The New World of Biosimilars: From Clinical Use to Reimbursement

Robert M. Rifkin, MD, FACPMedical Director - Biosimilars

McKesson Specialty Health | The US Oncology NetworkApril 13, 2018

Robert M. Rifkin, MD, FACPRelevant Disclosures

BiosimilarAdvisoryBoards:• Amgen• Coherus• Mylan• Pfizer(Hospira)• EMDSerono• Sandoz

Basics

Education

Reimbursement

The New World of Biosimilars:A Way to Increase Access and Decrease Cost

BiosimilarCostSavingsintheUnitedStatesInitialExperienceandFuturePotential;AndrewW.Mulcahy,etal;file:///C:/Users/m104482/Desktop/RAND_PE264.pdf

• Reductionof$54billionindirectspendingonbiologicdrugsfrom2017to2026

• 3%oftotalest.biologicspending;Rangeof$24to$150B

$250BillionProjectedSavings

Fromjust11biosimilars

RANDCorporationEstimatedCostSavings

http://lab.express-scripts.com/lab/insights/industry-updates/the -$250-billion-potential-of-biosimilars

Biosimilars Bringing Value to the U.S. Healthcare System

“Alotofmypatientscry—they'refrustrated,"saysDr.AyalewTefferi,ahematologistattheMayoClinic."Manyofthemspendtheirlifesavingsoncancerdrugsandendupbeingbankrupt."

“Patients Deserve Access to Effective & Affordable Biologics as they fight challenging diseases”

“Can a miracle drug also be a bitter pill?

It can when the PRICE of a life-saving prescription drug - is more than most people could possibly afford.”

“Aslongasit'sworking,youknow,I'llgoliveinatentdownbytheriver!Aslongasshefeelsgoodandshecanbeanormal10-year-oldgirl.”

ParentofachildonHumira®

ACCESSDENIED

TheaverageU.S.familymakes$52,000annually.Cancerdrugscaneasilycost

$120,000ayear.7/23/2015

http://health.usnews.com/health-news/health-wellness/articles/2015/02/06/why-are-biologic-drugs-so-costlyhttp://www.cbsnews.com/news/the-cost-of-miracles/Cachedhttp://www.cancersupportcommunity.org/living-cancer/living-cancer-topics/managing-cost-cancer-treatment/help-managing-cancer-costsDieguezG,FerroC,PysensonBS.Amulti-yearlookatthecostburdenofcancercare.MillimanResearchReport.April11,2017

Access and Affordability Remains an Issue for Many Patients

SmallMoleculeComparison

$542,000

US Annual Patient Cost by Product

$81,000 $3,700 $79,000 $52,000 $620,000 $4,700(Brand)

Source:EvaluatePharma2016USAnnualPatientCostbyProduct;Pharma’sAlmanacBiologics:DrivingForceinPharma

“Generally,biologicstreatmentscostabout22xmorethansmallmolecules”

Examplesofbiologicandinsulinmedicinesandassociatedcost:

Cost Burden to Patients – Biologics & Insulins

Price Increases Have Driven Up the Cost of Oncology Supportive Care

Historical Prices in the US US$ per unit (WAC)

2,500

3,000

3,500

4,000

4,500

5,000

5,500

14131207 15 2016102006 1108 09

ConsumerPriceIndex(1)pegfilgrastimWAC

Source:SHANationalData,MATNov2016,USBureauofLaborStatistics.(1)IndexedtoNeulastaWACinNovember2006.

pegfilgrastimWholesalerAcquisitionCost(WAC)hasnearlydoubledsince2006

+98%

+20%

Increases in Cancer-Drug Prices Have Been a Contributor to Declining Patient Affordability

Source:SaboL.TreatingCancer:Hopevs.Hype.PartII.KaiserHealthNews.March15,2017.Availableat:www.khn.org.

$10,000

$8,000

$6,000

$4,000

$2,000

$01975-79 1980-84 1985-89 1990-94 1995-99 2000-04 2005-09 2010-14

MedianmonthlycostfornewUScancerdrugs

Medianmonthlyhouseholdincome

The Oncologist’s Dilemma

Biological Medicines

• Biologicals started with the synthesis of human insulin via recombinant DNA technology in 1982

• Biologicals:• Are drugs manufactured from living organisms• Are complex• Display minor differences from lot to lot in molecular structure and

immunogenicity

What are Biosimilars?*

• Biosimilar• Products that have been shown to be highly similar to the reference

product in appropriate comparative, head-to-head quality, non-clinical and clinical studies

• Intended Copies of Biological Products (“me-too biologics”)• Copies of already licensed biological products that have not met the

regulatory criteria for biosimilars

• Biobetter• Biological that has been structurally and/or functionally altered to

achieve an improved or different clinical performance• Must go through the full development and approval process

*Lucio SD, et al. Am J Health Syst Pharm. 2013;70(22):2004-2017.

ASCO Statement: Biosimilars in OncologyKey Features*

1. SafetyandEfficacyofBiosimilars2. Interchangeability,Switching,andSubstitution3. Naming,Labeling,andOtherRegulatoryConsiderations4. ValueofBiosimilars5. PrescriberandPatientEducation

*LymanG,et.al.JClinOncMarch2018.

MonoclonalAntibody

Aspirin

Small-Molecule Generics Versus Biosimilars

• Precisely defined structure• Generally produced by

chemical synthesis• Structure can be

interrogated with high precision

• Generic forms demonstrating chemical identity can be validated with preclinical analytic methods

• Inherent variability based on a complex manufacturing process

• Biosimilars may not be identical to the reference product but must not have clinically meaningful differences

• FDA requires Pharmacokinetic, Pharmacodynamic and immunogenicity studies

• Need for additional clinical data depends on the need to address residual uncertainty

BiosimilarsSmall-MoleculeGenerics

Production-Variability, or “Drift,” Can Make Defining the Reference Product Challenging*

Sources of variation between manufacturers

*MellstedtH,etal.AnnOncol.2008;19(3):411-419.

1. Vezér et al(2016): Authorized manufacturing changes for therapeutic monoclonal antibodies (mAbs) in European Public Assessment Report (EPAR) documents, Current Medical Research and Opinion, DOI: 10.1185/03007995.2016.1145579, available at: http://dx.doi.org/10.1185/03007995.2016.1145579

2. ICH Q5E http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q5E/Step4/Q5E_Guideline.pdf

A PRODUCT THAT IS “HIGHLY SIMILAR” HAS THE “SAME” ACTIVE INGREDIENT, AND THE CLINICAL OUTCOME IS EXPECTED TO BE THE “SAME”

Manufacturing Changes are a Regulatory Norm – Subject to Review in Each Market - Each Biologic becomes “Biosimilar” to itself

Each manufacturing change is approved by the regulators in that jurisdiction:

§ Complete extrapolationbetween all indications

§ Interchangeability

§ The patient/HCP is not informed of the change because the label on the product does not change -the nonproprietary name stays the same when high similarity is established

THE GOOD NEWS: Huge experience with use of comparability2 on the reference products across all stakeholders

Challenges: Variability and Drift*

• Significant differences in drug products (variability and drift) can arise due to:

• production at different sites• changes to manufacturing processes after initial approval

• FDA or EMA approval required for changes in manufacturing process

• Manufacturers need to be vigilant for any changes in production and must always assume that they can result in clinically significant issues

Both biologics and biosimilars are subject to product variability and drift!

EMA = European Medicines Agency.*Ramanan S, et al. BioDrugs. 2014;28(4):363-372.

Biosimilars Represent Paradigm Shift in Product Development

Reference Biologic[1]]

Postmarketing Surveillance

Phase III Clinical

Phase II Clinical

Phase I Clinical

Preclinical

MolecularCharacterization

1. 1. FDA. Drug development overview. 2012.

2. 2. FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. 2015. 1.

Cont

ribut

ion

to C

linic

al P

redi

ctab

ility

High

Low

Contribution to Clinical Predictability

Low

High

Biosimilar[2]

Molecular Characterization

Preclinical

PK/PD

Immunogenicity

Clinical

Postmarketing Surveillance

Preclinical Assessment: Four Levels of Analytical Characterization*

Not similar

Similar

Highly similar

Highly similar with fingerprint-like

similarity

No further development through 351(k)

Additional information needed: analytical,

comparative PK/PD, etc.

High confidence; appropriate for targeted clinical studies

Very high confidence; appropriate for more

targeted clinical studies

Studies of Structure & Function: Residual

Uncertainty

High

Low

PK = pharmacokinetic; PD = pharmacodynamic.*FDA. Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product. Dec 2016. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm397017.pdf. Accessed September 5, 2017.

TechnologyThen

• Lowresolutioninstruments:Massspectrometer,SDS-Gel,Sanger’smethod,lowresolvingcolumnsetc.

• Cellbasedqualitativeassays

• Limitedassays forprocess&productrelatedsubstance&impurities

TechnologyNow

• HighresolutionMS,NMR,Sequencing,Capillaryelectrophoresis,highresolutioncolumnandchemistries

• Moresensitive,highlyspecificKineticassaysforefficacy&functionalaspect:Biacore,improvedstablecelllines

• ExtensivetestingforprocessrelatedimpurityandProductrelatedsubstance

• Severalorthogonalmethodstoconsolidateidentityandpurity

Advances in Technology: Innovator vs. Biosimilar Analytical & Characterization Tools

Significant enhancement in technology over two decades across development & analytics has been a game-changer

Rigorous Assessment of Critical Quality Attributes, to Assess Similarity in Structure, Functional Activity, Purity and Stability

Comprehensive analysis of > 30 attributes

• Amino acid sequence• PEG attachment• Disulfides• Free cysteine• Potency• Strength• Receptor binding• Molar mass

• PEG mass• PEG polydispersity• Oligomers• Dimers• UnPEGylated molecules• Clips• DiPEGylation• Oxidation

• Deamidation• Norleucine misincorporation• Subvisible particles• Intact mass• PEG linker analysis• UnPEGylated N-terminus• Free PEG

• Secondary structure• Tertiary structure• Extinction coefficient• Host cell proteins• Overall protein pattern• Charge profile• Size profile• Appearance and clarity

Use of 26 state-of-the-art analytical methods

• Reduced and non-reduced peptide mapping

• Proliferative bioassay• Protein concentration (A280)• SPR• SEC-MALS

• Intact mass by MS• SEC• SDS-PAGE• CEC• RPC• MFI• Mass Spectrometry

• Edman sequencing• SDS-PAGE with

iodine stain• CD• Fluorescence• 2D NMR• DSC

• HDX• SEC-UV-RI• 2D gels with silver stain• IEF• Analytical Ultracentrifugation• Visual inspection, turbidimetry

Comparability of Biosimilar Filgrastim with Reference Filgrastim*

*Sorgel F, et al. BioDrugs. 2015;29:123-131.

Protein Characterization (NMR Spectroscopy)

Comparability of Biosimilar Filgrastim with Reference Filgrastim*

*Sorgel F, et al. BioDrugs. 2015;29:123-131.

Protein Characterization (NMR Spectroscopy)Receptor Binding Affinities

Pharmacodynamic AnalysisPharmacokinetic Analysis: No Significant Differences

Between the Biosimilar and Reference Product

Biosimilar Filgrastim (EP2006) vs Reference:Patients with Breast Cancer Receiving

Myelosuppressive Chemotherapy*

Biosimilar Filgrastim Non-inferior to Reference Time Course of ANC in Cycle 1

*Blackwell K, et al. Ann Oncol. 2015;26:1948-1953.

218 patients receiving 5 µg/kg/day filgrastim over 6 chemotherapy cycles

Immunogenicity Concerns*

• All biologics (not just biosimilars) confer a risk of immunogenicity• Related to patient, disease, and product factors• Consequences include neutralizing antibodies or cytokine release• Scientific tools for detecting immunogenicity exist, but they are not precise

• Changes to the structure of the protein increase variation in immunogenicity• Lot-to-lot and between manufacturers• Variations in manufacturing must be minimized

• Clinical consequences• Loss or diminished efficacy or safety• General immune responses (eg, allergy, anaphylaxis) - case reports of rare but serious adverse

reactions have been reported

*Ebbers HC, et al. Exp Opin Biol Ther. 2012;12(11):1473-1485. Chamberlain PD. Biosimilars. 2014;4:23-43. FDA Immunogenicity Assessment for Therapeutic Protein Products [website]. https://www.fda.gov/downloads/drugs/guidances/ucm338856.pdf. Accessed September, 2017.

Switched (alternatingbiosimilar and reference)

N = 107

Reference (Neupogen) Only

n = 51

Incidenceoffebrileneutropenia(FN)

3.4% 0%[95%CI:-9.65; 4.96]

Infections 9.3% 9.9%Hospitalization duetoFN [1patientincycle6] 0

Treatment-emergentAEs 42.1% 39.2%

Anti-drugantibodies 0 0

Alternating Treatment Biosimilar Filgrastim and Reference for Prevention of Severe Neutropenia in Patients with Breast Cancer*

*Krendyukov A, et al. J Clin Oncol. 2017;35(15S):10116.

No evidence of clinically meaningful differences with switching

Basics

Education

Reimbursement

TheNewWorldofBiosimilars

*Sarshad M. GABI Journal 6(4):165-173,2018)

The Filgrastim Landscape – April 2018*

Awareness, Knowledge, and Perceptions of Biosimilars Among Specialty Physicians*

*Cohen H, et al. Adv Ther 33:2160-72,2016.

*Cohen H, et al. Adv Ther 33:2160-72,2016.

Awareness, Knowledge, and Perceptions of Biosimilars Among Specialty Physicians*

Pathway for Biosimilar Approval in the US:Biologics Price Competition and Innovation Act (BPCI):*

• Most biologics are approved under the Public Health Service Act (PHSA) (rather than the Food, Drug, and Cosmetics Act)

• DrugPriceCompetitionandPatentTermRestorationAct(informallyknownasHatch-WaxmanAct)whichenabledgenericdrugsof1984doesnotapply

• PriortoBiologicsPriceCompetitionandInnovationAct(BPCI),noabbreviatedpathwayinPHSA

• BPCI is a component of the Patient Protection and Affordable Care Act of 2010 • AmendsthePublicHealthServiceActtodefineanabbreviatedapplicationprocessforbiosimilars

• FDA Safety and Innovation Act (FDASIA)• BiosimilarUserFeeAct(BsUFA)

• Collectfeesfrombiopharmaceuticalindustryfortimelyreviewofapplications

• Performancemetrics

*Zelenetz AD, et al. J Natl Compr Canc Netw. 2011;9(suppl 4):S1-S22.

Approval Pathways for Biosimilars and Interchangeable Biologics in the US*

BIOSIMILAR

Candidate Biosimilar

Files Application: 351(k) BLA

BIOLOGIC

Files Application:351(a) BLA

(“Standalone” Pathway)

*As proposed by joint BsUFA/GDUFA legislationIC:= Interchangeable

INTERCHANGEABLE (IC) BIOLOGIC

Supplement: Interchangeability

Extrapolation: One, some, all indications

Files Application:

351(k) BLA interchangeable

e.g. Granix® (tbo-filgrastim)

e.g. Zarxio®(filgrastim - sndz)

Unique to US

Biologics Price Competition and Innovation Act Abbreviated the Licensure Pathway for Biosimilars

1FDArecommendssponsorsuseastepwiseapproachindevelopingevidencetosupportademonstrationofbiosimilarity,ensuringthatdevelopmentateachstepevaluatestheextenttowhichthereisresidualuncertaintyregardingademonstrationofbiosimilaritybetweentheproposedandreferenceproduct,andidentifynext stepstoaddressthatuncertainty.Source:U.S.DepartmentofHealthandHumanServices.ScientificConsiderationsinDemonstratingBiosimilaritytoaReference Product:GuidanceforIndustry.April2015Biosimilarity.

• Biologicalproductishighlysimilartoreferenceproductnotwithstandingminordifferencesinclinicallyinactivecomponents

• Noclinicallymeaningfuldifferencesbetweenbiologicalproductandreferenceproductintermsofsafety,purity,andpotency

Clinical

PK/PD & Immunogenicity

Non-Clinical

Analytical

Ifuncertaintyremains1

RequirementsforBiosimilarity StepwiseEvidenceDevelopment

The Regulatory Concept Biosimilarity Versus Originator Biologic*

McCamish, M., Pakulski, J., Sattler, C. and Woollett, G. (2015), Toward interchangeable biologics. Clinical Pharmacology & Therapeutics. doi: 10.1002/cpt.39, available at:: http://onlinelibrary.wiley.com/doi/10.1002/cpt.39/full

BIOSIMILARITY IS GROUNDED IN ANALYTICAL HIGH SIMILARITY –WHICH IS NECESSARY BUT NOT SUFFICIENT, AND A SINGULAR FOCUS OF FDA

The Approval Pathway for Each Biologic Is a Case-by-Case Decision

SponsorsNEEDTOWeightheRisks/RewardsofEach PathwayForEach Product

Candidate Biologic

“Standalone”Biologic[US351(a)]

• Data exclusivity 12 years (+)• Clinical trials required (- - - )

o One indication o All indications

• Patents independently litigated• Known payer/physician/

consumer perceptions regarding new entrants in a product “class”

Biosimilar[US351(k)]

• Limited exclusivity (1 year, 1st IC) • Extrapolation (+++)• Interchangeability (++)• Patent litigation provisions (-)• Regulatory uncertainty (- - )• Unknown payer/physician/

consumer perceptions (- - - )

The approval pathway selected for each biologic has important implications for commercialization strategy and market access

Key Principles for Extrapolation for Biosimilars in the Future:*

Extrapolation acrossindicationsfora biosimilarwilldependonseveralfactors,including:

• AcommonMOAandreceptor/target/interaction• Totalityoftheevidence showingcomparability• Acceptablesafetyprofilewithoutincreasedrisksofimmunogenicity• Clinicalexperiencewiththeoriginatorproductthatcanbeusedtosupporttheuseofabiosimilaracrossindications

*Weiss M. Blood. Nov 2014, Vol 124, No. 22

Extrapolation: Regulatory Perspective*

• Extrapolationisafamiliarconceptforregulators• Aimstoavoidunnecessarystudiesinthetargetpopulationforethicalreasons,forefficiency,andtoallocateresourceswhereneeded[1]

• FDAguidancestatesthatextrapolationofindicationsforabiosimilarispossiblegivensufficientscientificjustification[2]

• “Totality-of-evidence”approachsupportedbyextensiveexperienceinEurope

• Approvedbiosimilarshaveshownsimilarsafetyandefficacyprofilesasthereferencebiologicforextrapolatedindications[3-5]

1. EMA. Concept paper on extrapolation of efficacy and safety in medicine development. 2012. 2. FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. 2015. 3. Dmoszynska A, et al. 2012. EBMT Meeting 2012. Abstract P700. 4. Ianotto J, et al. Bone Marrow Transplant. 2012;47:874-876. 5. Publicover A, et al. Br J Haematol. 2013;162:107-111.

Extrapolation: Clinical Perspective*

• Extrapolation is an unfamiliar concept for clinicians

• Traditionally, clinicians have relied on clinical trial data to judge the safety and efficacy of therapeutic agents

• By definition, approval of a biosimilar for one indication may be based on extrapolation from the biosimilar to the reference biologic

• Therefore, no specific clinical trials with a biosimilar may have been performed in the approved indication/population

• Thus, the paradigm shift in biosimilar development also requires a paradigm shift in evaluation and use of biosimilars in the clinical setting

*Weise M, et al. Blood. 2014;124:3191-3196.

Framework for Extrapolation

Patient Factors• Similarity of biologic

disposition: PK/PD• Organ function• Age, ethnicity, etc

Disease Factors• Defined MOA• Similarity in target distribution• Single vs combo therapy

Endpoint Factors• Differential efficacy and toxicity• Short-term vs long-term• Sensitivity of surrogate outcomes

Quantitative Evidence Disease progression: Disease models could be used to characterize differences in disease progression between groups. PK and PD: using existing data and physiology-based PK (and PD) modelling and simulation to investigate the relationship betweenPK/PD, age and other important covariates. Clinical response: quantitative synthesis or modelling of all existing data (in vitro, preclinical and clinical) to predict the degree of similarity in clinical response (efficacy, some safety aspects) between source and target population.

Determine Appropriateness of Indication ExtrapolationNo extrapolation; extrapolation to some indications; extrapolation to all indications

MOA = mechanism of action.EMA. Concept Paper on Extrapolation of Efficacy and Safety in Medicine Development [website]. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/04/WC500142358.pdf. Accessed September 5, 2017. Weise M, et al. Blood. 2014;124(22):3191-3196.

Extrapolation to Additional Indications Possible With Scientific Justification*

Extrapolated indications

Convincing evidence to support extrapolation to a reference biologic’s approved indications[2]

Extrapolation: extending conclusions from studies in one pt population to make inferences in another population[1]

*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.

+

Biosimilar

Molecular Characterization

Preclinical

PK/PD

Immunogenicity

Clinical

Postmarketing Surveillance

Oncology Drug Advisory Board recommended to the FDA approval of filgrastim-sndz for all current FDA indications of filgrastim:

• Cancer patients receiving myelosuppressive chemotherapy

• Patients with acute myeloid leukemia receiving induction or consolidation chemotherapy

• Cancer patients receiving bone marrow transplant

• Patients undergoing peripheral blood progenitor cell collection and therapy

• Patients with severe chronic neutropenia

Biosimilar Filgrastim in USExtrapolation to Other Indications

40

Interchangeability of Biosimilars*

• A biosimilar may also be designated as “interchangeable” if there is proof that:• Switching or alternating between the biosimilar and the reference product does not affect safety or

efficacy any more than using the reference product more than once without such alternating or switching

• An “interchangeable” biologic product must demonstrate that it can be expected to produce the same clinical result as the reference product in any given patient

• In addition, if the biologic product is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biologic product and the reference product is not greater than the risk of using the reference product without such alternation or switch

*FDA. Considerations in Demonstrating Interchangeability With a Reference Product: Guidance for Industry [website]. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf. Accessed September 5, 2017. Figure adapted from: Castaneda-Hernandez, G. Does Interchangeability Really Matter for Biosimilars? https://www.slideshare.net/leongi1/does-interchangeability-really-matters-for-biosimilars.

The designation of “interchangeability” requires higher standards than “biosimilarity” alone

Interchangeability*

• Interchangeability - useofabiosimilarwithoutimpactingonsafetyorefficacyifitisalternatedorswitchingbetweenthebiosimilarandtheinnovatorcomparedtotheuseoftheinnovatorwithoutalternationorswitching

• DraftguidanceoninterchangeabilityevaluationissuedbyFDA• Therearenoapprovedinterchangeabledrugs

• Adrugmustbedesignatedtobeinterchangeabletopermitdrugsubstitutionbyapharmacist• DrugsubstitutionruleandregulationsaredeterminedattheStatelevel• Designationofabiosimilarasinterchangeabledoesnotautomaticallyallowdrugsubstitution

*FDA. Considerations in Demonstrating Interchangeability With a Reference Product: Guidance for Industry [website]. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf. Accessed September 5, 2017. Figure adapted from: Castaneda-Hernandez, G. Does Interchangeability Really Matter for Biosimilars? https://www.slideshare.net/leongi1/does-interchangeability-really-matters-for-biosimilars.

Interchangeability

InnovatorBiosimilar

Clinician Perspective: Finding the Right Balance

Basics

Education

Reimbursement

TheNewWorldofBiosimilars

A“PerfectStorm”forOncologyBiosimilars?*

APMs

Implications for Patients

MIPS

MACRA

OCM

*Adapted from McGivney Global Advisors – Personal Communication

$3B+

Big Brand Biologics Continue to Lose Patent Exclusivity Over Time

Source: IMS 2016 Data; Brand sales for major biologics going off patent through 2025

LoE:2008 2013 2014 2020 2021 2025

$95B+

LoE

LoE

LoE

Biosimilars may receive regulatory approval, but patent challenges may still exist

$26B+

$6B+

Biosimilar Manufacturers will Need to Overcome Several Physician Barriers to Adoption

• What are biosimilars?• Is the manufacturer as good

as the innovator?• Is the biosim drug as effective

and safe?• Can I switch existing patients?• Can I use it for all indications?

• Does this have the same support services as the brand?

• Will payers will cover it?• Is this a better deal for my

patient?• Will using this create more

hassle for my clinic, my patients?

Clinical Barrier

Ease of Use Barrier

Economic Barrier

• How good is the biosim’s cost?

• How much is my cost recovery?

• How will that change over time?

Physician Barriers to Adoption

*Sarshad M. GABI Journal 6(4):165-173,2018

How do you differentiate something that is essentially the same ?

The Launch of Zarxio*

*SarshadM.MajorLessonsLearnedfromZarxio’sUSLaunch:TheStartofaBiosimilarRevolution.GABIJournal6(4):165-173,2018

*Sarshad M. GABI Journal 6(4):165-173,2018

Medicare Part B Reimbursement

Drug Rebates and Provider Profits*

*Sarshad M. GABI Journal 6(4):165-173,2018

The Need for Payer Education*

*ASmallMidwesternHealthPlanCoverageDetermination

*Sarshad M. GABI Journal 6(4):165-173,2018

The Impact of ASP Adjustment*

History of FDA Approvals for Filgrastim-Based Therapies

Pegfilgrastim (Neulasta) approval

tbo-filgrastim (Granix) approval

Filgrastim-sndz (Zarxio)approval

20021991

Filgrastim (Neupogen)

approval

FDA begins expedited biosimilar pathway

2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

CHS-1701expectedapproval

351(k) pathway

NEUPOGEN®andNeulasta®areRegisteredTrademarksofAmgenInc.GRANIX®isaRegisteredTrademarkofTevaPharmaceuticalIndustriesZARXIO®isaRegisteredTrademarkofSandozInc.

MYL-1401Hexpectedapproval

Pegfilgrastims:

Oncology Biosimilars in Development*

*J Adv Prac Oncol 2017

Current U.S. Biosimilars & Insulins Approved Biosim

ilarsA

pproved

BiosimilarName ManufacturerofBiosimilar

Reference/Innovator

ApprovalDate Launch Date

Zarxio® (filgrastim-sndz) Sandoz Neupogen® March2015 Sept.2015

Inflectra™ (infliximab-dyyb) Pfizer/Hospira Remicade® April2016 Nov.2016

Renflexis™(Infliximab-abda) SamsungBioepis Remicade® April2017 Jul.2017

Erelzi™ (etanercept-szzs) Sandoz Enbrel® August2016 TBD

Amjevita™ (adalimumab-atto) Amgen Humira® September2016 TBD

Cyltezo™(adalimumab-adbm) BI Humira® August 2017 TBD

Mvasi®(bevacizumab-awwb) Amgen/Allergan Avastin® September2017 TBD

Ogivri™(trastuzumab-dkst) Mylan Herceptin® December2017 TBD

Ixifi™(infliximab-qbtx) Pfizer Remicade® December2017 TBD

505(b)(2) Basaglar®(insulinglargine) Eli Lilly/BI Lantus® December2015 December2016

505(b)(2) Lusduna®Nexvue(insulinglargine) Merck Lantus® July2017(tentativeapproval)

Approvalpendingpatent

infringementlawsuit

505(b)(2) Admelog®(insulinLispro) Sanofi Humalog Dec2017 TBD

Current U.S. Biosimilars Under Review* Biosim

ilarsUnd

erReview

BiosimilarName Manufacturer Innovator BsUFAGoal Datepegfilgrastim(Zioxtenzo) Sandoz Neulasta® Jun2016CRL

pegfilgrastim(CHS-1701) CoherusBiosciences Neulasta® June 2017CRL

epoetin-alfa(Retacrit) Pfizer/Hospira Epogen® Jun2017CRL

filgrastim(grastofil) Apotex Neupogen® TBD

pegfilgrastim Apotex Neulasta® TBD

pegfilgrastim(MYL-1401H) Mylan Neulasta® TBD

trastuzumab(ABP 980) Amgen/Allergan Herceptin® TBD

rituximab(Truxima(CT-P10)) Teva/Celltrion Rituxan® TBD

rituximab(GP2013) Sandoz Rituxan® TBD

trastuzumab(CT-P6) Teva/Celltrion Herceptin® TBD

trastuzumab(PF-05280014) Pfizer Herceptin® TBD

trastuzumab Merck/SamsungBioepis Herceptin® TBD

filgrastim Adello Neupogen® TBD

adalimumab Sandoz Humira® TBD

Asmorebiosimilarsareintroducedintothemarket,patientswill

havegreatertreatmentoptions,greateraccesstotheseoptions,andperhapsduetomarketdynamics,greater

degreeofaffordability

“TheBPD(BiosimilarsProductDevelopment)ProgramwascreatedasapartofBsUFAItoprovideamechanismandstructureforapplicantstoengagewithFDAduringthedevelopmentofabiosimilar.AsofFebruary2017…

64+productsenrolledintheBiosimilarProductDevelopment(BPD)Programrepresenting…*

23 distinctreferencebiologics*

73 BsUFAProgrammeetingswerescheduledin2016*

9 differentcompaniessubmittedbiosimilarapplicationsforreview*

https://www.fda.gov/NewsEvents/Testimony/ucm548273.htm (Testimony of Janet Woodcock, M.D., Director, Center for Drug Evaluation and Research, Before the United States House of Representatives, Committee on Energy and Commerce Subcommittee on Health, March 2, 2017https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm477734.htm

How do you differentiate something that is “essentially the same”?

Biosimilars: Everyone’s Dilemma