Biosimilars U.S.

and International Update

October 10, 2012

Disclaimer
The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Elsevier, or any organization with which the presenter is employed or affiliated.

Biosimilars -- Why We Are Here Biologic products continue to grow world wide and are >$150 billion as a market -- ~50% in The U.S.
Global Biologics Spending and Growth, 2001-2012
180 160 140
SPENDING (US$BN)

Global biologic sales Global biologic growth Global small molecule growth

25%

20%
GROWTH (CONST US$)

120 100 80 60 40 20 0
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 MAT Mar 2012

15%

10%

5%

0%

Source: IMS MIDAS, Mar 2012

The global traditional small molecule Patent Cliff peaks in 2012 and starts to decline biologics are the next logical target

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

Early Biotech Products Are Reaching Mid Age And By The Time Biosimilars Arrive.
Drug
Aranesp Enbrel Epogen Remicade Neulasta Rituxan Herceptin Lantus Avastin Humira Avonex Neupogen

FDA Approval Date

September 2001 November 1998 June 1989 August 1998 January 2002 November 1997 September 1998 April 2000 February 2004 December 2002 May 1996 February 1991

Current Age
10 13 22 13 9 14 13 11 7 9 15 20

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

Branded Biologics The Next Target

Bummer of a birthmark, Hal

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 be assessed or regulated as generic drugs

Background to BPCI (Biologics Price Competition 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 on March 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 for biological products shown to be biosimilar to OR interchangeable with an FDA licensed reference product. Referred to as 351(k) of the PHS Act

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, publicly available information regarding FDAs previous determination that the reference product is safe, pure and potent. This new licensure pathway under section 351(k) of the PHS Act permits a biosimilar biological product to be licensed based on less than a full complement of productspecific preclinical and clinical data abbreviated licensure pathway.
There is no abbreviated licensure pathway for related biological products not intended to be biosimilar to a reference product.

BPCI revised definition of biologic product

BPCI Act revises the definition of biological product in the Public Health Service Act (PHS Act) to include protein: . . . a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product applicable to the prevention, treatment, or cure of a disease or condition of human beings Historically, some proteins have been approved as drugs under section 505 of the FD&C Act (e.g., human growth hormone), and other proteins have been licensed as biologics under section 351(a) of the PHS Act (e.g., blood factors)

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 biological product and the reference product in terms of the safety, purity, and potency 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 an application submitted under section 351(k) of the PHS Act.

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 or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alternation or switch.

Note: The interchangeable product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product (subject to State laws).

General Requirements
A 351(k) application must include information demonstrating that 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 previously approved for the reference product; Has the same route of administration, dosage form, and strength as the reference product; and Is manufactured, processed, packed, or held in a facility that meets standards designed to assure that the biological product continues to be safe, pure, and potent

General Requirements
The 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 highly similar to the reference product notwithstanding minor differences in clinically inactive components; Animal studies (including the assessment of toxicity); and A clinical study or studies (including the assessment of immunogenicity and pharmacokinetics (PK) or pharmacodynamics (PD)) that are sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the reference product is licensed and for which licensure is sought for the biosimilar product FDA has the right to determine, at its discretion, that an element listed above is unnecessary in a 351(k) filing

Exclusivity
BPCIA has exclusivity provisions, and provisions for resolution of patent disputes 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 or already licensed products, and 1 Year exclusivity provision for the first interchangeable biosimilar approved under 351 (k)

Patent Disputes
Process for patent dispute resolution
Unlike the public patent listing process for generic drugs, the BPCIA provides for a detailed private disclosure process 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

U.S. Biosimilar Track Record

No 351(k) applications have arrived at the FDA as of September 12, 2012*
Sponsors have submitted 11 IND applications and conducted more 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) and deducted from the $1.96 Million total fee upon filing of marketing application

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

2006 A Meeting Of Payers Looking Into Biosimilars

2009 A Gathering of Payers Interested in Biosimilars

2012 Payers Eagerly Awaiting The Start of A Biosimilar Launch Meeting

Biosimilars So How Did We Get Here In The EU? EU Approach Based Upon Science
European Commission Directive June 2003
Directs EMA to create a regulatory pathway for biosimilars by establishing new Annex on an application for MA with specific dossier requirements for similar biological medicinal products

EMA & CHMP Guideline: Similar Biological Medicinal Product October 2005
Outlines requirements for Marketing Authorization Applications (MAA) based on the demonstration of the similar nature of the two biological medicines

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

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

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

Biosimilar Product Experience in EU as of September 2012

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

12 biosimilar medicinal products currently holding a valid marketing authorization

1 somatropin, 5 epoetins, 6 filgrastims

6 biosimilar Marketing Authorization Applications are currently under review

1 filgrastim, 1 follitropin alfa, 2 infliximab, 3 insulin human

Comparison across various biosimilar regulations Use of foreign comparator/reference product

US
RP must be licensed under 351(a)

EU
RP now (Sept 2012) permitted outside of EU based upon case by case approach and comparative data may be necessary

Japan
RP must be approved in Japan

Canada
RP should be authorized for sale and marketed in Canada

WHO
RP should be approved in licensing country

Comparative data involving non US licensed comparator produt may address, in part requirements under PHS 351(k); bridging data required

Same RP must be used throughout comparability program

Same RP should be used throughout comparability program

Comparative data involving non Canada product may be used only if, among other things, marketed by the same company and in jurisdiction with comparable standards

Same RP should be used throughout comparability program If licensing country lacks RP, an RP may be used that is widely marketed in a jurisdiction with well established regulatory framework and experience with biologics evaluation and post market surveillance

Comparison across various biosimilar regulations Extrapolation of indication

US
Possible with sufficient scientific justification addressing e.g. MoA in each proposed indication, PK and bio distribution in different populations; difference in expected toxicities in each population

EU
Possible depending on clinical experience, literature, MoA of proposed indications, safety issues in sub populations Concept paper proposes revising these criteria

Japan
Possible if a similar pharmacological result can be expected in the new indication Not possible if the MoA differs for each indication or is not clear

Canada
Possible depending on MoA, pathophysiological mechanisms of disease, safety profile in relevant indications and/or populations, and clinical experience with reference product

WHO
Possible if, e.g. sensitive clinical test model was used; MoA and/or receptors are the same (or a strong scientific rational and additional is provided); and no special safety issues are expected in the new indication

Comparison across various biosimilar regulations Clinical studies/testing

US
Generally will need a clinical study or studies; assessed on a case by case basis Scope and magnitude will depend on extent of residual uncertainty Similar human PK and PD profile may provide basis for targeted approach

EU
Comparative clinical trials usually necessary for recombinant proteins; in some cases, clinical PK/PD studies may be sufficient All biosimilar applications granted to date contained substantial clinical data

Japan
Clinical studies generally required, unless nonclinical PK, PD or PK/PD studies are sufficient Type and content of clinical studies assessed on a case by case basis

Canada
Comparative PK and PD should be conducted Comparative efficacy and safety trails are critical

WHO
Clinical trials are usually required Confirmatory human PK/PD data may be used in lieu of efficacy trials, provided that there is sufficient scientific justification

Comparison across various biosimilar regulations Interchangeability

US
Higher standard than biosimilarity
At this time, difficult to determine exact requirements without additional guidance For a product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alternation or switch.

EU
Determined by Member States Biosimilars are not a generic Decision to treat a patient with an RP or biosimilar should be made following an opinion of a healthcare professional

Japan
Important to assure traceability of adverse events during surveillance period Switching between a biosimilar and the RP should in principle be avoided throughout the treatment period

Canada
Biosimilars are not generics. Authorization is not a declaration of pharmaceutical or therapeutic equivalenence with the reference product

WHO
Biosimilars are not generics Determined by national authorities

Comparison across various biosimilar regulations Unique Naming

US
Adequate post marketing safety monitoring mechanisms should differentiate between adverse events associated with the biosimilar and the reference product
Guidance on naming is expected

EU
To support pharmacovigilance, the specific product given to the patient should be clearly identified All biosimilars authorized to date have borne either a brand name or a distinctive feature in the nonproprietary name

Japan

Canada

WHO
Biosimilars should be clearly identifiable by unique brand name, the WHOs policy on INNs should be followed
Lot number is essential for traceability

The non proprietary Not addressed names and brand names of biosimilars should be readily distinguishable from the names of reference products and other biosimilars
A very detailed naming policy with examples for biosimilar naming

Approvals, Failures and Launches of Biosimilars Second Enoxaparin Approved in September 2011 (US)
10/2010: Neutroval 12/2007: Insulin Marvel 1/2010: JCR EPO Alfa

8/2007: EPO Alfa Hexal 06/2006: Alpheon 8/2007: Abseamed 8/2007: Binocrit 04/2006: Omnitrope 04/2006: Valtropin 05/2006: Omnitrope
12/2007: Retacrit 12/2007: Silapo

9/2008: Filgrastim Ratiopharm 9/2008: RatioGrastim 7/2010: Enoxaparin

9/2008: Biograstim 4/2011: Epostim 9/2008: TevaGrastim 05/2009: Omnitrope 6/2010: Nivestim 9/2010: Nivestim

2/2009: Filgrastim Hexal 2/2009: Zarzio

2006

2007

2008

2009

2010
Growth hormone G-CSF Insulin

2011
IFN-alfa LMWH EPO-alfa EPO-zeta

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)

Sources: Datamonitor Consulting; EMA (click here); Australian TGA (click here); Japan MHLW (click here); Health Canada (click here); FDA (click here); company reported data (obtained f rom company websites during April 2011); EU approvals unless otherwise stated

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

Market Germany Italy UK France Spain

hGH 5.1% 15.3% 1.0% 12.5% 1.0%

EPO 52.1% 0.2% 0.9% 2.0% 0.9%

GCSF 31.0% 3.8% 24.0% 3.8% 3.8%

IMS August 2010 MAT Global Biosimilar Market Is $235 Million

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

Germany tends to have favorable biosimilar use -- why is Germany uptake of biosimilars better 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 the sick funds for the physicians

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

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

Biosimilar Epoetins: Gaps in Quality and Potential Safety EU Journal of Hospital Pharmacy Science v 11 2005
Biosimilar (or copy) versions of epoetins have been available in developing countries for many years and are widely used for economic reasons. Despite limited data on the efficacy and safety of biosimilar epoetins, they are prescribed under the assumption that they have 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 Safety Eu Journal of Hospital Pharmacy Science v 11 2005 -- 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.

EPO Brazil History of Biosimilar or copy biologics

12 Biosimilar Epoetins from 5 different manufacturers were analyzed Potency of 12 Epoetins vaired from 68% to 119% of that stated on 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 alpha products for failing to meet required standards 2,3
1. Schmidt CA, Ramos AS, da Silva JEP, Fronza M, Dalmora SL. Activity evaluation and characterization of recombinant human er ythropoietin in pharmaceutical 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 November 2004].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 November 2004].Available from URL: http://e-legis.bvs.br/leisref/public/showAct.php?id=8151

What Are Payers Doing With Biosimilars?

Germany payers are setting targets for physicians for prescribing of biosimilars Norway Payer attempted to use pharmacists to substitute biosimilar GCSF for branded Neupogen without physician intervention. Amgen sued and won Norway is not appealing Brasil - The Brazilian Ministry of Health (Ministrio da Sade) has announced that it has entered into an agreement with PharmaPraxis to manufacture a biosimilar version of Humira (adalimumab). Instituto Vital Brazil and PharmaPraxis, which is part of Axis Biotec, will be partners

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

EMA Pharmacovigilance Working Party Cites PRCA in Biosimilar EPO Trial Important That Accurate Medication Histories Are Maintained for Patients Treated With EPOs Why Unique Naming Is Important

U.K. State Regulatory Body Links Proper Identification of Biosimilar Products With Pharmacovigilance Due to same naming (INN) tracking should be done by brand name

Germany EPO Substitution New Proposal In May 2011 Linked Products That Are Identical For Purposes of Substitution. Identical Defined As Same Drug, Same Manufacturing Process i.e. Identical Regulatory Filing

Biosimilars that are identical among each other are substitutable for each other But NOT across biosimilars

Who Are The Mainstream Competitors?

Competitive landscape evolving

Traditional pharmaceutical companies once completely aligned as innovative manufacturers is fragmenting

Time, cost and credibility required to develop high quality biosimilars 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 Companies Now Clearly Entering Biosimilar Space
Branded Pharmaceutical Companies The Obvious

Merck Partners with Hanwha (Korea) for biosimilar Etanercept for a reported $720 Million Novartis already in biosimilar space with Sandoz subsidiary launched with HGH, EPO, GCSF Boehringer Ingelheim Phase I of biosimilar adalimumab and rituximab initiated 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 in this space

Merck Biosimilar Overview

Merck
December 2008 announced $1.5 Billion investment into biosimilars leading with their GlyoFi acquisition. Stated goal of 5 phase III compounds by 2012. February 2009, acquired biosimilar assets of Insmed in (INS-19 biosimilar Neupogen, INS-20 biosimilar Neulasta) June 2011, Partners with Hanwha (Korea) for biosimilar etanercept (HD203) for a reported $720 Million through 2024 for global markets except for Korea and Turkey
300 patient biosimilar etanercept S. Korea phase III study enrolled and believed completed 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 April 2012

Boehringer Ingelheim Biosimilar Overview

Boehringer Ingelheim Pharmaceuticals
September 2011, Boehringer Ingelheim announces establishment of a separate biosimilar division
http://www.boehringeringelheim.com/news/news_releases/press_releases/2011/26_september_2011biosimilars.html

December 2011, initialized Phase I PK/PD study of BI-695501 (biosimilar adalimumab) in 180 patient three arm trial (biosimilar adalimumab vs US Humira vs EU Humira). Expected completion July 2012
http://www.clinicaltrials.gov/ct2/show/NCT01505491

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 the largest 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) vs Rituxan in subjects with rheumatoid arthritis. 60 patient trial expected to complete in January 2012
http://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) could enter the US market as early as November 2013 (named Neutroval) after a settlement with Amgen

Tbo-filgrastim approved in the U.S. August 29th 2012 as a 351(a) application, and is therefore technically not a biosimilar since it was not approved under 351(k)
October 3, 2012 halts PIII development work on biosimlar rituximab

Amgen Biosimilar Overview

Amgen
April 2011, Amgen announced initiation of biosimilar program and seeking partners
http://wwwext.amgen.com/media/media_pr_detail.jsp?year=2011&releaseID=1553298

December 2011, Amgen and Watson pharmaceuticals announce a joint development program for oncology biosimilars. Watson will invest up to $400 Million into the venture and receive royalty and sales. The new venture will not target Amgen products
http://ir.watson.com/phoenix.zhtml?c=65778&p=irol-newsArticle&ID=1641101&highlight

Novartis Biosimilar Overview

Novartis via Sandoz subsidiary
Sandoz is one of the largest generic organizations in the world and has an active biosimilar development program Sandoz/Novartis has approved and launched biosimilar human growth hormone Omnitrope (launched 2006), Epogen (Binocrit launched October 2007) and Neupogen (Zarzio launched Feb 2009) in Europe.

January 2012, Initiated phase III U.S. trial for biosimilar filgrastim and 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 in 164 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 vs Rituxan in lymphoma. 618 patient trial expected to complete in October 2013
http://clinicaltrials.gov/ct2/show/NCT01419665

Sanofi Biosimilar Overview Sanofi

January 2012, Sanofi and Nichi-Iko announced plans to develop biosimilar infliximab in Japan. This is based upon an existing partnership designed to market small molecule and follow on biologic generics. Phase I trials are expected to start in January 2012 Analysts estimate that launch could be 2016

Celltrion Biosimilar Overview

Celltrion (S. Korea)
Celltrion is a biologic contract manufacturing organization that announced a biosimilar development program in September 2008 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

Celltrion Biosimilar Overview

Celltrion (S. Korea)
November 2011, Celltrion has completed Phase I and Phase III clinical studies in biosimilar inflixaimb and is expected to be launched in S. Korea in mid 2012
http://clinicaltrials.gov/ct2/show/NCT01217086

Celltrion has reported top level results of the Phase III trial as being successful, and expect approval in mid 2012 with a rolling submission Celltrion has GMP as they reportedly have a contract with BMS to manufacture Orencia (abatacept) Celltrion received approval in S. Korea for biosimilar infliximab in July 2012 and has launched in September 2012 at a 30% discount to branded Remicade (consistent with S. Korean price regulations) Celltrion files biosimlar infliximab with EMA Filing Accepted April 2012

Merck . Two strikes and youre ???

Merck Bioventure folds into Merck Merck formed Merck Bioventures in late 2008 to commercialize biosimilars. Led by Mike Kamarck, Merck Bioventures is folded under the biologics and vaccines division in April 2012. Strike 1? Merck attempts to build a biosimilar long acting Epo version of Aranesp (MK-2578) via their $400 million acquisition of GlycoFi in 2006. Because of potential cardiovascular risks in the class, FDA requests a cardiovascular outcomes trial for MK-2578. Merck terminates development in May 2010 Strike 2? Merck licenses in biosimilar etanercept from Hanwah in June 2011 for a reported $720 million over 12 years. Merck has development and manufacturing for all countries other than S. Korea and Turkey. November 2011, Amgen announces the approval of a new patent covering Enbrel in the United States. Filed in May of 1995, the patent if successfully defended could provide protection through November 2028 (US Patent 8,063,182)

Pfizer . Biosimilar developments..

Pfizer/Biocon biosimilar insulin divorce Pfizer had previously entered (October 2010) into a biosimilar insulin agreement with Biocon with an investment of $200 million. In March 2012, Pfizer decided to exit the agreement and focus on other biosimilar products Pfizer biosimilar rituximab in RA Pfizer initiates a Phase I/II biosimilar ritixumab clinical trial with 210 patients in moderate to severe rheumatoid arthritis treated with methotrexate. The trial (REFLECTIONS B328-01) compares rituximab US and EU vs biosimilar and is expected to complete in December 2013 Other biosimilars? Reportedly Pfizer has targeted at least 5 mAbs as potential biosimilars

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 however INNs are not currently unique except by regulatory decree (e.g. Japan) Many areas are still unclear, even with the passage of ACA/BPCI

Questions?

Backup

How Difficult Can It Be To Copy A Biologic?

Why Are Regulatory Bodies So Consistent On Substitution? It Is Not Easy To Make A Bioloigic Even If You Are The Original Inventor

Myozyme Scale Up From 160 liter to 2000 liter Facility Requires New Biologic License Application

Genzyme Initially Submits 2000 liter Application in Early 2007 For Myozyme

FDA Does Not Accept Myozyme Crossover Data Calls For Separate BLA

Delayed Access For Patients During Myozyme Filing

Lumizyme (2000 liter) Finally Approved By FDA in May 2010 Still Different from Myozyme