without prescriber consent[1]
Biosimilar
Interchangeable[2]
Same clinical result as reference product
Same clinical result as reference product
Same clinical result when switched or alternated with reference product
1. Ebbers HC, et al. GaBI Journal. 2014;3: FDA. Considerations in demonstrating interchangeability with a reference product: guidance for industry
Slide credit: clinicaloptions.com
1. Biologics Price Competition and Innovation Act
2. National Conference of State Legislatures web site. Accessed October 2, 2014.

7. FDA: 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
Biosimilar RB B RB B
Reference biologic
Biosimilar
B, biosimilar; RB, reference biologic.
FDA. Considerations in Demonstrating Interchangeability With a Reference Product: Guidance for Industry
Slide credit: clinicaloptions.com

8. Legislation on Biologics and Biosimilar Substitution, 2013-2017NH AK VT ME WA
Enacted law, (n = 35 states + Puerto Rico)
Filed; failed/adjourned (n = 8 states)
Other regulation: step therapy enacted law
2015 MT ND MA
2014
2013 MN
2013 NY OR
2017 ## WI
2017 RI
2016
2013; 2016 ID SD MI CT
2016 WY PA IA
2016 OH NE
2017 IL IN NJ
2015 NV
2016 UT
2017
2015
2014 WV VA DE
2013; 2015 CO
2014 ##
2017 KS MO KY
2013 CA
2015
2017
2016
2016 NC
2015 MD
2017 TN
2015
2015 SC OK AR
2017 DC AZ NM GA AL HI
2016 MS
2015
AS, American Samoa; GU, Guam; MP, Northern Mariana Islands; PR, Puerto Rico; VI, US Virgin Islands. LA
2016 TX
2015
2015 FL
2013 AS GU MP VI PR
2015
Image © 2017 NCSL. Adapted from: Cauchi R. State laws and legislation related to biologic medications and substitution of biosimilars. September Available at:
Slide credit: clinicaloptions.com

9. Consensus Recommendations for Biosimilar Use in Rheumatological Diseases
The availability of biosimilars must significantly lower the cost of treating an individual pt and increase access to optimal therapy for all pts with rheumatic diseases.
Approved biosimilars can be used to treat appropriate pts in the same way as their bio-originators.
As no clinically significant differences in immunogenicity between biosimilars and their bio-originators have been detected, antidrug antibodies to biosimilars need not be measured in clinical practice.
Relevant preclinical and phase I data on a biosimilar should be available when phase III data are published.
Since the biosimilar is equivalent to the bio-originator in its physicochemical, functional, and pharmacokinetic properties, confirmations of efficacy and safety in a single indication is sufficient for extrapolation to other diseases for which the bio-originator has been approved.
Currently available evidence indicates that a single switch from a bio-originator to one of its biosimilars is safe and effective; there is no scientific rationale to expect that switching among biosimilars of the same bio-originator would result in a different clinical outcome, but pt perspectives must be considered.
Multiple switching between biosimilars and their bio-originators or other biosimilars should be assessed in registries.
No switch to or among biosimilars should be initiated without the prior awareness of the pt and the treating HCP.
Slide credit: clinicaloptions.com
Kay J, et al. Ann Rheum Dis. 2017;[Epub ahead of print].

10. Biosimilars: FDA Naming Convention
Adalimumab-adbm
Adalimumab-atto
Bevacizumb-awwb
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

11. Extrapolation of Indications Beyond Study Populations
Biosimilar
Study Pt Population
Additional Indications Extrapolated to by FDA
Infliximab-dyyb[1-4]
AS, RA
Crohn’s, ulcerative colitis, PsA, plaque psoriasis[5]
Infliximab-abda[6,7] RA
Crohn’s, ulcerative colitis, AS, PsA, plaque psoriasis[8]
Etanercept-szzs[9]
Plaque psoriasis
RA, AS, PsA, polyarticular JIA[10]
Adalimumab-atto[11,12]
RA, plaque psoriasis
Crohn’s, ulcerative colitis, AS, PsA, polyarticular JIA[13]
Adalimumab-adbm
Crohn’s, ulcerative colitis, AS, PsA, plaque psoriasis, polyarticular JIA[14]
AS, ankylosing spondylitis; JIA, juvenile idiopathic arthritis; PsA, psoriatic arthritis; RA, rheumatoid arthritis.
References
1. Park W, et al. Ann Rheum Dis. 2013;72:
2. Park W, et al. Arthritis Res Ther. 2016;18:25.
3. Yoo DH, et al. Ann Rheum Dis. 2013;72:
4. Yoo DH, et al. Arthritis Res Ther. 2016;18:82.
5. FDA. AAC brief of infliximab-dyyb BLA application
6. Choe JY, et al. ACR/ARHP Abstract 2056.
7. Choe JY, et al. Ann Rheum Dis. 2017;76:58-64.
8. Infliximab-abda [package insert]
9. Griffiths CEM, et al. Br J Dermatol. 2017;176:
10. FDA. Summary review of etanercept-szzs BLA application
11. Cohen SB, et al. ACR/ARHP Abstract 2054.
12. Papp K, et al. J Am Acad Dermatol. 2017;[Epub ahead of print].
13. FDA. Summary review of adalimumab-atto BLA application
14. Adalimumab-adbm [package insert]
Slide credit: clinicaloptions.com
References in slidenotes.

12. Extrapolation for Biosimilars: Factors to Consider
Characteristic
Related Factors
MoA in each condition
Binding and molecular signaling
Location, expression of target/receptor
PK and biodistribution
PD measures may inform MoA
Expected toxicities
Differences may exist in each condition of use, pt population
Other
Comorbidities, concomitant medications
FDA guidance states that extrapolation of indications for a biosimilar is possible given sufficient scientific justification
MoA, mechanism of action; PD, pharmacodynamic; PK, pharmacokinetic.
FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry
Slide credit: clinicaloptions.com
1. FDA Guidance for Industry, Scientific Considerations
2. Weise M, et al. Blood. 2012:120:

13. NOR-SWITCH: Switch to Infliximab-dyyb for Multiple Indications
Treatment Difference: -4.4%
(95% CI: -12.7% to +3.9%)
Treatment Difference: 0.6%
(95% CI: -7.5% to +8.8%)
52-wk randomized, double-blind phase IV trial in pts with RA, SpA, CD, Ps, PsA, or UC on stable infliximab for ≥ 6 mos
Switching from infliximab to infliximab-dyyb noninferior to continued treatment with infliximab
Prespecified noninferiority margin: 15%
100 80 61 61 60
Pts (%) 40 30 26 20
53/
202
61/
206
123/
202
126/
206
CD, Crohn’s disease; Ps, chronic plaque psoriasis; PsA, psoriatic arthritis; RA, rheumatoid arthritis; SpA, spondyloarthritis; UC, ulcerative colitis.
n/N =
Disease
Worsening*
Remission
Continue infliximab
Switch to infliximab-dyyb
*Primary endpoint.
Slide credit: clinicaloptions.com
Jørgensen KK, et al. Lancet. 2017;389:

14. DANBIO: No Change in Disease Activity With Switch to Infliximab-dyyb
Comparison of disease activity 3 mos prior to and after switch from infliximab to infliximab-dyyb in pts with RA, PsA, or AxSpA in DANBIO registry (N = 802)
Follow-up, 413 days: median age, 55 yrs; median prior infliximab, 6.8 yrs
No observed negative impact of switch on disease activity
Withdrawal, n = 132 (lack of effect, 54%; AEs, 28%)
Median Disease Activity by Diagnosis
3 Mos Prior
At Switch
3 Mos After RA
DAS28
HAQ (0-3)
CRP, mg/L
Pt’s global score, mm
(n = 319)
2.2
0.6 4 26
(n = 310)
4.5 25
(n = 309) 5
PsA
(n = 94)
2.5
0.5 32
(n = 92)
2.3 34
2.4 3 35
AxSpA
BASDAI, mm
ASDAS
(n = 202) 23
1.8
(n = 199) 24 31
2.0
(n = 204) 27
AE, adverse event; ASDAS, Ankylosing Spondylitis Disease Activity Score; AxSpA, axial spondyloarthritis; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; CRP, C-reactive protein; DAS28, 28 Joint Disease Activity Score (four variables, CRP-based); HAQ, Health Assessment Questionnaire; RA, rheumatoid arthritis; PsA, psoriatic arthritis.
Slide credit: clinicaloptions.com
Glintborg B, et al. Ann Rheum Dis. 2017;76:

15. Go Online for More CCO Coverage of Biosimilars!
ClinicalThought commentaries on integrating biosimilars into practice
clinicaloptions.com/immunology