Biosimilars and the Changing Landscape of Biologic ...s3.proce.com/res/pdf/PharMEDium2017Sep.pdfBiosimilars and the Changing Landscape of Biologic Manufacturing PharMEDium Lunch and

Biosimilars and the Changing Landscape of Biologic ManufacturingPharMEDium Lunch and Learn Series

ProCE, Inc.www.ProCE.com 1

Biosimilars and the Changing Landscapeof Biologic Manufacturing

September 8, 2017

Featured Speaker: Steven Lucio, Pharm.D., BCPSAssociate Vice PresidentClinical Solutions and Pharmacy Program DevelopmentVizientIrving, Texas

LUNCH AND LEARN

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ProCE, Inc. (Pharmacist and Tech CE)

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Funding: This activity is self‐funded through PharMEDium.

It is the policy of ProCE, Inc. to ensure balance, independence, objectivity and scientific rigor in all of its continuing education activities. Faculty must disclose to participants the existence of any significant financial interest or any other relationship with the manufacturer of any commercial product(s) discussed in an educational presentation. Dr. Lucio has no relevant commercial and/or financial relationships to disclose.



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Biosimilars and the Changing Landscape of Biologic

Manufacturing

September 8, 2017

Steven Lucio, PharmD, BCPSAssociate Vice PresidentVizient

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Objectives

• Describe the financial imperative for competition within the biologic pharmaceutical market

• Review the nuances of biologic manufacturing and the implications for biosimilar development

• Discuss the principles for biosimilar development and approval

• Evaluate the anticipated economic and clinical practice impact of biosimiars

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Disclosures

• Steven Lucio has nothing to disclose.

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Why Should We Care About Biosimilars?

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2010 2016

Total Spend = $307.4 billion Total Spend = $450 billion

Rank Drug Name Total Sales (billions)

Rank Drug Name Total Sales (billions)

1 Atorvastatin (Lipitor) $7.2 1 Adalimumab (Humira) $13.6

2 Esomeprazole (Nexium) $6.3 2 Ledipasvir/sofosbuvir(Harvoni)

$10.0

3 Clopidogrel (Plavix) $6.1 3 Etanercept (Enbrel) $7.4

4 Salmeterol/Fluticasone (Advair Diskus)

$4.7 4 Insulin glargine (Lantus Solostar)

$5.7

5 Aripiprazole (Abilify) $4.6 5 Infliximab (Remicade) $5.3

6 Quetiapine (Seroquel) $4.4 6 Sitagliptin (Januvia) $4.8

7 Montelukast (Singulair) $4.1 7 Salmeterol/Fluticasone (Advair Diskus)

$4.7

8 Rosuvastatin (Crestor) $3.8 8 Pregabalin (Lyrica) $4.4

9 Pioglitazone (Actos) $3.5 9 Rosuvastatin (Crestor) $4.2

10 Epoetin alfa (Epogen) $3.3 10 Pegfilgrastim (Neulasta) $4.2

IMS, The Use of Medicines in the United States: Review of 2010; QuintilesIMS, Medicines Use and Spending in the U.S., a Review of 2016 and Outlook to 2021Blue = small molecule drugs, red = biologic medications

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Why Are We Talking about Biosimilars? (Total Spending on Medicines –

billions)

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The Consequence of “No” Competition

Nat Biotechnol. 2016;12:1231‐1241.

*WAC = wholesale acquisition cost, a list price paid by distributors to drug companies

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The Basics of Biosimilars

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What is a Biosimilar? A “highly similar” version of a branded biologic approved through an abbreviated, yet extremely rigorous regulatory process. Biosimilars are more complicated than generics

since biologics are more complex than small molecule drugs.

Aspirin

Monoclonal antibody biologic (e.g. adalimumab, bevacizumab, rituximab)

N Engl J Med. 2011;365:385‐388. 14



The Principles of Biologic Manufacturing

• As compared to small molecule drugs, all biologics products, whether originator reference or biosimilar, are:• More structurally complex

• More difficult to manufacture and demonstrate variability in their production

• And are more likely to elicit immunogenic responses

• Pharmacists, pharmacy technicians, and even more so physicians, have a limited awareness of these aspects of pharmaceutical manufacturing

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Biologic Medications Are More Complex Than Small Molecule Drugs

Morphine C17H10NO3

Infliximab C6428H9912N1694O1987S46

FilgrastimC845H1343N233O243S9

©2014 Novation Confidential.16

Ondansetron C18H19N3O

Norepinephrine C8H11NO3

EpoetinC815H1317N233O241S5

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Biologic Manufacturing Is More Complicated

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…And Subject to Variabiliy

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Biologics Can Generate Immune Responses

Product Antibodyformation (%)

Erythropoietin < 1

Factor VIII 15‐52

Factor IX 1‐2

Interferon α 44

Interferon β < 5

IL1 Ra 2

Growth hormone 1‐2

Infliximab 17‐60

• Biologics are large globular proteins that can induce a range of immune responses

• Factors contributing to immunogenicity:• Post‐translational

modifications

• Higher order structure

• Aggregation

Nephrol Dial Transplant. 2006;21[Suppl 5]:v4‐v8, Nat Rev Drug Discov. 2012;11:527‐540, J Investig Allergol Clin Immunol.2008;18:335‐342.

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Understanding Biosimilar Legislation

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Biologics Price Competition and Innovation Act of 2009

• Signed into law on March 23, 2010• Created the 351(k) or “biosimilar”

pathway granting FDA authority to approve “highly similar” versions of previously approved reference biologics

• Intended to be an “abbreviated” process

• Biosimilars must not have any clinically meaningful differences in safety, purity and potency as compared to the reference product.

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Approval Pathways (Small Molecules)

Product type Application typeApplication pathway

Clinical studies

Applicationrequirements

Drug(Food Drug and Cosmetic Act)

New Drug Application (NDA)

505(b)1 YesFull evaluation of safety and efficacy

505(b)2 YesStudies do not have to be done by the application sponsor

Abbreviated New Drug Application (ANDA)*

505(j) NoApproval based upon bioequivalence determination

*Created by Hatch‐Waxman AmendmentsAm J Health‐System Pharm. 2013;70:2004‐2017.

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Approval Pathways (Biologics)

Product type Application typeApplication pathway

Clinical studies

Applicationrequirements

Biologic(Public Health Service Act)

Biologics License Application (BLA)

351(a) YesFull evaluation of purity, safety and potency

BiosimilarApplication (established 2010)

351(k) YesYes, but abbreviatedprocess (one clinical trial)

Am J Health‐System Pharm. 2013;70:2004‐2017.

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Totality of the Evidence

Clinical

Animal Studies

Clinical Immunogenicity

Clinical Knowledge (ie, Post-Market Experience)

Human Pharmacokinetics and Pharmacodynamics

Structural and Functional Characterization

The more work you do here…

…the less you should have to do

here.

Adapted from FDA Webinar: Biosimilar Biological Products, available at: http://www.fda.gov/AboutFDA/Transparency/Basics/ucm364686.htm, (accessed 2015 September 26). 24



Biosimilar Analytical Characterization

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM484859.pdf, (accessed 2017 January 20).

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Novel Aspects about Biosimilars

Naming and Interchangeability

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Biologic Naming Considerations

• Question: What name do you use for a generic drug?

• Answer: The generic name.

• Question: What name do you use for a biosimilar?

• Answer: It’s complicated!

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What’s in a Name?• Two names for biologics

– Core name = (e.g. infliximab)

– Proper name = core name plus four letter suffix (e.g. infliximab‐dyyb)

• Suffix must be unique and devoid of meaning

– Will ultimately apply to all biologics• Why?

– Prevent inadvertent substitution– Improve pharmacovigilance– Encourage use of FDA‐designated suffixes– Advance accurate perceptions about biologicals

http://www.fda.gov/downloads/drugs/guidances/ucm459987.pdf, (accessed 2017 September 4).28



Naming in PracticeCurrent Proposed

Filgrastim Filgrastim‐jcwp

Filgrastim‐sndz Filgrastim‐bflm

Tbo‐filgrastim Filgrastim‐vkzt

Epoetin alfa Epoetin alfa‐cgkn

Infliximab Infliximab‐hjmt

• Approved biosimilars with proper names per guidance: infliximab‐dyyb, etanercept‐szzs, adalimumab‐atto, adalimumab‐abda, infliximab‐abda, adalimumab‐abdm

• No timeline for implementation of proposed proper names for existing products

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM459987.pdf, (accessed 2017 September 4). 29

Interchangeability (Purple is the New Orange)

• It is possible for a biosimilar to be declared as interchangeable, however,

• It is more difficult to obtain this designation,

• Usually not granted on initial approval,

• And the specific requirements are still under development

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf, (accessed 2017 September 3).

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States Interchangeability Designation

• 36 states have considered legislation

– 35 states, plus Puerto Rico have been signed into law

• Common features

– FDA determination as interchangeable – “Purple Book”

– Physician dispense as written authority

– Physician notification, patient notification and consent of substitution

– Record keeping requirements

– Cost information to the patient

http://www.ncsl.org/research/health/state‐laws‐and‐legislation‐related‐to‐biologic‐medications‐and‐substitution‐of‐biosimilars.aspx, (accessed 2017 July 31).

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And Then There Were Six (Approved Biosimilars)

• First biosimilar ‐ Filgrastim‐sndz (Zarxio®; Sandoz)

• Launched September 3, 2015

• Second biosimilar ‐ Infliximab–dyyb (Inflectra®; Celltrion/Pfizer)

• Launched November 2016

• Third biosimilar – etanercept‐szzs (Erelzi™; Sandoz)

• Estimated launch date: ??????

• Fourth biosimilar – adalimumab‐atto (Amjevita™; Amgen)

• Estimated launch date: ??????

• Fifth biosimilar – infliximab‐abda (Renflexis™; Samsung/Merck)

• Launched July 24, 2017

• Sixth biosimilar – adalimumab‐abdm (Cyltezo™; Boehringer Ingelheim)

• Approved August 25, 2017 – estimated launch date????

The Pink Sheet, FDA Performance Tracker, Pending Biosimilars (subscription), (accessed 2017 February 7); Drugs@FDA, (accessed 2017 August 29); http://www.mrknewsroom.com/news‐release/corporate‐news/merck‐announces‐us‐launch‐renflexis‐infliximab‐abda‐biosimilar‐remicade‐ (accessed 2017 August 31).

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Biosimilar MissesApplications Requiring More

Information • Filgrastim

• Apotex – likely complete response letter

• Pegfilgrastim

• Apotex – likely complete response letter

• Sandoz – confirmed complete response letter

• Coherus – confirmed complete response letter

• Epoetin

• Pfizer – complete response letter

The Pink Sheet, FDA Performance Tracker, Biosimilars, (accessed 2017 July 31).

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Biosimilar Pipeline for 2017‐2018INN Manufacturer

Application Submitted

Estimated FDA Approval Date

Bevacizumab (ABP 215) Amgen and Allergan 11/2016 9/14/2017

Trastuzumab (MYL‐1401O)

Mylan and Biocon 11/2016 12/3/2017

Pegfilgrastim (MYL‐1401H)

Mylan and Biocon 12/2016 10/2017

Rituximab (CT‐P10) Teva and Celltrion 4/2017 2/2018

Trastuzumab (CT‐P6) Teva and Celltrion 5/2017 03/2018

Trastuzumab (ABP 980) Amgen and Allergan 7/2017 05/2018?

The Pink Sheet, FDA Performance Tracker, Biosimilars, (accessed 2017 July 31); https://www.amgen.com/media/news-releases/2017/07/amgen-and-allergan-submit-biosimilar-biologics-license-application-for-abp-980-to-us-food-and-drug-administration/ (accessed 2017 September 4).

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What Have We Learned from Biosimilars Approved to Date?

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What Savings Have We Seen?

• Filgrastim‐sndz

– 15% initial discount (WAC)

• Tbo‐filgrastim

– 19% discount (WAC)

• Infliximab‐dyyb

– 15% of originator infliximab (WAC)

• Infliximab‐abda

– 35% of originator infliximab (WAC)

http://www.modernhealthcare.com/article/20160323/NEWS/160319919, (2016 September 27); www.drugcodelookup.com, (accessed 2016 September 27); http://www.bigmoleculewatch.com/2017/07/24/samsung‐bioepis‐and‐merck‐co‐launch‐renflexis‐a‐lower‐priced‐competitor‐to‐inflectra/, (accessed 2017 August 31).

WAC = wholesale acquisition cost

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The Dimensions of Payment (Medical and Pharmacy)

Wholesaler

Manufacturer

Hospital (Acute care)/Outpatient/MD

Patient (Beneficiary)

GPO

Health Plan/ Payer

Pharmacy (Retail)

PBM

AMCP Guide to Pharmaceutical Payment Methods, 2013 Update, http://www.amcp.org/pharmaceutical‐payment‐guide/ (accessed 2017 September 3).GPO = group purchasing organization; PBM = pharmacy benefit manager

Flow of Product Flow of Payment

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What Does This Mean to The Healthcare Market?

• Biosimilars have entered the market and more will be added in 2017

• Some uncertainty about these products remain• Relative safety and efficacy

• Approval processes

• Substitution

• While we have seen some savings, the complete extent of discounts remains to be determined.

• Biosimilars are critical to any efforts aimed at slowing the increasing cost of care and also reinforce the importance of high quality manufacturing.

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Documents

Biosimilars and the Changing Landscape of Biologic ...s3.proce.com/res/pdf/PharMEDium2017Sep.pdfBiosimilars and the Changing Landscape of Biologic Manufacturing PharMEDium Lunch and