Biosimilars–US-and-International-Update

8/13/2019 BiosimilarsUS-and-International-Update

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Biosimilars U.S. and International Update

October 10, 2012


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Disclaimer

The views and opinions expressed in thefollowing PowerPoint slides are those of theindividual presenter and should not beattributed to Elsevier, or any organization withwhich the presenter is employed or affiliated.


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Biosimilars -- Why We Are HereBiologic products continue to grow world wide and are>$150 billion as a market -- ~50% in The U.S.

Global Biologics Spending and Growth, 2001-2012

GR OWT H

( C ON

S T

U S $ )

S P E N D I N G

( U S $ B

N )

Source: IMS MIDAS, Mar 2012

0

20

40

60

80

100

120

140

160

180

2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 MAT Mar2012

0%

5%

10%

15%

20%

25%Global biologic salesGlobal biologic growthGlobal small molecule growth


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The global traditional small molecule Patent Cliff peaks in2012 and starts to decline biologics are the next logical target


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Credit Suisse forecasts that the largest 10 drugsworldwide in 2016 will be largely biologics


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Early Biotech Products Are Reaching Mid AgeAnd By The Time Biosimilars Arrive.

Drug FDA Approval Date Current Age Aranesp September 2001 10

Enbrel November 1998 13

Epogen June 1989 22

Remicade August 1998 13

Neulasta January 2002 9

Rituxan November 1997 14

Herceptin September 1998 13

Lantus April 2000 11

Avastin February 2004 7Humira December 2002 9

Avonex May 1996 15

Neupogen February 1991 20

Source: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm


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Branded Biologics The Next Target Bummer of a birthmark, Hal


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Whats in a name? Terminology Biosimilar/FOP/FPB/SEB/ . Similar Biological Medicinal Products (Biosimilars)

The official term in Europe Often abbreviated as 'biosimilar products Otherwise: 'a product claimed to be similar to another one already

marketed

Follow-on Biologics (FOB) or Follow On Proteins (FOP) - US The currently used term in the USA Sometimes called 'follow-on proteins FOB or FOP

Subsequent Entry Biologics (SEB) Canada

Follow on Proteins (FOP) - Japan

Note that typically US and EU regulators agree that the word 'generic'must not be used in this context, since biological products cannot beassessed or regulated as generic drugs


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Background to BPCI (Biologics PriceCompetition and Innovation Act of 2009)

The Biologics Price Competition and Innovation Act of 2009(BPCI Act)was passed as part of health reform (ACA -Affordable Care Act) that President Obama signed into law onMarch 23, 2010 and amends section 351 of the Public Health

Services (PHS) Act to create a biosimilar pathway

BPCI Act creates an abbreviated licensure pathway forbiological products shown to be biosimilar to OR

interchangeable with an FDA licensed reference product.Referred to as 351(k) of the PHS Act


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What is an abbreviated pathway?Creation of PHS 351(k)

A biological product that is demonstrated to be highly similar to an FDAlicensed biological product (the reference product )may rely for licensure on, among other things, publiclyavailable information regarding FDAs previous determinationthat the reference product is safe, pure and potent.

This new licensure pathway under section 351(k) of the PHSAct permits a biosimilar biological product to be licensed basedon less than a full complement of productspecific preclinicaland clinical data abbreviated licensure pathway.

There is no abb reviated l icens ure p athw ay for related biologic alprod ucts no t in tended to be bios im ilar to a reference prod uct .


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BPCI revised definition of biologic product

BPCI Act revises the definition of biological product in thePublic Health Service Act (PHS Act) to include protein: . . . avirus, therapeutic serum, toxin, antitoxin, vaccine, blood, bloodcomponent or derivative, allergenic product, protein (except

any chemically synthesized polypeptide), or analogous product applicable to the prevention, treatment, or cure of a diseaseor condition of human beings

Historically, some proteins have been approved as drugs undersection 505 of the FD&C Act (e.g., human growth hormone),and other proteins have been licensed as biologics undersection 351(a) of the PHS Act (e.g., blood factors)


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What is biosimilar or biosimilarity?

Biosimilar or biosimilarity means that the biological product is highly similar to the reference product

notwithstanding minor differences in clinically inactive components;and

there are no clinically meaningful differences between the biologicalproduct and the reference product in terms of the safety, purity, andpotency of product

Reference Product means the single biological product, licensed under section 351(a) of the

PHS Act, against which a biological product is evaluated in anapplication submitted under section 351(k) of the PHS Act.


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Interchangeability?

Interchangeable or Interchangeability means : the biological product is biosimilar to the reference product; it can be expected to produce the same clinical result as the reference product in any given patient ; and for a product that is administered more than once to an individual, the

risk in terms of safety or diminished efficacy of alternating orswitching between use of the product and its reference product is notgreater than the risk of using the reference product without suchalternation or switch.

Note: The interchangeable product may be substituted forthe reference product without the intervention of the healthcare provider who prescribed the reference product (subject toState laws).


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General Requirements

A 351(k) application must include information demonstratingthat the biological product:

Is biosimilar to a reference product; Utilizes the same mechanism(s) of action for the proposed

condition(s) of use --but only to the extent the mechanism(s) are

known for the reference product; Condition(s) of use proposed in labeling have been previouslyapproved for the reference product;

Has the same route of administration , dosage form , and strength asthe reference product; and

Is manufactured, processed, packed, or held in a facility that meetsstandards designed to assure that the biological product continues tobe safe, pure, and potent


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General RequirementsThe PHS Act requires that a 351(k) application include, among other things,information demonstrating biosimilarity based upon data derived from :

Analytical studies demonstrating that the biological product is highlysimilar to the reference product notwithstanding minor differences inclinically inactive components;

Animal studies (including the assessment of toxicity); and

Aclinical study or studies (including the assessment of immunogenicity andpharmacokinetics (PK) or pharmacodynamics (PD)) that are sufficient todemonstrate safety, purity, and potency in 1 or more appropriate conditionsof use for which the reference product is licensed and for which licensure issought for the biosimilar product

FDA has the right to determine, at its discretion, that anelement listed above is unnecessary in a 351(k) filing


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Exclusivity

BPCIA has exclusivity provisions, and provisions for resolution of patentdisputes that differ from ANDA process. Exclusivity for reference product: No 351(k) product can be approved until 12

years from first licensure of reference product No 351(k) application can be filed until 4 years from first licensure

A new 6 months exclusivity for pediatric studies Section 351 (m) for new oralready licensed products, and

1 Year exclusivity provision for the first interchangeable biosimilar approvedunder 351 (k)


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Patent Disputes

Process for patent dispute resolution Unlike the public patent listing process for generic drugs,

the BPCIA provides for a detailed private disclosureprocess in which

Applicant provides copy of application and shares manufacturing

information with innovator Innovator identifies its patents, including process and process

patents The parties negotiate and reduce to patents in dispute for

litigation, innovator can sue towards end of this process

Applicant gives 180 days notice before first commercial marketing,and innovator can seek preliminary injunction


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U.S. Biosimilar Track Record

Sponsors have submitted 11 IND applications and conductedmore than 30 meetings with FDA

FDA biosimilar fees will match those of prescription user fees Marketing Application fee requiring clinical data $1.96 Million An annual biosimilar development fee which is equal to 10% of the

total fee will be charged each year after reaching IND ($195,880) anddeducted from the $1.96 Million total fee upon filing of marketingapplication

Source: Per Kathleen Uhl, deputy director of CDER office of medical policy asquoted in Pink Sheet Daily September 12, 2012 article 14120912007

No 351(k) applications have arrived at the FDA as ofSeptember 12, 2012*


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2006 A Meeting Of Payers Looking Into Biosimilars


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2009 A Gathering of Payers Interested in Biosimilars


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2012 Payers Eagerly Awaiting The Start of A Biosimilar Launch Meeting


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Biosimilars So How Did We Get Here In The EU?EU Approach Based Upon Science

European Commission DirectiveJune 2003

Directs EMA to create a regulatory pathway for biosimilars by establishing new Annex onan application for MA with specific dossier requirements for similar biological

medicinal products

EMA & CHMP Guideline: Similar BiologicalMedicinal ProductOctober 2005

Outlines requirements for Marketing Authorization Applications (MAA) based on thedemonstration of the similar nature of the two biological medicines

Due to the complexity of biological/biotechnology derived products thegeneric approach is scientifically not appropriate for these products

EMA Guideline on similar biological medicinal products, section 2.1: Application of SimilarBiological Medicinal Products approach

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003517.pdf

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Biosimilar Product Experience in EU as ofSeptember 2012

19 Marketing authorization applications reviewed forbiosimilars 14 positive, 4 withdrawn, 1 negative

12 biosimilar medicinal products currently holding a validmarketing authorization 1 somatropin, 5 epoetins, 6 filgrastims

6 biosimilar Marketing Authorization Applications are currentlyunder review 1 filgrastim, 1 follitropin alfa, 2 infliximab, 3 insulin human

C i i bi i il l i


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Comparison across various biosimilar regulationsUse of foreign comparator/reference product

US EU Japan Canada WHORP must be licensedunder 351(a)

Comparative datainvolving non USlicensed comparatorprodut may address, inpart requirementsunder PHS 351(k);bridging data required

RP now (Sept 2012)permitted outside of EUbased upon case bycase approach andcomparative data maybe necessary

RP must be approvedin Japan

Same RP must be usedthroughoutcomparability program

RP should beauthorized for sale andmarketed in Canada

Same RP should beused throughoutcomparability program

Comparative datainvolving non Canadaproduct may be usedonly if, among otherthings, marketed by thesame company and in jurisdiction withcomparable standards

RP should be approvedin licensing country

Same RP should beused throughoutcomparability program

If licensing countrylacks RP, an RP maybe used that is widelymarketed in a jurisdiction with wellestablished regulatoryframework andexperience withbiologics evaluation andpost marketsurveillance


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Comparison across various biosimilar regulationsExtrapolation of indication

US EU Japan Canada WHOPossible withsufficient scientific justificationaddressing e.g.MoA in each

proposedindication, PK andbio distribution indifferentpopulations;difference inexpected toxicities

in each population

Possible dependingon clinicalexperience,literature, MoA ofproposed

indications, safetyissues in subpopulations

Concept paperproposes revisingthese criteria

Possible if a similarpharmacologicalresult can beexpected in thenew indication

Not possible if theMoA differs foreach indication oris not clear

Possible dependingon MoA,pathophysiologicalmechanisms ofdisease, safety

profile in relevantindications and/orpopulations, andclinical experiencewith referenceproduct

Possible if, e.g.sensitive clinicaltest model wasused; MoA and/orreceptors are the

same (or a strongscientific rationaland additional isprovided); and nospecial safetyissues areexpected in the

new indication

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Comparison across various biosimilar regulationsClinical studies/testing

US EU Japan Canada WHOGenerally will needa clinical study orstudies; assessedon a case by casebasis

Scope andmagnitude willdepend on extentof residualuncertainty

Similar human PKand PD profile mayprovide basis fortargeted approach

Comparativeclinical trials usuallynecessary forrecombinantproteins; in somecases, clinicalPK/PD studies maybe sufficient

All biosimilarapplicationsgranted to datecontainedsubstantial clinicaldata

Clinical studiesgenerally required,unless nonclinicalPK, PD or PK/PDstudies aresufficient

Type and content ofclinical studiesassessed on acase by case basis

Comparative PKand PD should beconducted

Comparativeefficacy and safetytrails are critical

Clinical trials areusually required

Confirmatoryhuman PK/PD datamay be used in lieuof efficacy trials,provided that thereis sufficientscientific justification

Comparison across ario s biosimilar reg lations


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Comparison across various biosimilar regulationsInterchangeability

US EU Japan Canada WHOHigher standard thanbiosimilarity

At this time, difficult todetermine exactrequirements withoutadditional guidance

For a product that isadministered more thanonce to an individual, therisk in terms ofsafety ordiminished efficacy ofalternating or switchingbetween use of theproduct and its referenceproduct isnot greater than the risk of using thereference product withoutsuch alternation or switch.

Determined byMember States

Biosimilars are nota generic

Decision to treat apatient with an RPor biosimilar shouldbe made followingan opinion of ahealthcare

professional

Important to assuretraceability ofadverse eventsduring surveillanceperiod

Switching betweena biosimilar and theRP should inprinciple beavoided throughoutthe treatment

period

Biosimilars are notgenerics. Authorization is nota declaration ofpharmaceutical or

therapeuticequivalenence withthe referenceproduct

Biosimilars are notgenerics

Determined bynational authorities

Comparison across various biosimilar regulations


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Comparison across various biosimilar regulationsUnique Naming

US EU Japan Canada WHO Adequate postmarketing safetymonitoringmechanismsshould differentiate

between adverseevents associatedwith the biosimilarand the referenceproduct

Guidance on

naming is expected

To supportpharmacovigilance,the specific productgiven to the patientshould be clearly

identified

All biosimilarsauthorized to datehave borne either abrand name or adistinctive feature

in thenonproprietaryname

The non proprietarynames and brandnames ofbiosimilars shouldbe readily

distinguishablefrom the names ofreference productsand otherbiosimilars

A very detailed

naming policy withexamples forbiosimilar naming

Not addressed Biosimilars shouldbe clearlyidentifiable byunique brandname, the WHOs

policy on INNsshould be followed

Lot number isessential fortraceability

A l F il d L h f Bi i il


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Approvals, Failures and Launches of BiosimilarsSecond Enoxaparin Approved in September 2011 (US)

04/2006: Omnitrope

2006 2007 2008 20112010 2009

04/2006: Valtropin

05/2006: Omnitrope

06/2006: Alpheon

12/2007: Insulin Marvel

8/2007: EPO Alfa Hexal

8/2007: Abseamed

8/2007: Binocrit

12 /2007 : Retacrit

12 /2007 : Silapo

9/2008: TevaGrastim

9/2008: Biograstim

9 /2008 : RatioGrastim

9 /2008 : Filgrastim Ratiopharm

2/2009: Filgrastim Hexal

2/2009: Zarzio

05/2009: Omnitrope

6/2010: Nivestim

9/2010: Nivestim

1/2010: JCR EPO Alfa

10/2010: Neutroval

7 /2010 : Enoxaparin

4/2011: Epostim

Biosimilar IFN-alfa, human insulin and EPO-alfa not approved by EMA

Teva received CRL from the FDA in Oct 2010 for BLA of Neutroval (filgrastim)

Growth hormone IFN-alfa EPO-alfa

G-CSF Insulin LMWH EPO-zeta

Sources: Datamonitor Consulting; EMA (click here); Australian TGA (cl ick here); Japan MHLW (click here); Health Canada (click here); FDA (clickhere); comp any reported data (obtained from company websites during April 2011); EU approv als unless otherwise s tated


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Commercial Impact Of Biosimilars Has Been Modest EU Biosimilar Market Share Value by Country 2009 (IMS)

Market hGH EPO GCSF

Germany 5.1% 52.1% 31.0%

Italy 15.3% 0.2% 3.8%UK 1.0% 0.9% 24.0%France 12.5% 2.0% 3.8%Spain 1.0% 0.9% 3.8%

IMS August 2010 MAT Global Biosimilar Market Is


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IMS August 2010 MAT Global Biosimilar Market Is$235 Million

Sandoz/IMS Estimates of Biosimilar Markets In 2010


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Sandoz/IMS Estimates of Biosimilar Markets In 2010 Was Only $380 Million

G d h f bl bi i il


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Germany tends to have favorable biosimilaruse -- why is Germany uptake of biosimilarsbetter than average?

Germany was first country of EPO generic launch

Biosimilar EPOs are manufactured/marketed by German firms

Germany generic penetration of small molecules is very high Germany branded pricing is high relative to other EU countries

Tender driven market

Biosimilar prescribing targets of 10%+ are being set by thesick funds for the physicians

The $64 000 Question What Does Biosimilar EPO In


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The $64,000 Question ..What Does Biosimilar EPO InGermany Sell For?

Emerging Markets Have Had Biosimilars (copy biologics)


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Emerging Markets Have Had Biosimilars (copy biologics)For Years -- EPO Biosimilar Share Is High in PharmergingMarkets

Biosimilar Epoetins: Gaps in Quality and Potential


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Biosimilar Epoetins: Gaps in Quality and PotentialSafety EU Journal of Hospital Pharmacy Science v 112005

Biosimilar (or copy) versions of epoetins have been available indeveloping countries for many years and are widely used foreconomic reasons.

Despite limited data on the efficacy and safety of biosimilarepoetins, they are prescribed under the assumption that theyhave similar safety and efficacy profiles as the original product.

The aim of this study was Systematically evaluate the quality of biosimilar epoetins Report the potential implications of the results

Biosimilar Epoetins: Gaps in Quality and Potential


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Biosimilar Epoetins: Gaps in Quality and PotentialSafety Eu Journal of Hospital Pharmacy Science v 112005 -- Methods

Biosimilar epoetin samples were procured from pharmacies in Brazil, Colombia,India, Indonesia, Iran, Jordan, Korea, Lebanon, Philippines, Thailand, Venezuela,Vietnam, and Yemen.

Samples were tested against the European quality specifications for epoetin alfa.The epoetin alfa reference standard was used as control.


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EPO Brazil History of Biosimilar or copy biologics

12 Biosimilar Epoetins from 5 different manufacturers wereanalyzed

Potency of 12 Epoetins vaired from 68% to 119% of that statedon the label

Isoform patters varied among the manufacturers Bacterial endotoxins was unacceptable for three of the

products 1

Brazil Regulatory suspends importation of two epoetin alphaproducts for failing to meet required standards 2,3

1. Schmidt CA, Ramos AS , da Silva JEP, Fronza M, Dalmora SL. Act ivity evaluation and characterization of recombinant human erythropoietin inpharmaceutical products [in Portuguese abstract in English]. Arq Bras Endocrinol Metabol 2003; 47: 183-9. 2. Agencia Nacional de Vigilancia Sanitaria (ANVISA). Resolution No. 1.174. SoPaulo, Brazil: 22 July 2003 [Accessed online 19 November2004].Available from URL: http://e-legis.bvs.br/leisref/public/showAct.php?id=9210 3. Agencia Nacional de Vigilancia Sanitaria (ANVISA). Resolution No. 1.250. So Paulo, Brazil: 1 August 2003 [Accessed online 19 November2004].Available from URL: http://e-legis.bvs.br/leisref/public/showAct.php?id=8151
http://e-legis.bvs.br/leisref/public/showAct.php?id=9210http://e-legis.bvs.br/leisref/public/showAct.php?id=8151http://e-legis.bvs.br/leisref/public/showAct.php?id=8151http://e-legis.bvs.br/leisref/public/showAct.php?id=8151http://e-legis.bvs.br/leisref/public/showAct.php?id=8151http://e-legis.bvs.br/leisref/public/showAct.php?id=9210http://e-legis.bvs.br/leisref/public/showAct.php?id=9210http://e-legis.bvs.br/leisref/public/showAct.php?id=9210


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What Are Payers Doing With Biosimilars?

Germany payers are setting targets for physicians forprescribing of biosimilars

Norway Payer attempted to use pharmacists tosubstitute biosimilar GCSF for branded Neupogen withoutphysician intervention. Amgen sued and won Norway isnot appealing

Brasil - The Brazilian Ministry of Health (Ministrio daSade) has announced that it has entered into anagreement with PharmaPraxis to manufacture a biosimilarversion of Humira (adalimumab). Instituto Vital Brazil andPharmaPraxis, which is part of Axis Biotec, will be partners

What Payer Substitution Can Do To A Brand Norway


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What Payer Substitution Can Do To A Brand NorwayPayer Allowed Substitution For A Short Period

EMA Pharmacovigilance Working Party Cites PRCA in Biosimilar EPO


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EMA Pharmacovigilance Working Party Cites PRCA in Biosimilar EPOTrial Important That Accurate Medication Histories Are Maintainedfor Patients Treated With EPOs Why Unique Naming Is Important

U.K. State Regulatory Body Links Proper Identification of


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g y y pBiosimilar Products With Pharmacovigilance Due to samenaming (INN) tracking should be done by brand name

Germany EPO Substitution New Proposal In May 2011 Linked Products That


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y p yAre Identical For Purposes of Substitution. Identical Defined As Same Drug,Same Manufacturing Process i.e. Identical Regulatory Filing

Biosimilars thatare identicalamong eachother are

substitutablefor each other But NOT acrossbiosimilars


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Who Are The Mainstream Competitors?

Competitive landscape evolving

Traditional pharmaceutical companies once completelyaligned as innovative manufacturers is fragmenting

Time, cost and credibility required to develop high qualitybiosimilars is high resulting in most (but not necessarily

all) of the high quality competitors to be know at this point

Sea Change in Biosimilar Landscape Branded


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Sea Change in Biosimilar Landscape BrandedCompanies Now Clearly Entering Biosimilar Space

Branded Pharmaceutical Companies The Obvious

Merck Partners with Hanwha (Korea) for biosimilar Etanercept for areported $720 Million

Novartis already in biosimilar space with Sandoz subsidiary launchedwith HGH, EPO, GCSF

Boehringer Ingelheim Phase I of biosimilar adalimumab and rituximabinitiated

Amgen Joint venture with Watson Pharmaceuticals to enter biosimilars

Pfizer in biosimilar space with Biocon insulin JV in emerging markets.Initiated phase III biosimilar rituximab clinical studies in Jan 2012

Eli Lilly stated in December 2008 that they were considering efforts inthis space

M k Bi i il O i


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Merck Biosimilar Overview

Merck

December 2008 announced $1.5 Billion investment into biosimilars leading withtheir GlyoFi acquisition.

Stated goal of 5 phase III compounds by 2012.

February 2009, acquired biosimilar assets of Insmed in (INS-19 biosimilarNeupogen, INS-20 biosimilar Neulasta)

June 2011, Partners with Hanwha (Korea) for biosimilar etanercept (HD203) fora reported $720 Million through 2024 for global markets except for Korea andTurkey

300 patient biosimilar etanercept S. Korea phase III study enrolled and believedcompleted in June 2012 product is reported to have been filed in S. Korea

http://www.clinicaltrials.gov/ct2/show/NCT01270997

-- Merck essentially folds biosimilar unit into operating units of Merck in April2012

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http://www.clinicaltrials.gov/ct2/show/NCT01270997http://www.clinicaltrials.gov/ct2/show/NCT01270997


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Boehringer Ingelheim Biosimilar Overview

Boehringer Ingelheim Pharmaceuticals September 2011, Boehringer Ingelheim announces establishment of a separate

biosimilar division

http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2011/26_september_2011biosimilars.html

December 2011, initialized Phase I PK/PD study of BI-695501 (biosimilaradalimumab) in 180 patient three arm trial (biosimilar adalimumab vs USHumira vs EU Humira). Expected completion July 2012

http://www.clinicaltrials .gov/ct2/show/NCT01505491

l
http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2011/26_september_2011biosimilars.htmlhttp://www.boehringer-ingelheim.com/news/news_releases/press_releases/2011/26_september_2011biosimilars.htmlhttp://www.clinicaltrials.gov/ct2/show/NCT01505491http://www.clinicaltrials.gov/ct2/show/NCT01505491http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2011/26_september_2011biosimilars.htmlhttp://www.boehringer-ingelheim.com/news/news_releases/press_releases/2011/26_september_2011biosimilars.htmlhttp://www.boehringer-ingelheim.com/news/news_releases/press_releases/2011/26_september_2011biosimilars.html


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Teva/Lonza Biosimilar Overview

Teva/Lonza January 2009, Teva and Lonza announce a strategic partnership in biosimilars.

Teva is one of the largest generic firms in the world, and Lonza is one of thelargest biologic contract manufacturing organizations in the world

http://www.lonza.com/group/en/company/news/archive/news_2009/teva_and_lonza_announce.html

May 2010, Teva initiates phase I PK/PD trial for TL011 (biosimilar rituximab) vsRituxan in subjects with rheumatoid arthritis. 60 patient trial expected to

complete in January 2012http://clinicaltrials.gov/ct2/show/NCT01123070

June 2011, Teva announced successful completion of Phase III study of XM22(lipegfilgrastim) vs branded Neulasta (pegfilgrastim)

http://www.tevapharm.com/en-US/Media/News/Pages/2011/1580531.aspx

July 2011, Tevagrastim (biosimilar neupogen) already approved in EU (2008) couldenter the US market as early as November 2013 (named Neutroval) after asettlement with Amgen

Tbo-filgrastim approved in the U.S. August 29 th 2012 as a 351(a) application, and istherefore technically not a biosimilar since it was not approved under 351(k)

October 3, 2012 halts PIII development work on biosimlar rituximab

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http://www.lonza.com/group/en/company/news/archive/news_2009/teva_and_lonza_announce.htmlhttp://clinicaltrials.gov/ct2/show/NCT01123070http://www.tevapharm.com/en-US/Media/News/Pages/2011/1580531.aspxhttp://www.tevapharm.com/en-US/Media/News/Pages/2011/1580531.aspxhttp://www.tevapharm.com/en-US/Media/News/Pages/2011/1580531.aspxhttp://www.tevapharm.com/en-US/Media/News/Pages/2011/1580531.aspxhttp://clinicaltrials.gov/ct2/show/NCT01123070http://www.lonza.com/group/en/company/news/archive/news_2009/teva_and_lonza_announce.html


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Amgen Biosimilar Overview

Amgen

April 2011, Amgen announced initiation of biosimilar program and seekingpartners

http://wwwext.amgen.com/media/media_pr_detail.jsp?year=2011&releaseID=1553298

December 2011, Amgen and Watson pharmaceuticals announce a jointdevelopment program for oncology biosimilars. Watson will invest up to $400Million into the venture and receive royalty and sales. The new venture willnot target Amgen products

http://ir.watson.com/phoenix.zhtml?c=65778&p=irol-newsArticle&ID=1641101&highlight

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http://wwwext.amgen.com/media/media_pr_detail.jsp?year=2011&releaseID=1553298http://ir.watson.com/phoenix.zhtml?c=65778&p=irol-newsArticle&ID=1641101&highlighthttp://ir.watson.com/phoenix.zhtml?c=65778&p=irol-newsArticle&ID=1641101&highlighthttp://ir.watson.com/phoenix.zhtml?c=65778&p=irol-newsArticle&ID=1641101&highlighthttp://ir.watson.com/phoenix.zhtml?c=65778&p=irol-newsArticle&ID=1641101&highlighthttp://wwwext.amgen.com/media/media_pr_detail.jsp?year=2011&releaseID=1553298


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Novartis Biosimilar Overview

Novartis via Sandoz subsidiary

Sandoz is one of the largest generic organizations in the world and has an activebiosimilar development program

Sandoz/Novartis has approved and launched biosimilar human growthhormone Omnitrope (launched 2006), Epogen (Binocrit launched October2007) and Neupogen (Zarzio launched Feb 2009) in Europe.

January 2012, Initiated phase III U.S. trial for biosimilar filgrastimand global Phase III for biosimilar pegfilgrastim

http:// www.sandoz.com/media_center/news/2012/press_releases/2012_01_19_biosimilars_phaseIII_trials.shtml

Sandoz/Novartis reportedly has 8-10 molecules in development including mAbs

January 2011, Sandoz initiates Phase I PK/PD trial with biosimilar rituximab in164 patients with expected trial completion date of April 2012

http://clinicaltrials.gov/ct2/show/NCT01274182

December 2011, Sandoz initiates Phase III clinical trial of biosimilar rituximab vsRituxan in lymphoma. 618 patient trial expected to complete in October 2013


S fi Bi i il O i
http://www.sandoz.com/media_center/news/2012/press_releases/2012_01_19_biosimilars_phaseIII_trials.shtmlhttp://clinicaltrials.gov/ct2/show/NCT01274182http://clinicaltrials.gov/ct2/show/NCT01419665http://clinicaltrials.gov/ct2/show/NCT01419665http://clinicaltrials.gov/ct2/show/NCT01274182http://www.sandoz.com/media_center/news/2012/press_releases/2012_01_19_biosimilars_phaseIII_trials.shtml


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Sanofi Biosimilar Overview

Sanofi

January 2012, Sanofi and Nichi-Iko announced plans to developbiosimilar infliximab in Japan. This is based upon an existingpartnership designed to market small molecule and follow on biologicgenerics.

Phase I trials are expected to start in January 2012 Analysts estimate that launch could be 2016

C llt i Bi i il O i


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Celltrion Biosimilar Overview Celltrion (S. Korea)

Celltrion is a biologic contract manufacturing organization that

announced a biosimilar development program in September2008

Disclosed targets Herceptin Remicade

Rituxan

Enbrel Erbitux Synagis Humira Avastin

Partners North America/Western Europe/Australia/NZ Hospira Japan Nippon Kayaku Latin America Oli Med CEE/CIS/Russia Egis Middle East/N Africa - Hikma

C llt i Bi i il O i


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Celltrion Biosimilar Overview

Celltrion (S. Korea)

November 2011, Celltrion has completed Phase I and Phase III clinicalstudies in biosimilar inflixaimb and is expected to be launched in S.Korea in mid 2012


Celltrion has reported top level results of the Phase III trial as beingsuccessful, and expect approval in mid 2012 with a rolling submission

Celltrion has GMP as they reportedly have a contract with BMS tomanufacture Orencia (abatacept)

Celltrion received approval in S. Korea for biosimilar infliximab in July2012 and has launched in September 2012 at a 30% discount tobranded Remicade (consistent with S. Korean price regulations)

Celltrion files biosimlar infliximab with EMA Filing Accepted April2012

M k T t ik d ???
http://clinicaltrials.gov/ct2/show/NCT01217086http://clinicaltrials.gov/ct2/show/NCT01217086


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Merck . Two strikes and youre ???

Merck Bioventure folds into Merck Merck formed Merck Bioventures inlate 2008 to commercialize biosimilars. Led by Mike Kamarck, MerckBioventures is folded under the biologics and vaccines division in April 2012.

Strike 1? Merck attempts to build a biosimilar long acting Epo version ofAranesp (MK-2578) via their $400 million acquisition of GlycoFi in 2006.Because of potential cardiovascular risks in the class, FDA requests acardiovascular outcomes trial for MK-2578. Merck terminatesdevelopment in May 2010

Strike 2? Merck licenses in biosimilar etanercept from Hanwah in June2011 for a reported $720 million over 12 years. Merck has developmentand manufacturing for all countries other than S. Korea and Turkey.

November 2011, Amgen announces the approval of a new patentcovering Enbrel in the United States. Filed in May of 1995, the patent ifsuccessfully defended could provide protection through November 2028(US Patent 8,063,182)

Pfi Bi i il d l t


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Pfizer . Biosimilar developments..

Pfizer/Biocon biosimilar insulin divorce Pfizer had previously

entered (October 2010) into a biosimilar insulin agreement withBiocon with an investment of $200 million. In March 2012, Pfizerdecided to exit the agreement and focus on other biosimilarproducts

Pfizer biosimilar rituximab in RA Pfizer initiates a Phase I/IIbiosimilar ritixumab clinical trial with 210 patients in moderate tosevere rheumatoid arthritis treated with methotrexate. The trial(REFLECTIONS B328-01) compares rituximab US and EU vsbiosimilar and is expected to complete in December 2013

Other biosimilars? Reportedly Pfizer has targeted at least 5mAbs as potential biosimilars

Conclusions


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Conclusions

Biosimilars are here, and will continue to develop as a

market Global standards (EU, US, Japan, WHO) do not see

biosimilars as generics Clinical trial requirements, in general, are different and

more complex than with small molecule generics Due to differences in biosimilar vs RP, ability to

track/trace and identify products is critical howeverINNs are not currently unique except by regulatorydecree (e.g. Japan)

Many areas are still unclear, even with the passage ofACA/BPCI

Questions?


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Questions?

Backup


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Backup

How Difficult Can It Be To Copy A Biologic?


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How Difficult Can It Be To Copy A Biologic?

Why Are Regulatory Bodies So Consistent On Substitution?I I N E T M k A Bi l i i E If Y A Th O i i l


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It Is Not Easy To Make A Bioloigic Even If You Are The OriginalInventor

Myozyme Scale Up From 160 liter to 2000 liter Facility


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Requires New Biologic License Application

Genzyme Initially Submits 2000 liter Application in Early


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2007 For Myozyme

FDA Does Not Accept Myozyme Crossover Data Calls


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For Separate BLA

Delayed Access For Patients During Myozyme Filing


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Delayed Access For Patients During Myozyme Filing

Lumizyme (2000 liter) Finally Approved By FDA in May


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2010 Still Different from Myozyme

Documents

Biosimilars–US-and-International-Update