mAbs 7:1, 9--14; January/February 2015; © 2015 BioProcess Technology Consultants, Inc.
`
`REVIEW
`
`The therapeutic monoclonal antibody market
`
`Dawn M Ecker, Susan Dana Jones, and Howard L Levine*
`
`BioProcess Technology Consultants, Inc.; Woburn, MA USA
`
`therapeutic
`the first
`Since the commercialization of
`monoclonal antibody product
`in 1986,
`this
`class of
`biopharmaceutical products has grown significantly so that,
`as of November 10, 2014, forty-seven monoclonal antibody
`products have been approved in the US or Europe for the
`treatment of a variety of diseases, and many of
`these
`products have also been approved for other global markets.
`At the current approval rate of » four new products per year,
`»70 monoclonal antibody products will be on the market by
`2020, and combined world-wide sales will be nearly $125
`billion.
`
`Introduction
`
`The commercial development of therapeutic monoclonal anti-
`bodies commenced in the early 1980s, and by 1986 the first ther-
`apeutic monoclonal antibody, Orthoclone OKT3, was approved
`for prevention of kidney transplant rejection. Since the approval
`of OKT3, therapeutic monoclonal antibodies and antibody-
`related products such as Fc-fusion proteins, antibody fragments,
`and antibody-drug conjugates (collectively referred to hereafter
`as monoclonal antibody products) have grown to become the
`dominant product class within the biopharmaceutical market.
`Monoclonal antibody products today are approved for the treat-
`ment of a variety of diseases, ranging from those that treat patient
`populations of a few thousand or less for such orphan indications
`as paroxysmal nocturnal hemoglobinuria or
`the cryopyrin-
`associated periodic syndromes to those treating hundreds of
`thousands of patients for some cancers and multiple sclerosis or
`even millions of patients for diseases such as asthma and rheuma-
`toid arthritis.
`
`Growth of the Monoclonal Antibody Market
`
`Following the approval of the first monoclonal antibody prod-
`uct in 1986, sales growth and approval of additional products
`was slow until the late 1990s when the first chimeric monoclonal
`antibodies were approved. With the approval of these products,
`followed by the approval of humanized and then fully human
`monoclonal antibodies, the rate of product approvals and sales of
`monoclonal antibody products has increased dramatically so that
`
`*Correspondence to: Howard L Levine; Email: hlevine@bptc.com
`Submitted: 09/16/2014; Revised: 11/03/2014; Accepted: 11/12/2014
`http://dx.doi.org/10.4161/19420862.2015.989042
`
`in 2013, global sales revenue for all monoclonal antibody prod-
`ucts was nearly $75 billion,1 representing approximately half of
`the total sales of all biopharmaceutical products. The continued
`growth in sales of the currently approved monoclonal antibody
`products, along with the over 300 monoclonal antibody product
`candidates currently in development, many for multiple indica-
`tions,1,2 will result in continued growth in sales of monoclonal
`antibody products in the coming years and will continue to drive
`the overall sales of all biopharmaceutical products.
`As shown in Figure 1, the number of monoclonal antibody
`products approved for commercial sale in the US and Europe has
`grown steadily, with three to five new products approved per year
`for the last several years. While a total of fifty-eight monoclonal
`antibody products have been approved in Europe and/or the US
`since 1986, eleven of these products have been withdrawn for
`various reasons, leaving forty-four approved monoclonal anti-
`body products currently on the market (Table 1). Of the forty-
`seven monoclonal antibody products approved and marketed in
`the United States and Europe as of November 10, 2014,1,3,4
`three are produced in E. coli while all of the other products are
`produced in mammalian cells. Of the products produced in
`mammalian cell culture, thirty-one are full-length naked mono-
`clonal antibodies; one is a bispecific antibody, two are antibody-
`drug conjugates, one is a radio-labelled antibody conjugate, one
`is an antigen-binding fragment (Fab), and eight are Fc‑fusion
`proteins containing the antibody constant
`region fused to
`another non-antibody-related protein domain. Two of the three
`products produced in E. coli are Fabs while the third is an Fc-
`fusion protein. Of the full length monoclonal antibodies, we con-
`sider Prolia and Xgeva as two separate products even though they
`are manufactured from the same biologically active substance.
`This decision is based on the fact that Prolia and Xgeva are pre-
`sented in different formulations and container/closure systems,
`and separate Biological License Applications (not Supplemental
`Applications) were filed in the US for each. The list of forty-seven
`approved monoclonal antibody products also includes the first
`biosimilar monoclonal antibodies approved in Europe, Inflectra
`and Remsima. The bulk monoclonal antibody used to produce
`these biosimilars is manufactured by a single supplier (Celltrion),
`however, we consider them as separate products since the final
`drug product for each is manufactured by a separate entity and
`two separate manufacturers are responsible for final batch release
`of the products. Furthermore, separate European Marketing
`Authorization Applications were submitted for each product.
`Based on a review of historical success and turnover rates (i.e.,
`the length of time required for a product to move from one stage
`of development to the next) of biopharmaceutical product devel-
`
`www.tandfonline.com
`
`mAbs
`
`9
`
`opment candidates, »26% of the monoclonal antibody products
`Mylan v. Genentech
`IPR2016-00710
`Genentech Exhibit 2135
`
`

`

`tons of all other recombinant protein products. The demand for
`monoclonal antibody products has resulted in a significant
`amount of global manufacturing capacity devoted to their pro-
`duction as well as to significant improvements in methods and
`approaches
`to monoclonal antibody manufacturing process
`design and optimization.8-12
`The forty-seven monoclonal antibody products on the market
`in the US and Europe as of November 10, 2014 are listed in
`Table 1. In 2013, eighteen of these monoclonal antibody prod-
`ucts (Humira, Remicade, Enbrel, Rituxan, Avastin, Herceptin,
`Lucentis, Erbitux, Synagis, Eylea, Soliris, Tysabri, Stelara, Xolair,
`Orencia, Simponi, Actemra, and Xgeva) achieved annual sales of
`over $1 billion, while six of these products (Humira, Remicade,
`Enbrel, Rituxan, Avastin, Herceptin) had sales of greater than
`$6 billion. Humira, recorded sales of nearly $11 billion, the high-
`est sales figure ever recorded for a biopharmaceutical product.
`To further highlight the growth in sales of monoclonal anti-
`body products during the last ten years, the sales growth profiles
`of the top six selling monoclonal antibody products (Humira,
`Remicade, Enbrel, Rituxan, Avastin, Herceptin) are compared to
`those of the two top-selling, recombinant protein products pro-
`duced in mammalian cell culture (the cytokines Avonex and
`Rebif) in Figure 3. The average compound annual growth rate
`for these six monoclonal antibody products over this period is
`20% while that of the two mature recombinant protein products
`was essentially flat.
`Based on a review of historical sales data, company annual
`reports, and sales projection data collected by BioProcess Tech-
`Ò
`database, we
`nology Consultants in our proprietary bioTRAK
`forecast that the monoclonal antibody market will continue to
`grow at a CAGR of 8% or more for the next several years. At this
`growth rate, sales of currently approved monoclonal antibodies
`plus sales from new products approved in the coming years will
`drive the world-wide sales of monoclonal antibody products to
`
`»$94 billion by 2017 and nearly $125 billion by 2020. Our pro-
`
`jections are consistent with those of others, such as a recent report
`from BCC Research that predicts the market for monoclonal
`antibody products will be nearly $90 billion by 2017.13
`
`Factors Contributing to Growth of the Monoclonal
`Antibody Market
`
`The continued interest in antibody product development is
`partially driven by the rapid advancement of our understanding
`of disease at a molecular level. Although failing to meet some
`observers’ initial high expectations, genomics, proteomics and
`other systems biology tools continue, in fact, to provide impor-
`tant new targets for modulating disease.14 Monoclonal antibody
`products often provide the most rapid route to a clinical proof-
`of-concept for activating, inhibiting, or blocking these new tar-
`gets. Since the production of most monoclonal antibody prod-
`ucts is easily amenable to efficient platform-based approaches
`and antibodies are generally well-tolerated and highly specific,
`the risk of unexpected safety issues in human clinical trials of
`monoclonal antibody products is lower than with many other
`
`Figure 1. Annual approvals of monoclonal antibody products.3,4 The
`number of monoclonal antibody products first approved for commercial
`sale in the US or Europe each year since 1982 is shown. The totals
`include all monoclonal antibody and antibody-related products. Prod-
`ucts approved but subsequently removed from the market are denoted
`in blue; products currently marketed are denoted in green. 2014 total is
`as of November 10, 2014.
`
`entering Phase 2 human clinical trials in recent years will ulti-
`mately achieve market approval with an average time from the
`
`start of Phase 2 clinical trials to approval of » seven years.5-7
`
`Given the large number of monoclonal antibody candidates cur-
`rently in development, we expect that the number of products
`approved each year for the coming years will be approximately
`the same or more than it has been for the last several years. In
`fact, as of November 10, six monoclonal antibody products were
`granted first approvals in 2014, with approval decisions for at
`least two additional products likely to be announced by the end
`of this year. Based on an approval rate of approximately four
`monoclonal antibody products per year, we anticipate that there
`will be 70 or more monoclonal antibody products on the market
`by 2020.
`Along with a higher approval rate than other biopharmaceuti-
`cal products, global sales of monoclonal antibody products have
`grown faster than these other products for the past five years.
`Figure 2 shows the breakdown of sales for monoclonal antibody
`products based on the product type (e.g., full length antibody,
`antibody conjugate, antibody fragment, etc.) and production sys-
`tem (e.g., mammalian cell culture, microbial fermentation). As
`seen from these data, sales of all monoclonal antibody products,
`
`regardless of the production system, have grown from »$39 bil-
`
`lion in 2008 to almost $75 billion in 2013, a 90% increase. By
`comparison, sales of other recombinant protein therapeutics have
`
`only increased »26% in the same time period.
`
`Corresponding to the increasing sales of monoclonal antibody
`products, there has been an increase in the total quantities of
`these products produced annually to meet the market demand.
`As shown in Figure 2, nearly 10 metric tons of monoclonal anti-
`
`body products were produced in 2013 compared to »8.6 metric
`
`10
`
`mAbs
`
`Volume 7 Issue 1
`
`

`

`(continuedonnextpage)
`
`1,030
`389
`1,527
`1,887
`NoMe
`1,504
`1,551
`30v
`1,432
`7,500
`127
`<1m
`
`5
`
`8,944
`824
`352
`1,444
`
`26
`427
`4,205
`
`3
`
`NoMe
`252
`<1m
`119
`
`10,659
`6,559
`
`3
`
`1,851
`1,926
`NoMe
`8,325
`NoMe
`NoMe
`789
`228
`6,748
`117
`17
`
`NoMe
`253
`1,119
`
`23
`
`2010
`2006
`2004
`1998
`2014
`2009
`2007
`1998
`2009
`1997
`1994
`2013
`2009
`1998
`2011
`2012
`2005
`2011
`2008
`2006
`2013
`2014
`2013
`2013
`2009
`2002
`1998
`2013
`2011
`2004
`2014
`1998
`2014
`2014
`2008
`2011
`2004
`2009
`2008
`2014
`2011
`2009
`2012
`
`GlobalSales($M)a
`
`2013
`
`Approval
`
`YearofFirst
`
`Amgen
`Amgen
`
`BiogenIdec
`
`Abbvie
`
`Johnson&Johnson
`Johnson&Johnson
`
`AlexionPharmaceuticals
`NovartisPharmaceuticals
`
`Merck&Co.
`
`Roche
`N/A
`
`Celltrion
`
`NeoPharmGroup
`
`Merck&Co.
`
`GlaxoSmithKline
`
`Roche
`
`Bristol-MyersSquibb
`Bristol-MyersSquibb
`
`Amgen
`
`NovartisPharmaceuticals
`
`Sanofi
`N/A
`Roche
`Hospira
`
`NovartisPharmaceuticals
`
`AbbVie
`Roche
`Roche
`
`BayerHealthcarePharmaceuticals
`
`MerckKGaA
`
`TakedaPharmaceuticalCo.
`
`Pfizer
`N/A
`N/A
`UCB
`
`GlaxoSmithKline
`
`Roche
`
`GlaxoSmithKline
`
`N/A
`N/A
`
`TakedaPharmaceuticalCo.
`
`Roche
`N/Ab
`
`Sales
`
`ReportingEU
`
`Company
`
`Amgen
`Amgen
`
`Roche
`Lilly
`N/A
`N/A
`
`Amgen
`Roche
`
`Amgen
`Roche
`N/A
`
`Roche
`N/A
`
`AbbVie
`Roche
`Roche
`
`Amgen
`
`UCB
`
`Roche
`
`Roche
`
`Company
`
`BiogenIdec
`AstraZeneca
`
`Johnson&Johnson
`Johnson&Johnson
`
`AlexionPharmaceuticals
`NovartisPharmaceuticals
`
`Johnson&Johnson
`
`Johnson&Johnson
`
`Bristol-MyersSquibb
`Bristol-MyersSquibb
`
`Merck&Co.
`
`NovartisPharmaceuticals
`
`Amgen
`Amgen
`
`BiogenIdec
`
`AbbottLaboratories
`
`JanssenBiotech
`
`Janssen-CilagInternational
`AlexionPharmaceuticals
`NovartisPharmaceuticals
`CentocorOrthoBiotech
`
`Genentech
`Centocor
`Celltrion
`
`FreseniusBiotech
`
`Centocor
`Amgen
`
`Genentech
`
`Bristol-MyersSquibb
`Bristol-MyersSquibb
`
`Amgen
`
`Genentech
`
`GenzymeTherapeutics
`
`Merck&Co.
`Genentech
`
`Hospira
`
`NovartisPharmaceuticals
`
`AbbottLaboratories
`
`Genentech
`Genentech
`
`RegeneronPharmaceuticals
`
`RegeneronPharmaceuticals
`
`Bristol-MyersSquibb
`
`ImCloneSystems
`
`TakedaPharmaceuticalCo.
`
`TakedaPharmaceuticalsU.S.A.,Inc
`
`BiogenIdec
`
`EliLillyandCo.
`
`Immunex
`BiogenIdec
`
`EliLillyandCo.
`
`UCB
`
`GlaxoSmithKline
`
`HumanGenomeSciences
`
`GlaxoSmithKline
`
`Genentech
`
`GlaxoSmithKline
`
`RegeneronPharmaceuticals
`
`RegeneronPharmaceuticals
`
`BiogenIdec
`
`SeattleGenetics
`
`BiogenIdec
`
`SeattleGenetics
`
`Roche
`
`GlaxoSmithKline
`
`HumanGenomeSciences
`
`ReportingUSSales
`
`Applicant
`BLA/MAA
`Original
`
`Xgevas(denosumab)
`Vectibix(panitumumab)
`Tysabri(natalizumab)
`Synagis(palivizumab)
`Sylvant(siltuximab)
`Stelara(ustekinumab)
`Soliris(eculizumab)
`Simulect(basiliximab)
`Simponi/SimponiAria(golimumab)
`Rituxan(rituximab)
`ReoProu(abciximab)
`Remsimakl(infliximab[biosimilar])
`Removabt(catumaxomab)
`Remicade(infliximab)
`Prolias(denosumab)
`Perjeta(pertuzumab)
`Orenciar(abatacept)
`Nulojixq(belatacept)
`Nplatep(romiplostim)
`Lucentiso(ranibizumab)
`Lemtrada(alemtuzumab)
`Keytruda(pembrolizumab)
`Kadcylan(ado-trastuzumabemtansine)
`Inflectrakl(infliximab[biosimilar])
`Ilaris(canakinumab)
`Humira(adalimumab)
`Herceptin(trastuzumab)
`Gazyva(obinutuzumab)
`Eyleaj(aflibercept)
`Erbitux(cetuximab)
`Entyvio(vedolizumab)
`Enbreli(etanercept)
`Eloctateh(FactorVIIIFcfusionprotein)
`Cyramza(ramucirumab)
`Cimziag(certolizumabpegol)
`Benlysta(belimumab)
`Avastin(bevacizumab)
`Arzerra(ofatumumab)
`Arcalystf(rilonacept)
`AlprolIXd(FactorIXFcfusionprotein)
`Adcetrisc(brentuximabvedotin)
`Actemra(tocilizumab)
`Abthrax(raxibacumab)
`
`Brandname(INN)
`
`Table1.Marketedtherapeuticmonoclonalantibodyproducts
`
`www.tandfonline.com
`
`mAbs
`
`11
`
`

`

`xAntibodyConjugate,Y-90.
`wFcFusionProtein,Fc-VEGFR.
`vFab,producedbypapaindigestionoffulllengthmonoclonalantibody.
`uSalesdatanotdisclosed,smallpatientmarket,bioTRAKÒestimateofglobalsales.
`tBispecific,Tri-functionalAntibody.
`sProliaandXgevaareconsideredastwoindividualproductseventhoughtheycontainthesamebulkmonoclonalantibody;seetext.
`rFcFusionProtein,Fc-CTLA-4.
`qFcFusionProtein,Fc-CTLA-4withaminoacidsubstitutions.
`pFcFusionProtein,Fc-TPO-Rbindingpeptide(producedbymicrobialfermentation).
`oFab(producedbymicrobialfermentation).
`nAntibody-DrugConjugate,DM1.
`mProductapprovalinlate2013;noannualsalesdisclosed,bioTRAKÒestimateofglobalsales.
`lInflectraandRemsimaareconsideredastwoindividualproducts;seetext.
`kBiosimilarAntibody,RemicadeOriginator.
`jFcFusionProtein,Fc-VEGFR(1,2).
`iFcFusionProtein,Fc-TNFR(p75).
`hFcFusionProtein,Fc-FactorVIII.
`gFabConjugate,PEG(producedbymicrobialfermentation).
`fFcFusionProtein,Fc-IL1R.
`eProductapprovalin2014;nosalesin2013.
`dFcFusionProtein,Fc-FactorIX.
`cAntibody-DrugConjugate,MMAE.
`bN/Adenoteproductnotavailableinthisregion.
`aSalesinformationobtainedfromcompanyannualreportsandotherpublicallyavailablesources.
`
`29
`70
`960
`1,465
`
`2002
`2012
`2011
`2003
`
`GlobalSales($M)a
`
`2013
`
`Approval
`
`YearofFirst
`
`SpectrumPharmaceuticals
`
`SpectrumPharmaceuticals
`
`Sanofi
`
`Bristol-MyersSquibb
`
`Novartis
`
`Sales
`
`ReportingEU
`
`Company
`
`Sanofi
`
`Bristol-MyersSquibb
`
`Roche
`
`ReportingUSSales
`
`Company
`
`IDECPharmaceuticals
`
`SanofiAventis
`
`Bristol-MyersSquibb
`
`Genentech
`
`Applicant
`BLA/MAA
`Original
`
`Zevalinx(ibritumomabtiuxetan)
`Zaltrapw(ziv-aflibercept)
`Yervoy(ipilimumab)
`Xolair(omalizumab)
`
`Brandname(INN)
`
`Table1.Marketedtherapeuticmonoclonalantibodyproducts(Continued)
`
`12
`
`mAbs
`
`Volume 7 Issue 1
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`

`

`types of therapeutic products. Therefore,
`for many of these novel targets, mono-
`clonal antibody products are often the
`first product candidates advancing to
`clinical
`trials. If
`the initial proof-of-
`concept studies with these products are
`successful,
`they
`can move
`rapidly
`towards commercialization, providing a
`“first-to-market” advantage.
`Also fueling the growth in monoclo-
`nal antibody product sales is the global
`market expansion of the pharmaceutical
`market in general resulting from the
`increasing and aging worldwide popula-
`tion and the increasing standard of living
`in emerging markets.15 In addition, the
`continued evaluation of monoclonal
`antibody products in new and expanded
`clinical indications results in continued
`demand for product for clinical studies
`subsequent
`sales
`in newly approved
`indications.
`As the biopharmaceutical industry
`matures,
`the number and types of
`diseases
`that will be
`economically
`treated with monoclonal
`antibody
`products will increase. Driven in part
`by the need for cost-effective supply
`of
`large quantities of products
`for
`such
`cost-sensitive
`indications
`as
`rheumatology and asthma,16 recent improvements in mono-
`clonal antibody production technologies have substantially
`improved process yields and reduced actual manufacturing
`
`Figure 2. Sales of biopharmaceutical products by product type. Total annual sales of biopharmaceuti-
`cal products are shown as a function of product type. Note that recombinant proteins produced by
`microbial fermentation include recombinant human insulin products which represent nearly 50% of
`the sales and >90% of the material produced in this category.
`
`costs.17-20 As a result, there is an ever-increasing opportu-
`nity for these products to penetrate more cost-sensitive indi-
`cations and markets.
`As the patents providing exclusive rights to many of the
`high-profile and blockbuster monoclonal antibody products
`expire, there has been a growing interest in the development
`of biosimilars. In September 2013, the first biosimilar mono-
`clonal antibodies, sold under the brand names Remsima and
`Inflectra, were approved for commercial
`sale in Europe.
`These biosimilar versions of the blockbuster monoclonal anti-
`body product Remicade are the first of many biosimilar
`monoclonal antibodies that will undoubtedly be approved for
`commercial sale in the US and Europe. Although the current
`impact of these and other biosimilar monoclonal antibody
`products in US and European biopharmaceutical marketplace
`cannot be gauged at this early stage, we anticipate modest
`acceleration of the sales growth of all monoclonal antibodies
`as these biosimilar products gain market acceptance. There is
`also a surging interest in biosimilar monoclonal antibodies in
`the global markets of Latin America, China, Southeast Asia,
`India, and Russia, with several monoclonal antibody products
`already approved in these regions. The introduction of biosi-
`milars in these markets is likely to have a very large impact
`on the global sales of monoclonal antibody products as biosi-
`milar monoclonal antibodies are approved in geographies that
`are currently unable to access expensive innovator products.
`
`Figure 3. Annual sales of monoclonal antibody products. Annual sales of
`the top six selling monoclonal antibodies compared to the non-antibody
`recombinant proteins Avonex and Rebif for the period 2004 to 2013.
`Each monoclonal antibody product had 2013 sales of greater than
`$6.5 billion. Sales information was obtained from company annual
`reports and other publically available sources.
`
`www.tandfonline.com
`
`mAbs
`
`13
`
`

`

`Conclusion
`
`As the development and commercialization of monoclonal
`antibody products continues with no limit in sight,
`lessons
`learned from the early monoclonal antibody product develop-
`ment, along with the use of advanced and novel technologies for
`their production and the increasing familiarity of global
`
`regulatory authorities with therapeutic monoclonal antibody
`products, will contribute to their continued dominance as the
`major class of biopharmaceutical products worldwide.
`
`Disclosure of Potential Conflicts of Interest
`
`No potential conflicts of interest were disclosed.
`
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`14
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`mAbs
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`Volume 7 Issue 1
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