Biosimilar Trastuzumab: The Heritage Trial

Hope S. Rugo, MDProfessor of MedicineDirector, Breast Oncology and Clinical Trials EducationUniversity of California San Francisco Comprehensive Cancer Center

Differences Between Chemical Drugs and Biologics

Chemical Drugs Biologics

Size Small, low molecular weight Large, high molecular weight

Structure Simple, well-defined Complex, heterogeneous

Manufacturing• Reproducible chemical reactions

• Identical copies can be made

• Living cells or organisms

• Impossible to ensure identical copies

Characterization Completely characterizedImpossible to fully characterize molecular composition

Stability StableUnstable, sensitive to external conditions

Immunogenicity Mostly nonimmunogenic Immunogenic

Declerck PJ. Generics and Biosimilars Journal. 2012;1(1)13-16.

• Biologics represent approximately 50% of the pharmaceutical market in oncology

• Biologics play a critical role in clinical care:

– Supportive care

• Myeloid growth factors

• Erythropoietin-stimulating agents

– Active therapy

• Monoclonal antibodies

• Antibody-drug conjugates

• Cytokines

Nowicki M. Kidney Blood Press Res. 2007;30:267-272.

Biologics in Oncology

1. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. London, UK: EMA; 2014. 2. US Food and Drug Administration. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Silver Spring, MD: FDA; 2015. 3. World Health Organization. Guidelines on evaluation of similar biotherapeutic products (SBPs). Geneva, Switzerland: WHO; 2014. http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf?ua=1. Accessed January 10, 2018.

What Is a Biosimilar?

Biosimilars are medicinal products that have received regulatory approval based on an overall assessment

of similarity to an existing biologic medicine1-3

Highly similar to an approved biologic product (reference product)

No clinically meaningful differences in terms of quality, safety, and effectiveness from the reference

product

Biosimilar ProductReference Product

IMS Global Oncology report . https://morningconsult.com/wp-content/uploads/2016/06/IMS-Institute-Global-Oncology-Report-05.31.16.pdf.

https://www.iqvia.com/institute/reports/the-global-use-of-medicine-in-2019-and-outlook-to-2023

Biologics accounted for >55% of antineoplastic drug costs in 2011 in the US but just over

half (55%) of new targeted therapies are available in pharmerging countries

Access To New Oncologic Treatments VariesWidely Across the Globe

2015 Availability of New Oncology Medicines Launched 2010-2014

The Hope: Effective and safe biosimilars will help to alleviate the substantial burden on healthcare systems

from biologic medications by stimulating price competition and improving patient access to

important and life-saving treatments

PD, pharmacodynamics; PK, pharmacokinetics.

1. Schneider CK, et al. Nat Biotechnol. 2012;30:1179-1185. 2. McCamish M. Presented at EMA Workshop on Biosimilars; London; October 2013. 3. Berghout A. Biologicals. 2011;39:293-296. 4.

US Food and Drug Administration. Abbreviated New Drug Applications (ANDA): Generics.

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/. Accessed January 3, 2016.

Development PathwaysStandard Biologics1,2

Nonclinical

Clinical pharmacology

PK/PD

Analytical

Clinicalstudies

Analytical

Bio-equivalence

in HealthyVolunteers

Small Molecule Generics1,4

Biosimilars1-3

Nonclinical

Comparative clinical

pharmacologyPK/PD

Analytical

Comparative Clinicalstudies

Confirm safety profile and efficacy in a disease population (dose ranging not necessary)

The Goal of Biosimilar Development Is to Demonstrate That There Are No Clinically

Meaningful Differences Based on the Totality of Evidence, Not to Reestablish Benefit1-4

Reference Biologics

NOT Identical

Reference BiologicsHighly Similar

Manufacturing/Process ChangesFDA: Demonstration of Comparability

Biosimilars

Reference Biologics

Variations Over Time

IdenticalGenerics Small Molecule Drugs

Generics

Biosimilars

Highly Similar

No Adverse Impact Upon Safety or Efficacy

of the Drug Product

Identical Copies of Biologics Cannot Be Made

• Variations in the reference product quality attributes over time can be used to evaluate comparability of the biosimilar product

McCamish M, Woollett G. MAbs. 2011;3(2):209-217.

Variation of Biologic Quality Attributes Following Expected Manufacturing Changes

Reference product

at approval

Range of variation of biologic

quality attributes

Reference product

following first postapproval

manufacturing change

Biosimilar product

Acceptable range of variation

Reference product

following second

postapproval manufacturing

change

Biosimilar product

Variation of Biologic Quality Attributes Over Time

Drifts in ADCC-Related Quality Attributes of Originator Trastuzumab:

Impact on Development of a Trastuzumab Biosimilar

Kim S, et al. MAbs. 2017; 9(4): 704–714.

trastuzumab

trastuzumab

trastuzumab

trastuzumab

trastuzumab

trastuzumab

trastuzumab

trastuzumab

Clinical Requirements

• At least one clinical pharmacokinetic study for establishing

bioequivalence to the reference product

• At least one study of clinical safety, efficacy, and immunogenicity to

establish clinical equivalence

– Typically performed in the most sensitive population

– Establishes similarity in efficacy

– Immunogenicity and safety data

• Additional clinical trials as necessary

– To rule out residual uncertainty

PK, pharmacokinetics; PD, pharmacodynamics.

1.. Weise M, et al. Blood. 2012;120(26):5111-5117. 2 Windisch J. Int J Clin Rheumatol. 2015;10(6):1-10. 3. US Food and Drug Administration. Scientific Considerations in Demonstrating Biosimilarityto a Reference Product: Guidance for Industry. Silver Spring, MD: FDA; April 2015

Extrapolation: After Biosimilarity Is Established, AllowsPotential Approval for Nonstudied Indications1-3

Biosimilarity Established Basedon Totality of Evidence1,2 Extrapolation for Biosimilars

Extrapolation builds on the thorough analysis of similarity between the biosimilar and reference biologic

supported by the scientific evidence generated in robust analytical, nonclinical, and clinical comparability

studies. Together with the well-known understanding of the reference biologic, this evidence is carefully

analyzed to support scientific justification of extrapolated indications.1,2

Comparative Clinical Studies

Comparative Clinical Pharmacology (PK/PD)

Comparative Nonclinical

Comparative Analytical

SCIENTIFIC JUSTIFICATION to support extrapolation to each

approved indication of the reference biologic1,3

Extrapolation indications

MOA, Mechanism of action

1. Weise M, et al. Blood. 2014;124(22):3191-3196. 2. European Medicines Agency. Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-clinical and Clinical Issues. London, UK: EMA; 2014. 3. US Food and Drug Administration. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Guidance for Industry. Silver Spring, MD: FDA; April 2015.

The Basis for Scientific Justification

Experience With the Reference Biologic1

• The molecular structure of the reference biologic forms the basis for its clinical effect

• Established clinical profile may define any differences between indications

The Totality of Evidence1,2

• Demonstrates highly similar structure and function of the biosimilar and the reference biologic molecules

• Clinical efficacy, safety, and immunogenicity in a key indication

2,3

Currently Approved Oncology Biosimilars in the United States….

And More in Development!Product Approval Date

trastuzumab-anns June 2019

trastuzumab-qyyp March 2019

trastuzumab-dttb January 2019

trastuzumab-pkrb December 2018

rituximab-abbs November 2018

pegfilgrastim-cbqv November 2018

filgrastim-aafi July 2018

pegfilgrastim-jmdb June 2018

trastuzumab-dkst December 2017

bevacizumab-awwb September 2017

filgrastim-sndz March 2015

U.S. Food and Drug Administration. Biosimilars > Biosimilar Product Information. https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/ucm580432.htm. Accessed June 20, 2019.

Integration Into Cancer Care

• Supportive care biosimilars (eg, filgrastim, peg-filgrastim) are acceptable to

clinicians and patients

– Biosimilar filgrastim in active clinical use

• Biosimilar cancer therapeutics (eg, rituximab, trastuzumab) have a higher bar

for acceptance

– Clinical trials with a short-term efficacy endpoint in a highly sensitive population

– PK and PD endpoints

– Immunogenicity

– Safety

– Post-approval surveillance

Comparative Clinical Studies

• Purpose: Exclude any clinically relevant differences

between the biosimilar and the reference product and

to address any residual uncertainly about biosimilarity

• Conducted stepwise

– Immunogenicity studies followed by comparative clinical

efficacy and safety

– Extrapolation is a critical concept

Selecting a Valid Clinical Endpoint• Critical and challenging for biosimilars

• Sensitive endpoints are recommended

Patient Criteria• Overall survivalDisease Criteria• Objective response rate• Disease free survival• Disease free progression• Pathological complete response

Endpoints for biosimilar clinical trials• Clinically relevant, short-term objective

measure able to detect differences• Continuous endpoints may be preferred over

binary endpoints• Length of the study should be sufficient to

allow for adequate safety and immunogenicity assessments

EMA-2. Committee for Medicinal Products for Human Use (CHMP). Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-clinical and Clinical Issues. London: European Medicines Agency; 2014.WHO-2. WHO Guidelines on evaluation of monoclonal antibodies as similar biotherapeutic products (SBPs), 2016. He K, et al. Clin Cancer Res. 2016 Nov 1;22(21):5167-5170. Gourgou-Bourgade S,et al. Ann Oncol. 2015;26(5):873-9. Fiteni F, et al. J Visc Surg. 2014;151(1):17-22. Pivot X, et al. 2017. Available at: http://meetinglibrary.asco.org/record/145553/abstract.

Optimal Clinical Trial Setting?

• Most treatment naïve

• Long drug exposure for a majority to assess safety and immunogenicity

• Highly sensitive endpoint (ORR) that allows evaluation of secondary endpoints (PFS/OS) in realistic time frame

• ORR correlates with PFS and OS in HER2+ disease

• All treatment naïve

• Short-term endpoint of pCR, one year drug exposure

• DFS and OS are long-term endpoints

• Post surgery treatment may impact long-term endpoints

First-line metastatic trials Neoadjuvant trials

Trastuzumab Biosimilars: The New Frontier

• Over-expression of HER2 implicated in the pathophysiology of ~ 25%

of breast and 18% gastric and gastroesophageal tumors

• Trastuzumab has changed the treatment course for HER2+ tumors

– In metastatic breast cancer, improves PFS, OS, and ORR

– In early stage breast cancer, improves DFS and OS

– As neoadjuvant therapy, improves pCR and DFS rates

– Improves PFS, OS, and ORR in metastatic gastric cancer

– Gold standard as treatment of early and late-stage HER2+ breast

cancer

– Is well tolerated with modest and manageable toxicity

HERITAGE: First-line Trastuzumab vs Biosimilar MYL-1401O

in HER2+ Metastatic Breast Cancer

• Primary endpoint (week 24): ORR

• Secondary endpoints (week 48): tumor progression rate, PFS, OS

HER2+ metastatic breast cancer, no prior tx in

metastatic setting. Stratify for time to mets, ER/PR status, and taxane used (N = 500)

MYL-1401O 6 mg/kg IV Q3W* + taxane† for minimum of 8 cycles

(n = 249)

Trastuzumab 6 mg/kg IV Q3W* + taxane† for minimum of 8 cycles

(n = 251)

Part 1Part 2

Continue assigned therapy if achieved at least SD

MYL-1401O 6 mg/kg IV Q3W* + taxane†

Trastuzumab 6 mg/kg IV Q3W* + taxane†

Week 24

Until PD, unacceptable

toxicity, or death

Multicenter, Randomized, Double-blind Phase III Equivalence Study

*After usual loading dose. †Physician choice of docetaxel or paclitaxel

Rugo HS, et al. JAMA. 2017;317:37-47 and ASCO 2018, Waller et al, ASCO 2019

Designed per FDA and EMA guidelines to detect any potentially clinically meaningful differences between biosimilar and originator trastuzumab

Key Baseline and Disease Characteristics: Comparable Between Treatment Groups

Patient characteristicsTrastuzumab-dkst

N=230Trastuzumab

N=228Age category, n(%)

<50 years 74 (32.2) 86 (37.7)≥50 years 156 (67.8) 142 (62.3)

Race, n(%)Asian 70 (30.4) 72 (31.6)Black 1 (0.4) 2 (0.9)White 159 (69.1) 154 (67.5)

Prior treatment (adjuvant), n(%)Trastuzumab 22 (9.6) 16 (7.0)Taxane 46 (20.0) 42 (18.4)

Assigned taxane, n(%)Docetaxel 193 (83.9) 192 (84.2)Paclitaxel 35 (15.2) 32 (14.0)

Visceral metastases, n(%)Yes 172 (74.8) 185 (81.1)No 58 (25.2) 43 (18.9)

Primary Endpoint:

Ratio of ORR (90% CI) at Week 24 Within the Prespecified Equivalence

Margin Supports Similar Efficacy

ITT, intention-to-treat; ORR, overall response rate; RECIST, Response Evaluation Criteria In Solid Tumors. aRatio of best ORR (defined as a complete or partial response per RECIST 1.1) by week 24 based on cumulative assessment done by a single, central, blinded oncologist.

Rugo et al. JAMA. 2017;317:37-47 and ASCO 2018

Parameter

Trastuzumab-dkst N=230

Trastuzumab N=228

ORR, n (%) 161 (70.0) 146 (64.0)

Ratio of ORR (90% CI) 1.09 (0.981, 1.218)

Difference in ORR (90% CI) 6.00 (-1.26,13.11)

Best ORR at week 24 in the ITT populationa

0.7 0.9 1.1 1.3

Ratio of ORR (90% CI) 1.09 (0.981, 1.218)

Prespecified equivalence margin

0.81 1.24

Stratified by taxane, tumor progression, tumor endocrine status.

Rugo HS, et al. JAMA. 2017;317:37-47 and ASCO 2018

Similar Efficacy Between Trastuzumab-dkst and Trastuzumab

Observed Through 48 Weeks

aStratified by assigned taxane, tumor progression, and tumor endocrine status. bAssessments are ongoing and OS will be calculated after 240

deaths or 36 months.

Progression-free survival Overall survivalb

Trastuzumab-dkst Trastuzumab Trastuzumab-dkst Trastuzumab

Median (95% CI) 11.1 (8.81-11.20)

11.1 (8.60-11.20)

NE NE

Log-rank P value 0.842 + censored 0.131 + censored

Stratified hazard ratio (95% CI)a 0.95 (0.714-1.251) 0.61 (0.360-1.039)

P value 0.694 —

NE, not estimable; OS, overall survival.

Similar Efficacy Between Trastuzumab-dkst and

Trastuzumab Observed Through 48 WeeksProgression-Free Survival Overall Survival (immature)

Trastuzumab-dkst

Log-rank P=0.131 + Censored

1.0

0.8

0.6

0.4

0.2

0.0

Surv

ival

pro

bab

ility

0 4 8 12 16 20

Time, weeks

++++++++++++++++ +++++++++++++++++++

++++

+++ + ++++++++++++ ++ + + ++++++ + ++ +++ +++++++ ++ +++ ++ ++++

++ +++

+ ++++

+

24 28 32 36 40 44 48 52

+++++++++ +

Trastuzumab

Log-rank P=0.842 + Censored

1.0

0.8

0.6

0.4

0.2

0.0

Surv

ival

pro

bab

ility

0 4 8 12 16 20

Time, weeks

24 28 32 36 40 44 48 52

++

+++++++

+++ +++++ + +++++++ ++ + +++++ +++ + ++ +++

+++++++ +

+ ++++++ ++++++++++ + +

++++

+++++ + ++ + + ++

+++

+++

+

Trastuzumab

Trastuzumab-dkst

PFS at Week 48 Correlates with ORR at Week 24

CR, complete response; ORR, overall response rate; PFS, progression-free survival; PR, partial response. Rugo et al, ASCO 2018

• At week 24, 1.3% and 0% of patients demonstrated CR, and 68.3% and 64.0% demonstrated PR, with trastuzumab-dkst and trastuzumab, respectively

• At week 48– An additional 2 patients (1 per group) demonstrated CR and an additional 5 patients demonstrated PR in the trastuzumab group– The confirmed ORR is 70.0% and 66.7% with trastuzumab-dkst and trastuzumab, respectively

Responder

Non-responder

ORR at week 24 with PFS at week 48

50

40

30

20

10

0

Responder Nonresponder

161N 146 69 82

++++++

PFS

at

we

ek

48

, we

eks

ORR at week 24

Trastuzumab-dkst + taxane

Trastuzumab + taxane

ORR at week 24 with PFS probability

Biserial correlation coefficient in the total sample is rb = 0.752

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

PFS

pro

bab

ility

0 10 20 30 40 50

Weeks since randomization

+ +++++ +++++++ + +

+++++++

++++ +++ + +++++++++

+++++++++

+++++

++

+

+++++++

+ +++ + ++++ ++

+

+

+++ ++ ++

+

+++

+++++++++++++

+++++

++

+++

+++

+ Censored

trastuzumab

trastuzumab-dkst

trastuzumab

trastuzumab-dkst

Further Lines of Therapy

Trastuzumab-dkstN=230

TrastuzumabN=228

Systemic therapy, % 38.2 32.6

Antineoplastic agents 34.6 29.9

Endocrine therapy 7.5 10.3

Most commonly used agents, %

Capecitabine 23.2 16.1

Trastuzumab 9.6 10.3

Cyclophosphamide 8.8 8.0

Lapatinib 8.3 4.9

Other HER2-targeted agents, %

Trastuzumab emtansine 1.8 2.2

Pertuzumab 0.4 0

HERITAGE: Overall Survival at 36 Months

Waller CF, et al. Presented at: 2019 American Society of Clinical Oncology. Abstract 1021.

Similar Final Efficacy Between Trastuzumab-dkst and

Trastuzumab Observed Through 36 Months

Progression-free survival Overall survival

Trastuzumab-dkstN=230

TrastuzumabN=228

Trastuzumab-dkstN=230

TrastuzumabN=228

Events 148 142 109 114

Median (95% CI) 11.1 (8.72, 13.78) 11.1 (8.95, 12.67) 35.0 (26.75, 39.88) 30.2 (25.00, 39.86)

Log-rank P value 0.864 0.427

Unstratified hazard ratio (95% CI)

0.98 (0.78, 1.24) 0.90 (0.69, 1.17)

HERITAGE: Safety Profile at Week 24Endpoint

MYL-1401O + Taxane(n = 247)

Trastuzumab + Taxane(n = 246)

Serious AE, % ≥ 1 serious AE Neutropenia Neutropenia with fever Leukopenia Pneumonia

38.127.54.51.61.6

36.225.24.14.92.0

Deaths due to serious AEs, n 4* 4†

Median LFEV values, % (range) Baseline Wk 24 Change from BL to Wk 24

64.0 (51 to 82)63.5 (50 to 81)-1.0 (-13 to 21)

63.0 (51 to 84)63.0 (41 to 82)-1.0 (-19 to 13)

Rugo HS et al. JAMA. 2017;317:37-47.

Incidence of AEs Is Low During Monotherapy

AEs, patients, %

Combination therapy: weeks 1-24 Monotherapy: weeks 24-48Trastuzumab-dkst

+ taxaneN=247

Trastuzumab+ taxaneN=246

Trastuzumab-dkstN=179

TrastuzumabN=163

Neutropenia 57.5 53.3 1.1 2.5Asthenia 21.9 16.3 2.8 1.8Nausea 19.8 13.8 2.2 2.5Edema peripheral 14.2 11.4 0.6 1.8Arthralgia 12.1 4.5 2.8 1.2Vomiting 10.5 7.7 1.7 3.1Urinary tract infection 8.5 6.5 0.6 2.5Upper respiratory tract infection 6.1 1.6 2.2 1.2Infusion-related reaction 6.9 4.5 0 0.6

AE, adverse event; TEAE, treatment-emergent AE.

Only 513 of 5015 total TEAEs (10%) started during monotherapy treatment

HERITAGE: Immunogenicity and Population PK

• Immunogenicity was similarly low for both MYL-1401O and trastuzumab arms

– Overall antidrug antibody rates: 2.4% vs 2.8%, respectively

– Median titer in antibody-positive pts: 2.5 vs 2.3, respectively

• Trough Cmin comparable between arms at Wk 15 (cycle 6)

– Ratio of geometric LSMs: 103.88% (90% CI: 93.7% to 115.11%)

• Population pharmacokinetics similar between MYL-1401O and trastuzumab arms

– Dose-normalized mean Cmax: 0.4321 vs 0.4196 µg/mL/mg, respectively

– Dose-normalized mean AUC: 98.350 vs 94.391 μg·d/mL/mg, respectively

Rugo HS et al. JAMA. 2017;317:37-47.

HERITAGE Study Data in Clinical PerspectiveHERITAGE STUDY HISTORICAL DATA

Endpoint MYL-1401O Herceptin1st line HER2+

MBC

ORR 24 Weeks (Primary) 70% 64% 55-69%1-5

ORR ratio (90% CI): FDA Requirement 1.09 (0.981, 1.218) N/A

ORR difference (95% CI): EMA Requirement 6.0% (-2.64%, 14.45%) N/A

Time to Progression (TTP) 48 Weeks 11.1 Months 11.1 Months11.3 -12.4 Months 1-

5

Overall Survival 48 Weeks 89.1% 85.1% 75%-89% 1-5

Safety & Toxicity Comparable Consistent

Immunogenicity 3.9% 4.4% 3.4%6-7.1%7

Exposure Comparable Consistent

1Slamon DJ, et al. N Engl J Med. 2001;344:783-792., 2Mass RD, et al. Clin Breast CA. 2005;6(3):240-246., 3Marty M, et al. J Clin Oncol. 2005;23(19):4265-4274. 4Baselga J, et al. N Engl J Med. 2012;366:109-119., 5Swain et al, N Engl J Med. 2015;372:724-734. 6Hegg R, et al. Presented at: 2012 ESMO Congress. Abstracts 273P, 7Jackisch C, et al. Annals of Oncology. 2015;26:320-325.

Summary of Phase III Trials for Trastuzumab Biosimilars

SB-3(Trastuzumab-dttb)

ABP-980(Trastuzumab-anns)

CT-P6 (Trastuzumab-pkrb)

MYL-1401O(Trastuzumab-dkst)

PF-05280014(Trastuzumab-qyyp)

Trial NCT02149524 NCT01901146 NCT02162667 NCT02472964 NCT1989676

Disease EBC EBC EBC and Metastatic

Metastatic NeoadjuvantMetastatic

No. of patients 800 725 549 500 225/707

Stage of development

FDA approved(January 2019)

FDA approved(June 2019)

FDA approved(December 2018)

FDA approved(December 2017)

FDA approved (March 2019)

EBC: Early breast cancer

Pharmacovigilance• Safety – As more biosimilars are marketed and market uptake increases, real-world safety and

efficacy data will emerge.

– Post-marketing pharmacovigilance efforts may likely be utilized to monitor safety and efficacy of

biosimilars.

– European Medicines Agency mandated pharmacovigilance monitoring for all approved biosimilars

approved.

• As a result, the European experience, with over 400 million patient days with biosimilars,

suggests that biosimilars would satisfy lingering safety concerns

– There are NO provisions in the Biologics Price Competition and Innovation Act (BPCIA) for

pharmacovigilance plans of biosimilars.

– FDA interchangeability guidance document refers back to documents for all products

• Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (March 2005)

• Postmarketing Adverse Experience Reporting for Human Drug and Licensed Biological Products: Clarification of

What to Report (August 1997)

European_Medicines_Agency.Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. 2014; Rifkin RM, Peck SR. J Oncol Pract. 2017;13(9_suppl):24s-31s; Grampp G, Felix T. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2015; 29: 309–21; AMCP Task Force on Biosimilar Collective Intelligence Systems. Journal of managed care & specialty pharmacy, 2015; 21: 23–34; FDA. Considerations in Demonstrating Interchangeability With a Reference Product Guidance for Industry. May 2019.

Unique Issues Relevant to Biosimilars

• Extrapolation

• Interchangeability

• Naming

Adalimumab-atto

Etanercept-szzs

Filgrastim-sndz*

Infliximab-abda

Bevacizumb-awwb

Infliximab-dyyb

Adalimumab-adbm

Pegfilgrastim-cbqv

Nonproprietary naming of biological products: guidance for industry. FDA.gov. March 2019.

*The suffix –sndz was named prior to the FDA-designation for biosimilar suffixes

Core name FDA-designated suffix must have: No recognizable meaning, 4 letters and lowercase

BOPA, British Oncology Pharmacy Association; EORTC, European Organisation for Research and Treatment of Cancer; FN, febrile neutropenia; NHS, National Health Service.

1. Aapro MS, et al. Eur J Cancer. 2011;47(1):8-32. 2. NHS guidelines. http://www.arden.nhs.uk/mf.ashx? ID=8817fd0e-e263-431a-90d1-b2fdb8732260. Accessed May 3, 2017. 3. Smith TJ, et al. J Clin Oncol. 2015;33; doi:10.1200/JCO.2015.62.3488. 4. Klastersky J, et al. Ann Oncol. 2016;27(suppl 5):v111-v118. 5. Tabernero J, et al. ESMO Open. 2016;1:e000142. doi:10.1136/esmoopen-2016-000142. 6. British Oncology Pharmacy Association. Guidelines on implementation of biosimilar monoclonal antibodies. February 5, 2017. 7. Lyman GH, et al. J Clin Oncol. 2018:JCO2017774893. doi:10.1200/JCO.2017.77.4893. [Epub ahead of print].

Impact of Biosimilars: Introduction of Biosimilars Into Treatment Guidelines

• Biosimilar products included in guidelines for the prevention of treatment-related neutropenia

NHS UPDATED GUIDELINES2

• Biosimilar products included in guidelines for the use of biosimilar monoclonal antibodies at the pharmacy

• Use for all commissioned indications, provided pharmacovigilance safeguards are in place

2010 2011 2012 2013 2014 2015 2016 2017 2018

BOPA GUIDELINES ON IMPLEMENTATION OF mABSAT PHARMACY6

Biosimilar products provide opportunity to both obtain desired outcomes and manage the cost of care for patients with cancer

ASCO POSITION STATEMENT7

• Biosimilar products included in guidelines as options to prevent FN and FN-related complications, where indicated

• Biosimilar products included in guidelines recommended for the prevention of treatment-related FN, where indicated

• Biosimilar products included in guidelines recommended for the prevention of treatment-related FN, where indicated

• ESMO endorses incorporating biosimilars into value framework

EORTC UPDATED GUIDELINES1

ASCO CLINICAL PRACTICE GUIDELINES3

ESMO CLINICAL PRACTICE GUIDELINES4 AND POSITION PAPER FOR ONCOLOGY BIOSIMILARS5

Lyman GH et al. J Clin Oncol. 2018;36(12):1260-1265.

Biosimilars Have The Potential To Decrease The Overall Cost Of Care For Complex Medical Conditions: ASCO Statement

Potential of biosimilars for patients, payers, and providers1-3

Summary • The goals of the biosimilar clinical trial program are to demonstrate similar

efficacy and safety compared to the reference product and to address residual uncertainty—not to re-establish benefit

• Experience with biosimilars has resulted in their introduction into multiple treatment guidelines and position statements about their use and clinical value

• Biosimilars may offer a variety of potential benefits to patients, payers, and health care providers, including:– Additional treatment choices at potentially lower cost to the health care system

– Increased access to biologics, which may lead to improved overall health outcomes

– Possible savings and efficiencies to the health care system

– A variety of therapeutic options

Biosimilars:

Improving Access to Biologic Therapy Worldwide