Lucio SD, et al. Am J Health Syst Pharm. 2013;70:2004-2017. FDA. Considerations in demonstrating
interchangeability with a reference product: guidance for industry. January 2017.
Manufacturing Drift: Originators Are
Biosimilars of Themselves
What is Acceptable Variation? Lot-to-Lot Variation of Innovator Products: Rituximab
Glycan Mapping
Significant change in ADCC likely related to the altered glycan map for unfucosylated G0 glycans
• Over the life of a biopharmaceutical changes are invariably introduced into manufacturing
– Improve yield
– Changes in sourcing of components
– Changes in production scale
• Manufacturing changes are governed by ICH Q5E regulation recognized by both the FDA and EMA
– Guidance aims to minimize the drift inherent in a reference product
– The regulations provide guidance to conduct a comprehensive assessment on the impact to the
product
• Key requirements include:
– Analytics should be selected and optimized to maximize the likelihood of detecting potential
differences
– Apply more than 1 analytical procedure to evaluate the same quality to maximize the detection of
potential differences
– Evaluate critical control points in the manufacturing process that affect product characteristics
International Council on Harmonisation. Guidance for industry: Q5E comparability of biotechnological/biological products subject to change
in their manufacturing process. June 2005.
Foundations of Biosimilarity:
Preclinical Assessment
Preclinical Assessment: Structure and Function
FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. April 2015.
Preclinical Assessment: 4 Levels of Analytical Characterization
FDA. Clinical pharmacology data to support a demonstration of biosimilarity to a reference product: guidance for industry.
December 2016.
Establishing Fingerprint-Like Similarity: Physiochemical Properties
FDA. Clinical pharmacology data to support a demonstration of biosimilarity to a reference product: guidance for industry.
December 2016.
Analytics for Characterization of Rituximab Biosimilar GP2013 and Originator Rituximab
Secondary and tertiary structure Circular dichroism, Fourier transform infrared (FTIR) spectroscopy, hydrogen deuterium exchange
(HDX)-MS, x-ray
General charge heterogeneity and amino 0K variant, acidic variants, basic variant, Gln-variant, Lys-variant, amidated proline Cation exchange chromatography digested/undigested
acid modifications
Glycosylation Galactosylation, sialylation, mannosylation, afucosylation, bisecting GlcNAc, NGNA, α-galactose, Normal-phase HPLC-fluorescence
qualitative glycosylation pattern
Size heterogeneity Monomer, low-molecular weight (LMW) and high molecular weight (HMW) variants (aggregates) Size exclusion chromatography, asymmetric flow field flow fractionation
Heavy chain (HC), light chain (LC), aglycosylated HC, clipped variants Reduced capillary electrophoresis with sodium dodecyl sulfate (CE-SDS)
Monomer, LMW (eg, half antibodies (HL) and HHL variant) and HMW variants Nonreduced CE-SDS
Functional characterization
Target and receptor binding FcRn binding; FcγR binding (FcγRIa, FcγRIIa, FcγRIIb, FcγRIIIa[F158], FcγRIIIa[V158], FcγRIIIb) Surface plasmon resonance
1D 1H NMR Spectra
Electrophoresis of Nonreduced
Proteins, Highlighting Ig Chains
Functional Assays
Parameter, % Target ADCC CDC Apoptosis
Binding
GP2013 97-108 86-105 99-111 88-97
Reference 96-110 70-132 95-127 88-102
range
2-sided P value < .0001 < .0001 < .0001 < .0001
Visser J, et al. BioDrugs. 2013;27:495-507.
Animal Toxicity Studies
• Useful when there are unresolved questions about the safety of the candidate
biosimilar based on studies of structure/function
• Utilize comparative animal toxicology
• “The scope and extent of any animal toxicity studies will depend on information about
the reference product, information about the proposed product, and the extent of
known similarities or differences between the two.”
FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. April 2015.
Clinical Evaluation of Biosimilars
Moving a Biosimilar Into the Clinic: Equivalent Pharmacokinetics is the First Critical Hurdle
FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. April 2015.
Isakov L, et al. Am J Ther. 2016;23:e1903-e1910.
Clinical Studies: FDA
• Specific clinical study design will depend on what residual questions remain
– Clinical evaluation should evaluate relevant and sensitive endpoints for PK (and PD, if possible)
• Trials do not need to establish primary efficacy and safety of the biosimilar
• Safety and efficacy have been established by the originator
– Clinical studies should be designed to demonstrate neither decreased nor increased activity
– The extent of study results will differ between ‘highly similar’ and ‘fingerprint similarity’
• Clinical immunogenicity
– Goal is to evaluate potential differences in incidence and severity of immune responses using
endpoints such as antibody formation (binding, neutralizing), cytokine levels, etc.
– FDA recommends a comparative parallel study in treatment-naive patients
• May also need to descriptively assess major risk of immunogenicity, hypersensitivity, or other
reactions following a single crossover from reference to biosimilar
FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. April
2015.
Immunogenicity Concerns
FDA. Guidance for industry: immunogenicity assessment for therapeutic protein products. August 2014.
Extrapolation and Interchangeability
Extrapolation: Current Use and Role in Biosimilar Development
• Extrapolation: expansion of use to other approved indications based on clinical and safety data from
one indication
• Extrapolation is an established principle that has historically used by regulators
– Major process changes in manufacture of an originator typically requires a trial to confirm
equivalent clinical activity in a single indication
• Trial design is similar to that used in evaluation of biosimilars
• Extrapolation is provided to all approved indications
– Alteration in route of administration (eg, IV to SC)
• Typically one study demonstrates equivalent safety and efficacy
• Extrapolation is provided to other approved uses
• Extrapolation is key concept in the development of biosimilars
– Requires similar MOA, PK, PD, and patient populations
– Potentially provides substantial saving in drug development
FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. April 2015.
Framework for Extrapolation
Quantitative evidence
Disease progression: Disease models to characterize differences in progression between groups.
PK/PD: Modeling simulation with existing data to investigate the relationship between PK/PD, age, and other important
variables.
Clinical response: Quantitative synthesis or modeling of all existing data (in vitro, preclinical, and clinical) to predict degree of
similarity between source and target population in clinical response (efficacy, some safety aspects).
FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. April
2015. EMA. Concept paper on extrapolation of efficacy and safety in medicine development. September 2012.
Weise M, et al. Blood. 2014;124:3191-3196.
What a Clinician Wants Before They Feel Comfortable With Extrapolation
FDA. Considerations in demonstrating interchangeability with a reference product: guidance for industry. January 2017.
Barlas S. P T. 2017;42:509-512.
FDA. Prescribing biosimilar and interchangeable products. October 2017.
Summary
• Biologics are complex molecules and therefore identical ’generic’ copies are not possible
– Lot-to-lot variation of innovator drugs is inevitable and is closely regulated
• Regulations to enable the development of biosimilars were created to improve access to essential
medications
• Biosimilars are biological copies of an innovator with no meaningful differences in safety and efficacy
• The development of biosimilars is the inverse of innovator molecules, with the preclinical development
being the key to success
• Clinical trials to compare to the innovator are not aimed at establishing safety and efficacy in an
indication – this was accomplished by the innovator
– The goal is to establish equivalence in PK and PD endpoints and show clinical activity within an
accepted equivalence margin
• Major cost saving in the development of biosimilars comes from extrapolation to scientifically and
clinically justified indications already approved for the innovator
Latest Updates of Supportive Oncology
Biosimilars and Integration Into Practice
Jeffrey Crawford, MD
George Barth Geller Professor for Research in Cancer
Co-Program Leader, Solid Tumor Therapeutics
Program
Duke Cancer Institute
Durham, North Carolina
Preclinical Preclinical
Molecular
Molecular Characterization
Low Characterization High
Immunogenicity
a
Convincing evidence to
+
thw
Preclinical
Bio
Molecular Characterization
Image adapted from Sherman RE. Biosimilar Guidance Webinar. February 15, 2012.
1. EMA. Concept paper on extrapolation of efficacy and safety in medicine development. 2012.
2. Weise M, et al. Blood. 2012;120:5111-5117. Slide credit: clinicaloptions.com
First FDA-Approved Biosimilar:
Filgrastim-sndz—Analytics, PK/PD, Safety
Approved March 6, 2015; first FDA-approved oncology-related biosimilar
Structural and functional studies demonstrated same amino acid sequence
as US-licensed filgrastim
Biological activity, receptor binding and physiochemical properties, product-
related substances and impurities, and stability profile are highly similar to
US-licensed filgrastim, notwithstanding minor differences in clinically inactive
components
5 studies in healthy subjects evaluating ANC, Cmax, and CD34+ cell counts
demonstrated PK/PD similarity with US-licensed and EU-approved filgrastim
Safety data in 204 healthy subjects and 214 pts with breast cancer were
similar to US-licensed and EU-approved filgrastim
37Drugs Advisory Committee Meeting. 2015.
FDA. Oncologic Slide credit: clinicaloptions.com
Comparability of Biosimilar Filgrastim With
Originator Filgrastim: Protein Characterization
Protein characterization by NMR spectroscopy
10 9 8 7 6 5 4 3 2 1 0 ppm
Sorgel F, et al. BioDrugs. 2015;29:123-131. Slide credit: clinicaloptions.com
Comparability of Biosimilar Filgrastim With
Originator Filgrastim: Receptor-Binding Affinities
Biosimilar Filgrastim Originator Filgrastim
250 250
200 200
-50 -50
0 200 400 600 800 1000 1200 1400 0 200 400 600 800 1000 1200 1400
Time (Secs) Time (Secs)
Sorgel F, et al.39
BioDrugs. 2015;29:123-131. Slide credit: clinicaloptions.com
Comparability of Biosimilar Filgrastim With
Originator Filgrastim: Pharmacokinetics
Analysis: no significant differences between the biosimilar and originator product
100
Geometric Mean Filgrastim 90
80
Concentration (ng/mL)
70 Biosimilar filgrastim
60 US-licensed originator filgrastim
50
40
30
20
10
0
0 4 8 12 18 20 24 28 32 36 40 44 48
Hrs
Sorgel F, et al.40
BioDrugs. 2015;29:123-131. Slide credit: clinicaloptions.com
Biosimilar Filgrastim (Filgrastim-sndz) vs
Reference Filgrastim: ANC Recovery
N = 218 pts with breast cancer receiving myelosuppressive chemotherapy
Filgrastim 5 µg/kg/day administered over 6 chemotherapy cycles
Conclusion: biosimilar filgrastim noninferior to originator filgrastim at improving ANC counts
Time Course of ANC in Cycle 1 x Biosimilar (cycle 1):
30
biosimilar plus
biosimilar-originator
ANC (109/L)
Reference (cycle 1)
20 x originator plus
x originator-filgrastim-sndz
x
10 x x
ANC recovery x
x x x x
≥ 2 x 109/L 5 x x x
after ANC nadir 2 x
x x
0
Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 21
Biosimilar, n 97 97 100100101 99 98 97 98 83 51 16 6 5 4 99
Reference, n 102102103103102103103102102 97 43 15 7 4 2 102
Weise M, et al.46
Blood. 2014;124:3191-3196. Slide credit: clinicaloptions.com
ODAC Recommendation for FDA Approval of
Biosimilar Epoetin Alfa for Anemia
On May 25, 2017, the FDA Oncologic Drugs Advisory Committee
(ODAC) recommended approval of an epoetin alfa biosimilar
across all indications of originator biologics for treatment of
anemia
– Preclinical data supported similarity to epoetin alfa in structure,
function, and mechanism of action
– Clinical PK/PD, immunogenicity similar to epoetin alfa
– 2 phase III trials showed comparable safety and efficacy in the
treatment of pts with chronic kidney disease and anemia
Final FDA approval pending
47Drugs Advisory Committee briefing document. May 25, 2017.
FDA Oncologic Slide credit: clinicaloptions.com
FDA-approved Biosimilars (Supportive, Non-Oncology)
Drug Approval Comparative Phase III Clinical Trial Data
Biosimilar Indications
Class Date Leading to Approval
PIONEER: noninferiority to prevent
Filgrastim-sndz [1]
rG-CSF 2015 Prevention of severe neutropenia neutropenia in breast cancer pts on
myelosuppressive chemotherapy[2]
TNF-α Crohn’s, ulcerative colitis, RA, PLANETRA: equivalent ACR20 in RA pts [5]
Infliximab-dyyb[3,4] 2016
inhibitor AS, PsA, plaque psoriasis PLANETAS*: equivalent ASAS20 in AS pts [6]
TNF-α Crohn’s, ulcerative colitis, RA, Equivalent ACR20 in RA pts[8,9]
Infliximab-abda[7] 2017
inhibitor AS, PsA, plaque psoriasis
TNF-α Crohn’s, ulcerative colitis, RA, REFLECTIONS B537-02: Equivalent ACR20
Infliximab-qbtx[10] 2017
inhibitor AS, PsA, plaque psoriasis in RA pts[11]
TNF-α 2016; ongoing RA, AS, PsA, EGALITY: equivalent PASI75 in pts with
Etanercept-szzs[3,4]
inhibitor patent litigation plaque psoriasis, polyarticular JIA plaque psoriasis[12]
Crohn’s, ulcerative colitis, RA, Equivalent ACR20 in RA pts[14]
TNF-α 2016; ongoing
Adalimumab-atto[13] AS, PsA, plaque psoriasis, JIA Equivalent PASI improvement in pts with
inhibitor patent litigation
psoriasis[15]
Crohn’s, ulcerative colitis, RA, VOLTAIRE-RA: Equivalent efficacy, safety,
TNF-a 2017; ongoing
Adalimumab-adbm [16]
AS, PsA, plaque psoriasis, JIA and immunogenicity in mod-to-severe RA
inhibitor patent litigation
pts, including pts switching agents [17]
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 PI. 2017. 8.
Choe JY, et al. ACR/ARHP 2015. Abstract 2056. 9. Choe JY, et al. Ann Rheum Dis. 2017;76:58-64. 10. Infliximab-qbtx PI. 11.
Cohen SB, et al. Arthritis Rheumatol. 2017; 69 (suppl 10). 12. Griffiths CE, et al. Br J Dermatol. 2017;176:928-938.13. Kaur P, et
al. Ann Rheum Dis. 2017;76:526-533. 14. Cohen S, et al. Ann Rheum Dis. 2017;76:1679-1687. 15. Papp K, et al. J Am Acad Slide credit: clinicaloptions.com
Dermatol. 2017;76:1093-1102. 16. Adalimumab-adbm PI. 17. Thatcher N, et al. ASCO 2016. Abstract 9095.
Selected Supportive Care Biosimilars in the
Pipeline
Originator Drug Paten
Indication Biosimilars with Phase III Clinical Trials
Biologic Class t Exp.
EMA-approved epoetin alfa biosimilar
Epoetin alfa[1,2] r-EPO 2013 Anemia recommended by FDA panel but not
approved; others registered/ongoing
EMA-approved filgrastim biosimilar accepted
rG-
Filgrastim[1,2] 2013 Neutropenia for FDA review
CSF
Registered trial for MK-4214 ongoing
rG- 2 pegfilgrastim biosimilars accepted for FDA
Pegfilgrastim[1,2] 2015 Neutropenia
CSF review, including CHS-1701
1. Stevenson JG, et al. Ann Pharmacother. 2017;51:590-602.2. Butteri E, et al. Eur J Cancer. 2018;89:49-55. Slide credit: clinicaloptions.com
Myeloid Growth Factors for Neutropenia:
Best Practices
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN
Guidelines®) for Myeloid Growth Factors. v1.2018. © National Comprehensive Cancer Network,
Inc 2018. All rights reserved. Accessed March 12, 2018. To view the most recent and complete
version of the guideline, go online to NCCN.org.
Biosimilars: Issues in Practical Use
Formulary analysis
Therapeutic substitution
Pharmacovigilance
Economics of biosimilars
Provider and pt education
Lucio SD, et al. Am J Health Syst Pharm. 2013;70:2004-2017. Slide credit: clinicaloptions.com
Latest Updates of Therapeutic Oncology
Biosimilars and Integration Into Practice
35
30 13.6
25 44.1
20
15
23.4
10
5
0
2011 New Branded Branded LOE Generics 2016
Therapies Volume Price
Since 2011
IQVIA, MIDAS Q4 2016; IQVIA Institute for Human Data Science, March 2017. Slide credit: clinicaloptions.com
Cost of Biologic Anticancer Agents
Bortezomib Temsirolimus
90 Brentuximab Trastuzumab 78% over 10 years[1]
80 Cetuximab Ziv-aflibercept
70 Denosumab Inflation Cost of biologics[2]
60 Ipilimumab Health-related
Ofatumumab inflation
50
Panitumumab
‒ 2005: 32% of $9.5B,
40
30 Pertuzumab Medicare Part B
20
10 ‒ 2014: 62% of $18.5B,
0 Medicare Part B
-10
-20
-30
0 05 006 007 008 009 010 011 012 013 014 015 016 018
2 2 2 2 2 2 2 2 2 2 2 2 2
Yr
1. Gordon N, et al. J Clin Oncol. 2017;36:319-325. 2. Nabhan C, et al. JAMA Oncol. 2018;4:241-247. Slide credit: clinicaloptions.com
Where Will Cost Control Come From?
Which of the Clinical standardization 63%
ACCC. 2017 Trending Now in Cancer Care Survey. Slide credit: clinicaloptions.com
FDA-Approved Therapeutic
Oncology Biosimilars
FDA-approved Therapeutic Oncology
Biosimilars
Drug Approval Comparative Phase III Clinical
Biosimilar Indications
Class Date Trial Data Leading to Approval
mCRC, NSCLC, Comparable ORR, grade ≥3
Bevacizumab- VEGF Sept.
glioblastoma, mRCC, AEs, and TEAEs[1]
awwb[1] inhibitor 2017
cervical
Breast, met HERiTAge: equivalent ORR and
Trastuzumab- HER2 Dec.
gastric/GEJ cancer PFS, and comparable safety to
dkst[2] inhibitor 2017
trastuzumab[2]
1. Stevenson JG, et al. Ann Pharmacother. 2017;[Epub ahead of print]. 2. Trastuzumab-dkst PI. Slide credit: clinicaloptions.com
Regulatory Status of Bevacizumab and
Trastuzumab: Originators and Biosimilars
Patent for branded bevacizumab expires in 2020
Bevacizumab biosimilar: bevacizumab-awwb (ABP-215)
– FDA approval in September 2017
Patent for branded trastuzumab expires in 2019
Trastuzumab biosimilar: trastuzumab-dkst (MYL-14010)
– FDA approval in December 2017
42.9 44.3
26.2 23.0
Median
Agent ORR, %
DoR, Mos
4.0 3.6
Bevacizumab-awwb (n = 324) 39 5.8
Bevacizumab (n = 314) 41.5 5.6 AE SAE Fatal AE
Grade ≥ 3
FDA Advisory Committee document. ABP 215 – Bevacizumab biosimilar candidate. Slide credit: clinicaloptions.com
Bevacizumab-awwb: Indications
Metastatic colorectal cancer
– First- or second-line treatment combined with IV 5-FU-based chemotherapy
– Second-line treatment with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy after
progression with first-line bevacizumab regimen
– Not indicated for the adjuvant treatment of surgically resected colorectal cancer
Non-squamous NSCLC
– First-line treatment of unresectable, locally advanced, recurrent, or metastatic NSCLC in combination with
carboplatin/paclitaxel
Glioblastoma
– Second-line treatment in progressive disease following prior therapy, based on improvement in ORR
Cervical cancer
– In patients with recurrent, persistent, or metastatic disease, in combination with paclitaxel/cisplatin or paclitaxel/topotecan
FDA. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm576112.htm.
Trastuzumab in Breast Cancer
Trastuzumab Biosimilars: Considerations
1. Stevenson JG, et al. Ann Pharmacother. 2017;51:590-602.2. Butteri E, et al. Eur J Cancer. 2018;89:49-55.
3. Rugo HS, et al. Cancer Treat Rev. 2016;46:73-79. 4. Panesar K. US Pharm. 2016;41:26-29. Slide credit: clinicaloptions.com
Selected Trastuzumab Biosimilars in 1:1
Randomized Phase III Trials
Agent Study Design Endpoints Results Researcher
Conclusions
ABP 980 ABP 980 vs OriT (both + paclitaxel q3w x 4 1st: RD, RR of pCR in ABP 980 vs ABP 980 and OriT
(LILAC)[1] cycles neoadjuvant, then w/out paclitaxel pCR in breast OriT: 48.0% vs 40.5%; clinically equivalent
q3w to 1 yr adjuvant) on pCR in patients with tissue + axillary RD: 7.3%; RR: 1.19%. in neoadjuvant
HER2+ EBC (N=725; n = 696 in pCR lymph nodes. 2nd: Grade ≥3 TEAEs: setting for these
evaluable pop.). safety 14.8% vs 14.1%. patients.
PF-05280014 PF-05280014 vs T-EU (8 mg/kg→6 mg/kg 1st: steady state Ctrough >20 µg/mL in PF- PF-05280014
(REFLECTIONS q3w x 6 cycles w/docetaxel + carboplatin) in drug concentration 05280014 vs T-EU: showed similarity to
B327-04)[2] patients with HER2+ EBC (N=226), stratified Ctrough >20 µg/mL 92.1% vs 93.3%. pCR, T-EU in safety and
by hormone receptor status, primary tumor at Cycle 5; 2nd: 47% vs 50%; ORR, immunogenicity, and
size. ORR, pCR 88.1% vs 82.0%. noninferiority in PK
PF-05280014 First-line PF-05280014 vs T-EU (first dose 4 1st: ORR. 2nd: PF-05280014 vs T-EU: PF-05280014 similar
(REFLECTIONS mg/kg; then 2 mg/kg weekly until at least safety, tumor ORR = 0.940; Safety, to T-EU for efficacy,
B327-02)[3] week 33 (both + paclitaxel) in patients with control, PK, PK, immunogenicity immunogenicity,
HER2+ MBC (N=707). immunogenicity equivalent. safety, and PK.
SB3[4] SB3 vs OriT (8→6 mg/kg q3w x 8 cycles) + 1st: pCR in breast bpCR in SB3 vs OriT: SB3 comparable to
DOC and FEC (4 cycles) neoadjuvant in pts tumor. 2nd: safety, 51.7% vs 42.0%.PK, OriT for safety, PK,
w/HER2+ EBC or LABC, LVEF ≥ 55% (N = immunogenicity, safety, immunogenicity immunogenicity, and
875)*, then 10 cycles adjuvant SB3 vs OriT. EFS, OS equivalent. efficacy.
https://education.nccn.org
clinicaloptions.com/oncology