FEATURE

Biopharmaceutical benchmarks 2018

Gary Walsh

Monoclonal antibodies (mAbs) continue to reign supreme, although cellular and gene therapies are slowly starting to gather momentum. Burgeoning growth in biosimilars may threaten future brand monopolies for mAbs and other biologics.

ntibodies continue to dominate biophar- a Amaceutical approvals, but new nucleic 70 36 acid modalities and cellular therapies are US 28 also slowly launching on the market. This 60 EU article provides an update on three previous surveys of biopharmaceutical approvals1–3. 50 19 The current survey period (January 2014 23 19 to July 2018) witnessed the approval of 155 40 14 17 biopharmaceutical products (see Table 1 20 for definition) in the United States and/or 30 European Union, when counted by product trade name. Some products contain identical 20 active ingredients or are sold under different Number of product approvals trade names in the two regions. Taking this 10 into account, 129 distinct biopharmaceutical active ingredients entered the market. 0 With these new approvals, the number of 2014 2015 2016 2017 individual biopharmaceutical products hav- Year ing gained a license in these regions now b totals 374, containing 285 distinct active bio- 120 pharmaceutical ingredients. However, over 112 the years, 58 products have been withdrawn 100 from the market following approval in one or 80 both regions, almost always for commercial 60 reasons. When withdrawals are taken into 60 58 56 54 account, the number of individual biopharma- 40 ceutical products with current active licenses stands at 316 (Table 1). 20 16 9 Annual approval numbers over the cur- Number of product approvals 0 rent survey period ranged from a low of 14 in Up to 1989 1990–1994 1995–1999 2000–2004 2005–2009 2010–2014 2015–July 2018 Europe in 2014 to a high of 36, also in Europe, Time period in 2017 (Fig. 1a). Products approved over the four and a half years include 68 mAbs, 23 Figure 1 Product approvals profile. (a) Annual product approval numbers (by product trade name) by individual region. (b) Number of product approvals in one or both regions over the indicated hormones, 16 clotting factors, 9 enzymes, 7 periods. vaccines, 5 nucleic acid–based products and 4 engineered cell–based products. As this study period was coming to a close, the first RNA Here I list all recombinant biologics the US Food and Drug Administration (FDA) interference (RNAi) drug was approved in the approved during the past four and a half years classifies as pure medical devices. United States. (from January 2014 to July 2018), examining the types of biopharmaceutical drugs that In a snapshot Gary Walsh is in the Industrial Biochemistry have reached the US and EU markets as well Overall, new approvals followed relatively Program, Department of Chemical Sciences and as the indications for which they are regis- predictable lines, with cancer representing the Bernal Institute, University of Limerick, Ireland. tered. As in previous articles1–3, I have not single most common indication (33 products). e-mail: [email protected] included tissue-engineering products, which Other common indications included various

1136 VOLUME 36 NUMBER 12 DECEMBER 2018 NATURE BIOTECHNOLOGY FEATURE inflammation-related conditions (24 prod- ucts), hemophilia (16 products) and diabetes Table 2 Biopharmaceuticals approved in the US and/or EU January 2014–July 2018 (15 products). Approvals for other indications, by category less commonly targeted by biopharmaceuti- Category Products (by trade name) cals, included asthma, migraine, HIV and Genuinely new Adynovi/Adynovate, Vonvendi, Obizur, Elocta/Eloctate, Andexxa, Rebinyn/ biopharmaceuticals Refixia, Alprolix, Idelvion, Suliqua/Soliqua, Xultophy, Myalepta/Myalept, inhalational anthrax. Ozempic, Eperzan/Tanzeum, Trulicity, Oxervate, Plegridy, Shingrix, Trumenba, Of the 155 individual biopharmaceutical pandemic influenza vaccine H5N1, Mosquirix, Aimovig, Crysvita, Fasenra, products approved, 81 (52%) were genuinely Hemlibra, Ilumya, Trogarzo, Bavencio, Besponsa, dinutuximab beta Apeiron/ Qarziba, Dupixent, Imfinzi, Kevzara, Kyntheum/Siliq, Rituxan Hycela, Tecentriq, new to the market, with the remaining prod- Tremfya, Zinplava, Anthim, Cinqair/Cinqaero, Darzalex, Empliciti, Lartruvo, ucts representing biosimilars, me-too products, Taltz, Blincyto, Cosentyx, Keytruda, Nivolumab BMSa/Opdivo, Nucala, Praluent, and products previously approved elsewhere. Praxbind, Repatha, Unituxina, Cyramza, Entyvio, Sylvant, Palynziq, Lamzede, Those 81 new products (by trade name) con- Brineura, Mepsevii, Kanuma, Strensiq, Vimizim, Tegsedi, Luxturna, Spinraza, Exondys 51, Imlygic, Alofisel, Kymriah, Yescarta, Strimvelis, Zalmoxis tained a total of 71 distinct active biophar- Biosimilars Semglee, insulin lispro Sanofi, Lusduna, Abasaglar/Basaglar, Bemfola, Movymia/ maceutical ingredients (Table 2). Looking at Terrosa, Retacritb, Fulphila, Nivestym/Nivestimb, Zarxiob, Accofil, Halimatoz/ each region independently, 97 products were Hefiya/Hyrimoz, Herzuma, Kanjinti, Mvasi, Trazimera, Zessly, Amgevita/ licensed in the United States in the survey Amjevita/Solymbic, Blitzima/Truxima/Ritemvia/Rituzena, Cyltezo, Imraldi, Ixifi, Ogivri, Ontruzant, Renflexis/Flixabi, Rixathon/Riximyo, Inflectra/Remsimab, timeframe while 109 products gained market- Erelzi, Benepali ing authorization in the European Union. Reformulated, me-too, Afstyla, Vihuma/Nuwiq, Iblias/Kovaltry, Ixinity, Admelog, Fiasp, Toujeo, Afrezza, In the same period, US regulators approved different indication, Rekovelle, Natpara, Natpar, Saxenda, Ristempaa, Heplisav-b, Gardasil 9, a grand total of 207 products containing novel and related Ocrevus, Portrazza, Zinbrytaa, Oncaspar, Lifmior, Spectrila molecular (chemical or biological) entities, Previously approved Rixubis, Ruconest, Ryzodeg 70-30/Ryzodeg, Tresiba, Bexsero, Mylotarg, Gazyva/ indicating that 47% of all genuinely new drug elsewhere Gazyvaro aProducts were both approved and subsequently withdrawn from one or both regions within the survey timeframe. approvals in the US were biopharmaceuticals. bBiosimilars approved in one region since 2014, but which were approved in the other region before 2014. This represents a substantial increase over val- ues reported in our previous surveys in 2010 and 2014 (21% and 26%, respectively)1,2, but The relative importance of mAbs in terms of the trend toward mammalian cell lines has tallies well with data presented in our 2006 the percentage of overall biopharmaceutical accelerated dramatically in the past three survey3, which estimated that some 44% of product sales also continues to grow steadily to four years. Sixty-two of the 71 genuinely all drugs in the then developmental pipeline (Fig. 2b), although not so dramatically as new biopharmaceutical active ingredients were biotech-based. Ambiguity in EU data product approval numbers might imply. that have come on the market in the survey reporting structures precludes calculation of However, antibody sales, both in terms of period (Table 2) are recombinant proteins. Of an analogous figure for Europe. absolute value and as a percentage of overall those, 52 (84%) are expressed in mammalian biopharmaceutical sales, will likely continue cell lines, one (Kanuma, sebelipase alfa) is Overall trends to increase, particularly as revenues derived expressed in a mammalian transgenic system, Comparing approvals over the current survey from the recent glut of mAb approvals grow and the remaining nine are produced using period with those in earlier periods, or with toward maximum market value. Escherichia coli (five products) or yeast (four cumulative approvals, reveals interesting, if Notably, approvals of gene- and other products), all in S. cerevisiae. The surge in not somewhat predictable, trends. Approval nucleic acid–based products (antisense oli- mammalian-based production is unsurpris- numbers in each five-year period from 1995 gonucleotides (ASOs) and gene therapies, ing, given the many recent mAb and clotting until 2014 have remained remarkably constant including gene-engineered cells) increased as factor product approvals, with both product (54–60 approvals; Fig. 1b). However, approvals well during this period. The number of nucleic classes bearing post-translational modifica- have accelerated markedly since that time. The acid and cell-based products approved in the tions and thus requiring mammalian expres- past three and a half years alone (January 2015 period totaled nine, five nucleic acid and four sion systems. to July 2018) have seen 112 (Fig. 1b) prod- engineered cells (Table 1). Chinese hamster ovary (CHO) cell-based uct approvals—essentially double the typical The period of this study also witnessed a systems remain by far the most common five-yearly historical approval pace. Although pickup in approvals of some traditional prod- mammalian cell line in use; 84% (57 of the 68 a wave of biosimilar approvals contributed uct classes as compared with previous study mAb products approved in the current survey to this trend, the number of genuinely novel periods, notably clotting factors (Box 1) and period) are produced in CHO systems, with approved products hasn’t lagged far behind: some hormones, although approvals of most the remaining antibodies approved produced such drugs represented 52% of approvals in traditional product classes continued to drop in either NS0 cells (nine products) or Sp2/0 the past four and a half years compared with off. For example, no recombinant throm- cells (two products). Overall, recent approv- 59% in the period 2010 to 2014 (ref. 1). bolytic agent, anticoagulant, interleukin or als (Tables 1 and 2) also confirm that there is human growth hormone has been approved little industrial enthusiasm for exploring new The era of the antibody is upon us since 2014, and only one interferon and one expression systems. The data also show an increasing domi- erythropoietin were approved. This continued The current survey period has also been nance of mAbs within the universe of bio- trend likely reflects market saturation relative characterized by a continual rise in the market pharmaceutical approvals. Although they to demand for these products. value of biopharmaceuticals. Data from various represented just over a quarter (27%) of Another continuing trend is the increased La Merie financial reports indicate that cumu- all first-time approvals from 2010 to 2014, prominence of mammalian over nonmam- lative sales over 2014–2017 reached $651 bil- they comprise over half (53%) of first time malian expression systems used for pro- lion, whereas total sales for 2017 alone reached approvals from 2015 to July 2018 (Fig. 2a). ducing approved products (Fig. 3). In fact, $188 billion (http://www.lamerie.com)4.

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a of product is maturing. When considered by product trade name, 52 biosimilars have 60 gained approval in the European Union and/ 53 or the United States since 2006 (Table 4), 50 although 3 were subsequently withdrawn for commercial reasons. 40 By product category, the majority of bio- similar product approvals were antibody 30 26.5 based (27 of 52), with 10 approvals of gran- 24 22 ulocyte colony stimulating factor (G-CSF) 20 20 biosimilars and single-digit approvals of all 13 11 others. The 52 licensed biosimilar products 10 are actually based on 34 distinct active ingre- dients (Table 4). For example, the four ritux- 0

mAb approvals as a percentage of total imab-based biosimilars approved in Europe Up to 1989 1990–1994 1995–1999 2000–2004 2005–2009 2010–2014 2015–July 2018 in 2017 (under the trade names Blitzima, Time period Truxima, Ritemvia and Rituzena) all contain the same active substance: Celltrion’s biosimi- b lar rituximab, developed as CT-P10. 70 By region, 48 biosimilar products have 65.6 63.5 received marketing authorization in the 60 58.3 59.5 European Union, with 31 of these (65%) hav- 54.1 ing gained authorization in the current survey 51.7 49.9 period. In the United States, far fewer (13) bio- 50 similars gained a license, the first being Zarzio (filgrastim-sndz) in March 2015, with the first 40 biosimilar mAb (Inflectra; infliximab-dyyb) gaining approval in April 2016. This geo- graphical discrepancy is unsurprising, given 30 that the EU biosimilar regulatory framework (including the underpinning legislation and 20 follow-on regulatory guidelines) pre-dates the US regulatory framework by almost a decade. Of the 52 biosimilars approved thus far, mAb sales as a percentage of total 10 two-thirds (35) are first-time approvals since 2014. This period witnessed few approvals of 0 ‘traditional’ biosimilars, unlike earlier peri- 2011 2012 2013 2014 2015 2016 2017 ods, in which most biosimilars approved Year were human growth hormone, erythropoi- Figure 2 Overview of mAb approvals. (a) mAbs approved for the first time in the indicated periods, etin or G-CSF products. Since 2014, approv- expressed as a percentage of total biopharmaceuticals approved for the first time in the same time als of these biosimilars have invariably been period. (b) mAbs global annual sales value expressed as a percentage of total biopharmaceutical global sales for the indicated years. Financial data from La Merie Business Intelligence. approvals in the United States of products previously approved in the EU. In recent years, the focus of approvals has shifted The mAb Humira (adalimumab) has been Moreover, mAbs represented eight of the top toward engineered insulins (4 approvals) by far the single most lucrative product each ten products by sales in 2017 (six of the top ten and mAbs (25 product approvals; Table 4). year during the survey period, having gener- if the fusion traps are excluded). In terms of Drivers here are market value, coupled with ated global sales just short of $19 billion in target indications, the vast majority of antibody patent expiry and the availability of analyti- 2017 and $62.6 billion cumulatively between or antibody-like trap fusion products target cal methodology capable of demonstrating 2014 and 2017 (Table 3). The top ten selling inflammatory, autoimmune conditions (cumu- structural similarity in the context of proteins biopharmaceuticals together generated sales lative 2017 sales of $64.6 billion, with products as large and complex as mAbs (Box 2). The of $80.2 billion in 2017, representing almost targeting tumor necrosis factor (TNF)-α alone survey period has therefore witnessed the 44% of total biopharmaceutical product rev- generating $39.8 billion) and cancer (2017 approval of a raft of products demonstrating enues. Forty-five individual biopharmaceuti- cumulative sales of $43.1 billion). In terms of biosimilarity to the top-selling drugs, with cal products recorded ‘blockbuster’ status sales non-antibody-based products, insulins are the biosimilar versions having come on-stream (>$1 billion) last year. next most lucrative product class, collectively for eight of the top ten global-selling origina- mAbs continue to represent the most lucra- generating sales of $22 billion in 2017. tor products (Table 3). tive single product class. Total mAb sales Biosimilars have achieved a widespread (including Fc fusion protein–based antibody- Biosimilars blossom degree of acceptance in the European Union, like traps) reached $123 billion last year The survey period witnessed a surge in bio- where several such products have been on ($103.4 billion if fusion products are excluded). similar approvals, signaling that this class the market for over a decade. In that time,

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Box 1 Clotting factors

Genetic defects characterized by lowered expression (or altered amino acid sequence) of any clotting factor can compromise the blood clotting process, leading to congenital hemophilia. Characterized by spontaneous and prolonged hemorrhage, hemophilia is due in over 80% of cases to a deficiency in factor VIII activity (hemophilia A), while in most of the remainder it is due to a deficiency in factor IX (hemophilia B). Global incidence of hemophilia is estimated at between 200,000 and 400,000, with hemophilia A having an average incidence of ~2 people per 10,000. Disease severity is linked to the percentage of residual active factor produced by the patient, and the disease is treated via intravenous administration of the missing clotting factor. Before the introduction of clotting factor concentrates in the 1960s, the life expectancy was of the order of 15–25 years. In the early 1980s, before the advent of screening tests of HIV in donated blood, large numbers of hemophiliacs contracted AIDS from clotting factors purified from human plasma. The introduction of recombinant clotting factors beginning in the early 1990s drastically reduced dependence on plasma-derived products, and the 2017 global market value for such recombinant products stood at $8.5 billion. Treatment costs typically vary from $30,000 to several hundred thousand dollars annually, depending on condition severity and the development of inhibitory antibodies (which 20–30% of hemophilia A patients can develop). The current survey period witnessed a surge in clotting factor approvals, with ten factor VIII and six factor IX products coming on-stream, although several share the same active ingredient (Table 1). In the main, the products approved either are characterized by manufacturing process improvements over earlier-generation products or are engineered to increase serum half-life. For example, Bayer’s Kovaltry/Iblias is essentially an updated Kogenate, a recombinant factor VIII. Unlike Kogenate, Kovaltry/Iblias is produced in a baby hamster kidney (BHK) cell line that also expresses heat shock protein 70, with resulting improvement in recombinant productivity. Moreover, all animal- and human-derived additives have been eliminated from the cell culture and purification processes, and a virus filtration step has been introduced for improved nonenveloped viral clearance robustness. Clotting factor products are usually administered therapeutically (to control active bleeding) or prophylactically (to reduce frequency of future bleeding events). Administration for therapeutic purposes is tailored to individual circumstance while prophylactic administration of unmodified (first-generation) factors typically occurs three times weekly. Engineering to increase serum half-life has relied on PEGylation (Adynovi/Adynovate and Rebinyn/Refixia), Fc fusion (Elocta/Eloctate and Alprolix) or albumin fusion (Idelvion). Engineering had typically reduced prophylactic administration to twice weekly, and such products would be described by some as biobetter clotting factors. The current survey period also witnessed the approval of a novel mAb-based product indicated for the prophylaxis of hemophilia A in patients who produce anti–factor VIII antibodies, which neutralize any exogenously administered factor VIII). Hemlibra (emicizumab) is a bispecific IgG, one arm of which binds factor IXa while the other binds factor X, effectively triggering factor VIII–independent clot formation. Market analysts predict Hemlibra may attain blockbuster status (sales above $1 billion) by 2019, reaching $4 billion by 2022 (https://clarivate.com/blog/life-sciences-connect/green-light-market-hemlibra-hemophilia-inhibitors-us/).

EU-monitoring systems for safety concerns biosimilar entry drove a 30% savings across the clinical performance. The current period wit- have not identified any relevant difference in board in relation to all these products. nessed the approval of very few such products; the nature, severity or frequency of adverse The development of so-called ‘biobetters’ mainly, they included novel insulin formula- effects between biosimilars and their reference represents a potential threat to biosimilar tions or combinations (Suliqua/Soliqua and medicines, and a decade of clinical experience development. A biobetter describes an already Xultophy; Table 1), as well as clotting factors accrued with these products shows that the approved biopharmaceutical entity altered in with extended half-lives (Box 2). Biobetter approved biosimilars can be used as safely and some way (e.g., a structural modification or development is likely tempered by the fact effectively in all their approved indications an altered finished product combination or that such products are treated as a new product as other biological medicines5. Acceptance formulation) to improve some aspect of its from a regulatory perspective. in the United States is not as strong, which is unsurprising given the shorter window of Nonmammalian Mammalian experience with biosimilars. 66 50 53 45 42 40 21 A 2016 report from consultants IMS Health 33 50 47 55 58 60 79 on the impact of biosimilar competition in the 100 European economic area6 identifies EU-wide average price reductions from 8% in the case 80 of anti-TNF biosimilar products to 33–34% savings in the context of erythropoietin and 60 G-CSF biosimilars, relative to reference prod- 40 uct pricing the year before biosimilar entrance. Percentage of approvals Moreover, the report found that biosimilar 20 entry affected not only the price of the relevant reference product, but of the whole product 0 class. Globally, 2017 sales generated cumu- Up to 1989 1990–1994 1995–1999 2000–2004 2005–2009 2010–2014 2015–July 2018 latively by all biosimilar reference products Time period reached $73.3 billion. An interesting although Figure 3 Relative use of mammalian- versus nonmammalian-based production cell lines in the hypothetical calculation suggests savings of up manufacture of biopharmaceuticals approved over the indicated periods. Each dataset is expressed as a to $22 billion to global healthcare systems if percentage of total biopharmaceutical product approvals for the period in question.

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Table 3 The 20 top-selling biopharmaceutical products in 2017 Rank Product Sales, 2017 Cumulative sales, Year first Company Patent Biosimilar version(s) approved ($ billions)a 2014–2017 approved expiryb ($ billions) 1 Humira (adalimumab; 18.94 62.6 2002 AbbVie, Eisai 2016 (US) Halimatoz/Hefiya/Hyrimoz, anti-TNF) 2018 (EU) Amgevita/Amjevita/Solymbic, Cyltezo, Imraldi 2 Enbrel (etanercept; 8.34 35.4 1998 Amgen, Pfizer, Takeda 2015 (EU) Erelzi, Benepali anti-TNF) Pharmaceuticals 2028 (US) 3 Rituxan/MabThera 7.78 29.1 1997 Roche, Biogen Idec 2013 (EU) Blitzima/Truxima, Ritemvia, Rituzena, (rituximab; anti-CD20) 2016 (US) Rixathon/Riximyo 4 Remicade (infliximab; 7.77 35.6 1998 Johnson & Johnson, Merck, 2015 (EU) Zessly, Ixifi, Renflexis/Flixabi, Inflectra/ anti-TNF) Mitsubishi Tanabe Pharma 2018 (US) Remsima 5 Herceptin (trastu- 7.39 27.1 1998 Roche 2014 (EU) Herzuma, Kanjinti, Trazimera, Ogivri, zumab; anti-HER2) 2019 (US) Ontruzant 6 Avastin (bevaci- 7.04 27.0 2004 Roche 2017 (US) Mvasi zumab; anti-VEGF) 2019 (EU) 7 Lantus (insulin 6.72 27.4 2000 Sanofi 2014 Semglee, Lusduna, Abasaglar/Basaglar glargine) (EU & US) 8 Eylea (aflibercept; 5.93 18.0 2011 Regeneron, Bayer 2020 (EU) anti-VEGF) 2021 (US) 9 Opdivo (nivolumab; 5.79 11.4 2014 Bristol-Myers Squibb, Ono 2027 (US) anti-PD-1 receptor) Pharmaceutical 2026 (EU) 10 Neulasta 4.53 20.1 2002 Amgen, Kyowa Hakko Kirin 2014 (US) Fulphila (pegfilgrastim) 2015 (EU) 11 Stelara (ustekinumab; 4.01 12.2 2009 Janssen Cilag (Johnson & 2023 (US) anti-IL-12 & IL-23) Johnson) 2024 (EU) 12 Keytruda (pembroli- 3.81 5.7 2014 Merck 2036 (US) zumab, anti-PD-1) 2028 (EU) 13 Prolia/Xgeva (deno- 3.54 11.6 2010 Amgen 2025 (US) sumab, anti-RANKL) 2022 (EU) 14 Lucentis (ranibi- 3.38 14.3 2006 Roche, Novartis 2016 zumab; anti-VEGF) (EU & US) 15 Novolog/Novorapid 3.31 11.7 1999 Novo Nordisk 2015 (insulin aspart) (EU & US) 16 Soliris (eculizumab; 3.14 10.7 2007 Alexion Pharmaceuticals 2021 (US) anti–C5 complement 2020 (EU) protein) 17 Simponi (golimumab; 2.94 9.7 2009 Merck, Janssen, Mitsubishi 2024 anti-TNF) Tanabe (EU & US) 18 Humalog mix 50:50 2.86 11.3 1996 Eli Lilly 2014 (US) Insulin lispro Sanofi (insulin lispro) 2015 (EU) 19 Xolair (omalizumab) 2.75 8.7 2003 Roche, Novartis 2017 anti-IgE (EU & US) 20 Aranesp/Nesp (darbe- 2.62 10 2001 Amgen, Kyowa Hakko Kirin 2016 (EU) poetin alfa) 2024 (US) aFinancial data from La Merie Business intelligence. bPatent data from various sources, including http://www.gabionline.net/Biosimilars/General/Biologicals-patent-expiries. HER2, human epidermal growth factor receptor 2; IgE, immunoglobulin E; IL, interleukin; PD-1, programmed cell death receptor 1; RANKL, receptor activator of nuclear factor-κB ligand; VEGF, vascular endothelial growth factor.

mAb approvals several anti-interleukin mAbs to treat psoriasis, way: virtually all novel antibodies approved are The data in our survey underscore the cur- as opposed to the more traditional anti-TNF either humanized or fully human. One new rent and increasing dominance of mAbs in products for this indication. The new prod- antibody–drug conjugate (Besponsa, inotu- the biopharma sector, in terms of overall ucts include Cosentyx (secukinumab), Ilumya zumab ozogamicin) made it to market, along product approvals, biosimilar approvals and (tildrakizumab-asmn), Kyntheum/Siliq (bro- with two new bispecific products (Hemlibra, market value. Whereas cancer remains the dalumab), Tremfya (guselkumab) and Taltz emicizumab/emicizumab-kxwh; Blincyto, most common target indication, during the (ixekizumab). Taltz is also unusual in that it is a blinatumomab; Boxes 1 and 3). Tecenetriq period several products aimed at nontradi- humanized immunoglobulin G4 (IgG4). It was (atezolizumab), a mAb against programmed tional mAb target conditions were approved. consequently engineered to contain a serine- cell death receptor ligand 1 (PD-L1), is unusual These include Aimovig (erenumab), indicated to-proline substitution (S228P), which reduces in that it contains an amino acid substitution for migraine; Fasenra (benralizumab) and the frequency of half-antibody formation or (asparagine to alanine) at position 298, in the Cinqair/Cinqaero (reslizumab) for asthma; other heterologous antibody combinations CH2 domain of each heavy chain. This sub- Trogarzo (ibalizumab) for HIV infection; sometimes observed with IgG4 antibodies. stitution prevents antibody glycosylation and and Anthim (obiltoxaximab) for inhalation It is also notable that all the mAbs approved thus blocks glycan-dependent Fc-effector func- anthrax. Also notable was the approval of in the survey period were engineered in some tions, which is in turn important in the context

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Table 4 Biosimilar products that had gained marketing authorization within the European Union and/or the United States by July 2018 Product type Biosimilar (trade name) Year (and region) approved Reference product Drug (active ingredient) manufacturer Somatropin-based Human growth Omnitrope 2006 (EU) Genotropin Sandoz (Kundl, Austria) hormone–based Valtropin 2006 (EU) Humatrope LG Life Sciences (Jeonbuk-do, Republic of Korea) Withdrawn 2012 Epoetin-based Epoetin-based Binocrit 2007 (EU) Eprex/Erypo Rentschler (Laupheim, Germany) & Lek (Menges, Slovenia) Epoetin alfa hexal 2007 (EU) Eprex/Erypo Rentschler & Lek Abseamed 2007 (EU) Eprex/Erypo Rentschler & Lek Retacrit 2018 (US) Eprex/Erypo (EU) Norbitec (Uetersen, Germany) 2007 (EU) Epogen/Procrit (US) Norbitec (Uetersen, Germany) Silapo 2007 (EU) Eprex/Erypo Norbitec Filgrastim-based G-CSF-based Ratiograstim 2008 (EU) Neupogen Sicor (Vilnius, Lithuania) Filgrastim ratiopharm 2008 (EU) Neupogen Sicor Withdrawn 2011 Biograstim 2008 (EU) Neupogen Sicor Withdrawn 2015 Tevagrastim 2008 (EU) Neupogen Sicor Zarxio (US) 2015 (US) Neupogen Sandoz (Kundl, Austria) Zarzio (EU) 2009 (EU) Filgrastim hexal 2009 (EU) Neupogen Sandoz (Kundl, Austria) Nivestym (US) 2018 (US) Neupogen Hospira (Pfizer) (Zagreb, Croatia) Nivestim (EU) 2010 (EU) Grastofil 2013 (EU) Neupogen Intas Biopharmaceuticals (Gujarat, India) Accofil 2014 (EU) Neupogen Intas Biopharmaceuticals Pegfilgrastim-based Fulphila 2018 (US) Neulasta Mylan (Zurich) Follicle-stimulating hormone–based Follicle-stimulating Ovaleap 2013 (EU) Gonal F Merckle Biotec (Ulm, Germany) hormone–based Bemfola 2014 (EU) Gonal F Polymun Scientific Immunbiologische Forschung (Klosterneuburg, Austria) Insulin-based Insulin glargine–based Abasaglar 2014 (EU) Lantus Lilly del Caribe (Carolina, Puerto Rico, USA) Eli Lilly (Indianapolis) Lusduna 2017 (EU) Lantus Merck Sharp & Dohme (Elkton, VA, USA) 2017 (US), tentative Semglee 2018 (EU) Lantus Biocon Nusajaya (Johor, Malaysia) Insulin lispro–based Insulin lispro Sanofi 2017 (EU) Humalog Sanofi-Aventis (Frankfurt) mAb-based and related Infliximab-based Inflectra 2016 (US) Remicade Celltrion (Incheon, Republic of Korea) 2013 (EU) Remsima 2013 (EU) Remicade Celltrion Flixabi 2016 (EU) Remicade Biogen (Hillerod, Denmark) Samsung Bioepis (Incheon, Republic of Korea) Renflexis 2017 (US) Remicade Biogen (Hillerod, Denmark) Samsung Bioepis Ixifi 2017 (US) Remicade Pfizer Zessly 2018 (EU) Remicade Boehringer Ingelheim (Biberach an der Riss, Germany) Adalimumab-based Amgevita (EU) 2017 (EU) Humira Amgen (Thousand Oaks, CA, USA) Amjevita (US) 2016 (US) Solymbic 2017 (EU) Humira Amgen Cyltezo 2017 (EU & US) Humira Boehringer Ingelheim (Fremont, CA, USA) Halimatoz 2018 (EU) Humira Cook Pharmica (Bloomington IN, USA) Sandoz (Langkampfen, Austria) Hefiya 2018 (EU) Humira Cook Pharmica (Bloomington IN, USA) Sandoz (Langkampfen, Austria) Hyrimoz 2018 (EU) Humira Cook Pharmica (Bloomington IN, USA) Sandoz (Langkampfen, Austria) Imraldi 2017 (EU) Humira Biogen (Research Triangle Park, NC, USA) Biogen (Hillerød, Denmark)

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Table 4 Continued Product type Biosimilar (trade name) Year (and region) approved Reference product Drug (active ingredient) manufacturer Rituximab-based Blitzima 2017 (EU) MabThera Celltrion Truxima 2017 (EU) MabThera Celltrion Ritemvia 2017 (EU) MabThera Celltrion Rituzena 2017 (EU) MabThera Celltrion Rixathon 2017 (EU) MabThera Sandoz (Langkampfen, Austria) Riximyo 2017 (EU) MabThera Sandoz (Langkampfen, Austria) Trastuzumab-based Ontruzant 2017 (EU) Herceptin Biogen (Hillerød, Denmark) Ogivri 2017 (US) Herceptin Mylan Herzuma 2018 (EU) Herceptin Celltrion Kanjinti 2018 (EU) Herceptin Patheon Biologics (Groningen, the Netherlands) Trazimera 2018 (EU) Herceptin Boehringer Ingelheim (Biberach an der Riss, Germany) Bevacizumab-based Mvasi 2018 (EU) Avastin Amgen 2017 (US) Etanercept-based Benepali 2016 (EU) Enbrel Biogen (Hillerød, Denmark) Erelzi 2017 (EU) Enbrel Sandoz (Novartis) (Langkampfen, Austria) (EU) 2016 (US) Novartis Pharma (Stein, Switzerland) (US) Teriparatide-based Teriparatide-based Movymia 2017 (EU) Forsteo Richter-Helm BioLogics (Bovenau, Germany) Terrosa 2017 (EU) Forsteo Richter-Helm BioLogics of the product’s mode of action and safety pro- approved for non-small-cell lung cancer) CRISPR-based gene editing, which overcome file. Fasenra, by contrast, is engineered such from Bristol-Myers Squibb were withdrawn, some of these technical difficulties7, change the that its glycocomponent is afucosylated (like due to drug supply difficulties in the case of industry outlook. Ovalbumin, for example, is that of Gazyva/Gazyvaro (obinutuzumab), Unituxin and for commercial reasons in the expressed at two grams per hen egg, with one approved initially in 2013), which increases the case of nivolumab BMS. Biogen and AbbVie’s hen capable of laying more than 300 eggs a antibody-dependent cell-mediated cytotoxicity Zinbryta (daclizumab), which was approved year. CRISPR-targeted insertion of a therapeu- activity important for its mode of action. The in 2016 for multiple sclerosis, was withdrawn tic-protein-encoding sequence into the oval- period also witnessed the approval of one Fab globally in 2018 after serious adverse events, bumin gene could therefore afford high-level antibody fragment (Praxbind; idarucizumab), such as liver damage and immune reactions, protein production8. designed to bind and thus neutralize the anti- became apparent. coagulant drug dabigatran. Nucleic acid–based approvals Although technically outside the timeframe Recombinant enzymes and transgenic Nucleic acid–based products (gene therapies, of this survey, the approval of Cablivi (caplaci- production DNA or RNA vaccines, ASOs, small interfer- zumab) in Europe at the end of August repre- The survey period also witnessed the approval ing RNAs (siRNA), aptamers and modified sents a major milestone in mAb therapeutics, of nine recombinant enzymes for the treatment RNA molecules) have yet to exert a profound as it is the first nanobody to gain regulatory of various genetic conditions. From a techno- influence on the biopharma product landscape, approval. It is indicated to treat acquired logical perspective, Alexion Pharmaceuticals’ although the period witnessed the approval of thrombotic thrombocytopenic purpura, which Kanuma (sebelipase alfa; recombinant human five such products (three ASOs and two gene is a rare, life-threatening, autoimmune blood lysosomal acid lipase) is interesting in that it therapies). This brings the total tally of approv- clotting disorder. Cablivi is a humanized, 259 is produced in the eggs of transgenic chick- als in this category to nine, although the gene amino acid, 2.78 kDa bivalent nanobody pro- ens, with enzyme purification directly from therapy Glybera (alipogene tiparvovec) was duced in E. coli that binds to von Willebrand transgenic egg white. The transgenic chicken withdrawn from the market last year. factor, a key protein in hemostasis. This in turn line was developed via injection of a retroviral Glybera was approved as a single-adminis- inhibits the interaction of von Willebrand fac- vector carrying the human coding sequence tration gene therapy for adults suffering from tor with blood platelets, preventing platelet into chick embryos. familial lipoprotein lipase deficiency with a adhesion and hence the clotting characteristic However, transgenic-based platforms for treatment price tag on the order of $1 million. of the condition. biopharmaceutical production have failed to The developer and manufacturer opted not to Although often considered the poster child gain widespread use in the biopharmaceuti- renew its European marketing authorization of biopharma, antibody-based products are cal sector. Technical challenges arising from in 2017 due to lack of demand for the prod- just as susceptible to commercial influence random integration of transgenes into host uct. Luxturna (voretigene neparvovec-rzyl), and pharmacovigilance as any other thera- chromosomes and the difficulty of controlling approved last year in the United States, appears peutic product. Three mAbs approved in the transgene copy number in production animals set to be almost as costly; the one-time treat- current survey period have been withdrawn has limited the appetite for commercial invest- ment will cost $850,000. Luxturna contains within this period. European marketing ment in transgenic animal platforms capable a live, nonreplicating adeno-associated virus authorizations for Unituxin (dinutuximab, of generating economically viable levels of serotype 2 genetically modified to express the approved for neuroblastoma) from United recombinant proteins. It will be interesting human retinal pigment epithelium-specific Therapeutics and nivolumab BMS (nivolumab, to follow whether recent developments in 65-kDa (RPE65) gene. Delivered directly via

1142 VOLUME 36 NUMBER 12 DECEMBER 2018 NATURE BIOTECHNOLOGY FEATURE subretinal injection, it is indicated for patients with inherited retinal disease due to mutations Box 2 Analytical approaches to validating biosimilar mAb quality in both copies of this gene. The headline costs Biosimilar guidelines require the generation of comparative data between a proposed new of either of these products likely reflect the biosimilar product and the reference product to which it claims similarity, at the levels rarity of the target conditions and thus poten- of both the active substance and finished product. The marketing application, relative tial market size, as opposed to a fundamen- to a standard product application, must contain a full quality module, incorporating tal cost basis for gene therapy products per comparative quality analysis, as well as reduced comparative clinical and nonclinical se. The third gene therapy approval, Imlygic data modules. Comparative quality studies largely rely on analytical techniques and (talimogene laherparepvec), for example, is instrumentation, now capable of fully characterizing biopharmaceuticals as large and projected to cost an average of $65,000 per complex as mAbs, with mass spectrometry (MS)-based techniques coming to the fore. Any patient. Indicated for the treatment of mela- comparative differences identified (for example, differences in glycocomposition) are then noma recurrent after initial surgery, Imlygic considered in terms of effect on biosimilarity, with further investigation via biological assay is a live, attenuated herpes simplex virus or preclinical or clinical evaluation, as appropriate. type 1 carrying the human GM-CSF coding An analysis of the comparative quality information presented in the European public sequence. Viral replication subsequent to assessment reports of approved biosimilar mAbs provide insight into the broad range of injection directly into the tumor is believed state-of-the-art analytical techniques used in practice (similar techniques are used as to trigger cell lysis, and it is believed that the appropriate in the context of other protein-based biosimilars). The commonly applied release of tumor-derived antigens along with analytical approaches discernible in these documents include the following: the GM-CSF may also promote an antitumor • Determination of intact molecular mass by electrospray MS. Other size analysis effect. modalities cited included size exclusion high performance liquid chromatography (SE- Three approved ASO products hold orphan HPLC) and capillary electrophoresis in the presence of sodium dodecyl sulfate. status for the treatment of rare conditions • Primary structural analysis by methods including classic C- and N-terminal sequencing with limited therapeutic options. It is nota- (partial sequence determination), with full sequence determination invariably relying ble that one of these ASO products, Ionis on initial protein fragmentation, peptide mapping and MS techniques such as Pharmaceuticals’ Spinraza (nusinersen) for matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS or liquid spinal muscular atrophy, was the main source chromatography/tandem MS (LC-MS/MS). This includes the detection of C-terminal of sales growth for Biogen in 2017, generat- lysine variability (common in IgGs, but without anticipated clinical impact as ing $188 million in sales in the first quarter C-terminal lysines are rapidly removed in serum). of 2018. Spinraza targets splicing defects that • Sulfhydryl analysis via ultraviolet (UV)/visible light spectrophotometry and SE-HPLC, lead to this disorder, and rare conditions aris- with disulfide linkage assignment via LC-MS-based peptide mapping under reducing ing due to mRNA mis-splicing are likely to be and nonreducing conditions. an increasing area of focus for this modality. • Higher order structural analysis: secondary structural analysis via far-UV circular In terms of downregulation of misregu- dichroism spectroscopy and/or Fourier transform infrared spectroscopy; tertiary lated mRNA expression, ASOs now have to analysis via near-UV circular dichroism spectroscopy or intrinsic fluorescence compete with siRNAs. Although technically spectroscopy; thermal stability of higher order structure via differential scanning outside the timeframe of this current survey, calorimetry; X-ray crystallography of the Fc domain. the recent approval of Alnylam’s Onpattro • Glycosylation analysis: composition or structural determination, including levels of (patisiran) represents the most notable fucosylation and terminal galactosylation (which can influence antibody effector recent approval of an oligonucleotide-based functions), by exoglucanase digestion and hydrophobic interaction chromatography therapeutic. Approved in both US and EU analysis, high-performance anion-exchange chromatography with pulsed amperometric in August 2018, Onpattro is the first RNAi- detection (HPAE-PAD). based gene expression silencing product to • Analysis of additional modifications (for example, site specific deamidation, oxidation) gain approval in either region. by MS-based methods, peptide mapping with LC-MS). • Charge heterogeneity profile by ion exchange-based HPLC, isoelectric focusing. Traditional biotech product approvals • Purity analysis: HPLC-based separation modalities based on size, charge and The current survey period also witnessed hydrophobicity, capillary gel electrophoresis, western blot analysis. the approval of 46 traditional biotech prod- ucts classified as new by regulatory authori- ties in terms of active substance—just one Engineered cell–based approvals (axicabtagene ciloleucel), Zalmoxis and more than recorded in our previous survey. Traditional cell-based therapeutics containing Strimvelis. These products may be viewed Traditional products refer to those produced cells extracted from human tissue or blood as both cell and gene therapies, given that naturally or via nonrecombinant means in or continue to come on the market. Examples the cells carry a therapeutic gene into the by a biological source. include hematopoietic progenitor cells derived patient’s body. All four products have orphan The profile of approvals (Supplementary from cord blood, as well as autologous cultured status or target niche conditions and either Table 1) by and large mirrors product types chondrocytes used to treat cartilage defects are under additional monitoring or require approved in previous surveys and include a (Supplementary Table 1). further postauthorization safety studies. range of blood-derived products (for exam- A notable recent milestone in cell-based Three of the four (Kymriah, Yescarta and ple, plasma-purified human albumin, clot- therapeutics is the approval of geneti- Strimvelis) use autologous cells, whereas ting factors and immunoglobulins), as well cally engineered cell–based therapies, the fourth (Zalmoxis) uses allogeneic cells as traditional (nonrecombinant) vaccines and four of which have been approved since as a starting point. One is a hematopoietic nonengineered cells. 2016: Kymriah (tisagenlecleucel), Yescarta stem cell therapy (Strimvelis) and the other

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mainstreaming of biosimilar mAbs and, Box 3 BiTE technology potentially, the development of competing product types, such as CAR-T cell immuno- Pioneered by Micromet, a biotechnology company acquired by Amgen, the first bispecific therapies, further increases the competitive T-cell engager (BiTE) product, Blincyto (blinatumomab), gained approval in the United pressure and incentive to innovate. Not sur- States and European Union for the treatment of B-cell precursor acute lymphoblastic prisingly, a greater diversity of modalities and leukemia during the current survey period. The BiTE platform consists of a bispecific targets is seen further back in the developmen- antigen-binding antibody fragment, one arm of which is designed to bind the CD3 cell tal pipeline, reflected in various antibody for- surface receptor complex, invariably found on cytotoxic T cells, while the other arm is mats engineered to enhance functionality in designed to bind a surface tumor antigen associated with a target cancer cell type17,18. some way, the pursuit of novel disease targets The BiTE construct therefore acts as a bridge, bringing cytotoxic T cells into close and the assessment of mAbs in combination proximity to the target cancer cells and triggering lysis of the latter by the former. The Blincyto construct consists of two single-chain variable fragments (scFv domains) with a second therapeutic agent. joined by a short, flexible linker sequence consisting of glycine and serine residues. The Indeed, such competitive pressures have 55 kDa, 504 amino acid construct includes a C-terminal hexahistidine sequence, which driven, and continue to drive, innovation facilitates purification using zinc-immobilized metal affinity chromatography. One scFv among categories other than mAbs. For domain targets the T-cell CD3 receptor, while the other binds the pan-B-cell antigen example, incentive to innovate is illustrated by CD19, facilitating T-cell-mediated lysis of B cells. Because of its relatively low molecular the recent approval of several clotting factors mass, the construct has a short serum half-life (2–3 h). This requires continuous infusion engineered to increase serum half-life and an over a four-week period, representing a limitation in terms of patient convenience. increasing number of trials assessing both pre- Approaches to the development of next-generation constructs with extended serum half- viously approved and experimental biophar- lives include fusion to human albumin and Fc-based constructs, with an aim of facilitating maceuticals in combination with other drugs a once-weekly dosage schedule. to treat various cancers. The Amgen pipeline contains several more BiTE constructs undergoing phase 1 Biosimilars will continue to feature with clinical trials for the treatment of various cancers, including multiple myeloma and increasing prominence in the global biophar- acute myeloid leukemia. BiTE constructs targeting solid tumors have thus far yielded maceutical landscape, but their greatest impact limited success. Limitations may include the degree of tumor penetration (by the will continue to be in regions outside the more construct and T cells), as well as the relatively broad expression of target antigen, which developed markets, such as the United States may limit dose escalation. and European Union. Thus far, an estimated 260 biosimilar products have been approved in at least one global market—of which only a rel- three are T-cell therapies. In all cases, genetic The profile of products in advanced-stage atively small minority (52) have been approved modification is undertaken ex vivo using a clinical trials suggests that biopharmaceutical in the European Union and/or the US. That viral vector to achieve transduction, followed approvals over the next few years will continue being said, many of the additional products by infusion of the genetically modified cells to be predominantly protein-based (rather approved would likely find it challenging to into the patient. than nucleic acid- or cell-based), that they will meet EU and US regulatory expectations in Two of the products (Kymriah and Yescarta) be produced largely using conventional mam- the context of biosimilarity. fall into the new wave of cellular immunothera- malian cell expression systems, that mAb- Globally, some 188 biosimilars are in devel- pies for oncology. They are notable in that they based products will continue to dominate the opment, 61 of which are in phase 3 trials12. are the first chimeric antigen receptor (CAR)-T approvals, that a steady stream of biosimilars Specifically within Europe and the United cell-based products9,10 to gain regulatory will continue to gain approval (particularly States there are an estimated 50 biosimilars approval, effectively validating this technol- in indications with large, lucrative markets), in development (https://www2.deloitte.com/ ogy from a regulatory standpoint. In addition and that cancer will remain the primary target content/dam/Deloitte/us/Documents/life- to US approval in 2017, both gained market- indication. sciences-health-care/us-lshc-biosimilars- ing authorization in Europe in August 2018. In Fifty-four genuinely new mAbs in late-stage whitepaper-final.pdf). Despite recent headline the case of both approved products, the CAR-T clinical trials are under regulatory review in approvals, penetration in the US market in cells target the CD19 antigen, found on the the United States and European Union11, particular is likely to occur relatively slowly, surface of B lymphocytes, facilitating efficient framing nearer-term putative approvals in underscored by regulatory and legal uncer- T-cell-mediated destruction of B cells—thus these regions. Of these, 28 (52%) target can- tainties, complex pricing and contracting their indication for the treatment of B-cell- cer, 7 for liquid malignancies and 21 for solid mechanisms and, of course, patient and clini- based cancers, against which they have shown tumors. Most are fully human or humanized cian acceptance. Overall, however, biosimilar striking clinical results. IgGs, along with a smaller number (5) of anti- market growth is anticipated to be strong, with body fragment (Fab or single-chain variable market reports (e.g., https://www.marketsand- Future directions fragment (scFv)) products. Of the 28 antican- markets.com/Market-Reports/biosimilars-40. Although published estimates vary somewhat, cer products, 9 are conjugated to an effector html) typically forecasting a $23 billion global some 40% of the 6,000 or more products cur- molecule (radiolabel, chemical or toxin). market value within the next five to six years, rently in clinical development globally are The antibody market, although highly up substantially from an estimated 2017 value biopharmaceuticals. This suggests that the sub- successful, is also becoming very crowded. of the order of $4.5 billion. stantial increase in the proportion of approved In some cases, multiple mAbs target the The predominance of protein-based pharmaceutical products that are biopharma- same therapeutic target (for example, CD20, approved biopharmaceuticals is likely to ceuticals seen in this survey period is not a blip, TNF and vascular endothelial growth fac- remain an industry reality for the foreseeable but will be sustained into the future. tor) and have overlapping indications. The future. Nucleic acid–based products have yet

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to make a substantial and sustained impact developments in biopharmaceutical prod- 6. The impact of biosimilar competition on price, volume and market share, June 2016. http://ec.europa.eu/ on the list of biopharmaceutical products that ucts have been particularly notable over the growth/content/impact-biosimilar-competition-price- are registered in Europe and the United States. past five years. First, the massive proliferative volume-and-market-share-updated-version-2016-0_en A study13 from the Journal of Gene Medicine capacity of cellular therapy has been effectively (2016). 7. Bertolini, L.R. et al. The transgenic animal platform estimates that 2,597 gene therapy–based clinical harnessed in the form of immunotherapy for for biopharmaceutical production. Transgenic Res. 25, trials have been approved globally since 1989. late-stage cancers. It is this ability to identify, 329–343 (2016). Despite this large body of data, gene-therapy- expand, attack and destroy malignant cells that 8. Park, T.S. et al. Deposition of bioactive human epi- dermal growth factor in the egg white of transgenic based approvals in Europe and the United States has made CAR-T cell therapies so successful hens using an oviduct-specific minisynthetic promoter. remain in the single digits. Advances in adeno- and overshadowed the longer term goal of cel- FASEB J. 29, 2386–2396 (2015). associated virus (AAV) and lentiviral gene ther- lular therapy: regeneration. Regenerative cell 9. Miliotou, A.N. & Papadopoulou, L.C. CAR T-cell ther- apy: a new era in cancer immunotherapy. Curr. Pharm. apy modalities (particularly in ex vivo cellular therapy was for many years seen as the main Biotechnol. 19, 5–18 (2018). therapy contexts)—together with increasing opportunity for modalities based on living 10. June, C.H., O’Connor, R.S., Kawalekar, O.U., Ghassemi, S. & Milone, M.C. CAR T cell immunotherapy for interest in CRISPR endonuclease-based gene cells and, in particular, stem cells; that is no human cancer. Science 359, 1361–1365 (2018). editing, with several companies now poised to longer the case. Second, increasing evidence 11. Kaplon, H. & Reichert, J.M. Antibodies to watch in take such approaches into human testing—are of safety and growing familiarity of physi- 2018. MAbs 10, 183–203 (2018). 12. FirstWord. Charting the Global Biosimilar Pipeline likely to provide further impetus to the develop- cians and insurers with biosimilars means the (FirstWord Publishing, 2018). ment of nucleic acid–based treatments. economic advantages of these products are no 13. Ginn, S.L., Amaya, A.K., Alexander, I.E., Edelstein, M. The rapid advances and clinical adoption longer being ignored. It seems likely that the & Abedi, M.R. Gene therapy clinical trials worldwide to 2017: an update. J. Gene Med. 20, e3015 (2018). of T-cell-based adoptive therapies (including rapid growth of biosimilar products will con- 14. Zheng, P.P., Kros, J.M. & Li, J. Approved CAR-T cell CAR-T cells) is a particularly notable develop- tinue over the years to come. therapies: ice bucket challenges on glaring safety risks and long-term impacts. Drug Discov. Today 23 1175– ment in the period of this study. The success 1182 (2018). of this cellular gene therapy is built on the Note: Any Supplementary Information and Source Data 15. Labanieh, L., Majzner, R.G. & Mackall, C.L. files are available in the online version of the paper exceptional responses obtained in some trials Programming CAR-T cells to kill cancer. Nat. Biomed. (doi:10.1038/nbt.4305). Eng. 2, 377–391 (2018). for some cancers, particularly liquid malig- 16. Köhl, U., Arsenieva, S., Holzinger, A. & Abken, H. CAR nancies. However, scientific, technological and 1. Walsh, G. Biopharmaceutical benchmarks 2014. Nat. T cells in trials: recent achievements and challenges manufacturing hurdles may all complicate its Biotechnol. 32, 992–1000 (2014). that remain in the production of modified T cells for 2. Walsh, G. Biopharmaceutical benchmarks 2010. Nat. clinical applications. Hum. Gene Ther. 29, 559–568 more widespread adoption, certainly in the Biotechnol. 28, 917–924 (2010). (2018). nearer term14–16. 3. Walsh, G. Biopharmaceutical benchmarks 2006. Nat. 17. Klinger, M., Benjamin, J., Kischel, R., Stienen, S. & Biotechnol. 24, 769–776 (2006). Zugmaier, G. Harnessing T cells to fight cancer with Overall, the past four and a half years have 4. La Merie Business Intelligence. http://www.lamerie.com BiTE® antibody constructs—past developments and witnessed continued and accelerated growth (2018). future directions. Immunol. Rev. 270, 193–208 in the biopharma sector. Antibodies con- 5. Biosimilars in the EU report: information guide for (2016). health professionals. https://www.ema.europa.eu/ 18. Trivedi, A. et al. Clinical pharmacology and translational tinue to reign supreme and look to dominate documents/leaflet/biosimilars-eu-information-guide- aspects of bispecific antibodies. Clin. Transl. Sci. 10, for several years to come. Elsewhere, two healthcare-professionals_en.pdf (2017). 147–162 (2017).

NATURE BIOTECHNOLOGY VOLUME 36 NUMBER 12 DECEMBER 2018 1145 Table 1 Continued Table 1 Continued Table 1 Continued ■ ■ BIOPHARMACEUTICAL Product Company (location) Therapeutic indication Date approved Product Company (location) Therapeutic indication Date approved Product Company (location) Therapeutic indication Date approved Admelog (insulin lispro injection), rapid-acting human insulin ana- Sanofi (Bridgewater, NJ, USA) Diabetes mellitus 2017 (US) Saxenda (liraglutide), human GLP-1 analog, produced in S. cere- Novo Nordisk Obesity 2015 (EU) Rebetron (ribavirin/interferon alfa-2b), produced in E. coli Schering Plough Chronic hepatitis C 1999 (US) log, produced in E. coli visiae and covalently modified by palmitic acid. Active substance Infergen (interferon alficon-1), r IFN-α, synthetic type I, produced Astellas Pharma Europe Chronic hepatitis C 1999 (EU) Fiasp (insulin aspart injection), rapid-acting insulin analog, pro- Novo Nordisk Diabetes mellitus 2017 (US) same as that in Victoza (see below) in E. coli (Leiderdorp, the Netherlands) 1997 (US) Benchmarks duced in S. cerevisiae Eperzan in EU, Tanzeum in US (albiglutide), GLP-1 receptor ago- GSK (Carrigaline, Ireland, & Diabetes mellitus type 2 2014 (EU & US) Kadmon Pharmaceuticals Withdrawn 2006 Insulin lispro Sanofi, produced in E. coli, biosimilar to Humalog Sanofi-Aventis (Paris) Diabetes mellitus 2017 (EU) nist: two tandem copies of modified human GLP-1 fused to human Research Triangle Park, NC, (Warrendale, PA, USA) (EU) albumin, produced in S. cerevisiae USA) Biopharmaceuticals are defined here as recombinant proteins, including recombinant antibody-based products, and nucleic acid– Lusduna (insulin glargine), engineered insulin, produced in E. coli, Merck Sharp & Dohme Diabetes mellitus 2017 (EU) Roferon A (interferon alfa-2a), produced in E. coli Roche Hairy cell leukemia 1986 (US) Trulicity (dulaglutide), fusion protein consisting of a GLP-1 analog Eli Lilly (Utrecht, the Diabetes mellitus type 2 2014 (EU & US) Withdrawn 2007 based and genetically engineered cell–based products. They are listed consecutively from most recent approval in each class, with biosimilar to Lantus (Hoddesdon, UK) 2017 (US, tentative) linked to a human IgG Fc domain, produced in a mammalian cell Netherlands, & Indianapolis) registrations since 2014 in bold and withdrawals in red. Eight categories are shown: recombinant clotting factors; recombinant line Interferon-β and interferon-γ thrombolytics, anticoagulants and other blood-related products; recombinant hormones; recombinant growth factors; recombinant Suliqua in EU, Soliqua in US (insulin glargine/lixisenatide), com- Sanofi-Aventis (Paris) Diabetes mellitus type 2 2017 (EU) bination of long-acting insulin glargine, produced in E. coli, and a Sanofi (Bridgewater, NJ, USA) 2016 (US) Gattex in US, Revestive in EU (teduglutide), rh GLP-2 analog, NPS Pharma (Dublin) Short bowel syndrome 2012 (EU & US) Plegridy (peginterferon beta-1a), rh PEGylated IFN- β-1a, Biogen Idec (Maidenhead, UK) Multiple sclerosis 2014 (EU & US) interferons, interleukins and tumor necrosis factor; recombinant vaccines; monoclonal antibody–based products; and other synthetically produced human GLP-1 analog produced in E. coli produced in CHO cells recombinant products. Where more than one drug in the same category was approved in a single year, they are listed alphabetically Xultophy (insulin degludec/liraglutide), a combination of 2 previ- Novo Nordisk Diabetes mellitus type 2 2016 (US) Victoza (liraglutide), GLP-1 analog with attached fatty acid, pro- Novo Nordisk Diabetes mellitus type 2 2010 (US) Extavia (interferon beta-1b), rh IFN β-1b, produced in E. coli Novartis Europharm (Camberley, Multiple sclerosis 2009 (US) by trade name. Several products have been approved for multiple indications, but only the first indication for which it was approved ously approved products, Victoza and Tresiba 2014 (EU) duced in S. cerevisiae 2009 (EU) UK) 2008 (EU) is listed here. Some product entries describe the product as being the same as another listed product. In such instances differences Preotact, rh parathyroid hormone, produced in E. coli NPS Pharma Osteoporosis 2006 (EU) Novartis Pharmaceuticals (East Abasaglar (previously Abasria) in EU, Basaglar in US (insulin Eli Lilly (Indianapolis), Diabetes mellitus 2015 (US) Hanover, NJ, USA) invariably exist in terms of approved indication range or the company holding the marketing authorizations, usually as a result of glargine), produced in E. coli, biosimilar (in EU) to Lantus Boehringer Ingelheim 2014 (EU) Withdrawn 2014 Rebif (interferon beta-1a), rh IFN-β-1a, produced in CHO cells EMD Serono (London) Relapsing/remitting multiple 2002 (US) commercial agreements. (Ridgefield, CT, USA) Fortical, r salmon calcitonin, produced in E. coli Upsher-Smith Laboratories Postmenopausal osteoporosis 2005 (US) Eli Lilly (Vienna) (Minneapolis) sclerosis 1998 (EU) Ryzodeg 70/30 in US, Ryzodeg in EU (insulin degludec/insulin Novo Nordisk Diabetes mellitus type 1 and 2 2015 (US) Unigene Laboratories (Fairfield, Avonex (interferon beta-1a), rh IFN-β-1a, produced in CHO cells Biogen Idec (Maidenhead, UK) Relapsing multiple sclerosis 1997 (EU) Table 1 Biopharmaceuticals approved in the United States and European Union through end of July 2018 aspart), combination of two engineered insulins, produced in 2013 (EU) NJ, USA) 1996 (US) S. cerevesiae Luveris (lutropin alfa), rh luteinizing hormone, produced in EMD Serono (Rockland, MA, Some forms of infertility 2004 (US) Betaferon (interferon beta-1b), r IFN- -1b differing from native Bayer Pharma Multiple sclerosis 1995 (EU) Product Company (location) Therapeutic indication Date approved β Toujeo (insulin glargine), produced in E. coli Sanofi (Bridgewater, NJ, USA) Diabetes mellitus 2015 (US) CHO cells USA) 2000 (EU) protein by C17S, produced in E. coli Recombinant clotting factors Merck Europe (Amsterdam) Tresiba (insulin degludec), engineered long-acting human insulin Novo Nordisk Diabetes mellitus type 1 and 2 2015 (US) Betaseron (interferon beta-β-1b), differing from human protein by Berlex Laboratories (Richmond, Relapsing/remitting multiple 1993 (US) Factor VIII analog, produced in S. cerevisiae (see also Ryzodeg above) 2013 (EU) Forsteo in EU, Forteo in US (teriparatide), r shortened human Eli Lilly (Houten, the Established osteoporosis in some 2003 (EU) C17S, produced in E. coli CA, USA) sclerosis Adynovi (rurioctocog alfa pegol), extended half-life PEGylated form Baxalta Innovations (Vienna) Hemophilia A 2018 (EU) parathyroid hormone, produced in E. coli Netherlands) postmenopausal women 2002 (US) Chiron (Emeryville, CA, USA) Afrezza (rh insulin), produced in E. coli MannKind (Danbury, CT, USA) Diabetes mellitus 2014 (US) of full-length r factor VIII product Advate (see below). Same prod- Natrecor (nesiritide), rh natriuretic peptide, produced in E. coli Johnson & Johnson/Scios Acutely decompensated conges- 2001 (US) Actimmune (interferon gamma-1b), produced in E. coli Vidara Therapeutics (Dublin) Chronic granulomatous disease 1990 (US) uct as Adynovate (see below) Novolog mix (insulin aspart mix), a 50:50 mixture of engineered Novo Nordisk Diabetes mellitus 2008 (US) (Titusville, NJ, USA) tive heart failure rh insulin, produced in S. cerevisiae in soluble and protamine Afstyla (lonoctocog alfa), B-domain-truncated rh coagulation factor CSL Behring (Marburg, Germany, Hemophilia A 2017 (EU Others suspension forms Ovitrelle in EU, Ovidrel in US (choriogonadotropin alfa) rh chori- Merck Serono Selected assisted reproductive 2001 (EU) VIII, produced in CHO cells & Kankakee, IL, USA) 2016 (US) onic gonadotropin, produced in CHO cells techniques 2000 (US) Kineret (anakinra), rh IL-1 receptor antagonist, produced in E. coli Swedish Orphan Biovitrum Rheumatoid arthritis 2001 (US) Insulin Human Winthrop (rh insulin), produced in E. coli Sanofi (Frankfurt) Diabetes mellitus 2007 (EU) Vihuma (simoctocog alfa), rh B-domain-deleted factor VIII, pro- Octapharma (Stockholm) Hemophilia A 2017 (EU) Withdrawn 2018 Thyrogen (thyrotropin alfa), rh thyroid-stimulating hormone, pro- Sanofi Genzyme (Cambridge, Thyroid cancer (detection and 1998 (US) Beromun (tasonermin), rh TNF-α, produced in E. coli Boehringer Ingelheim Adjunct to surgery for subsequent 1999 (EU) duced in HEK cells. Same product as Nuwiq (see below) duced in CHO cells MA, USA) treatment) 2000 (EU) (Ingelheim, Germany) tumor removal to prevent or delay Exubera (inhalable rh insulin), produced in E. coli Pfizer (Sandwich, UK) Diabetes mellitus 2006 (EU & US) Iblias (octocog alfa), rh coagulation factor VIII, produced in BHK Bayer Pharma (Berlin) Hemophilia A 2016 (EU) amputation Withdrawn 2008 Forcaltonin, r salmon calcitonin, produced in E. coli Unigene UK (Bushey Heath, UK) Paget disease 1999 (EU) cells using the same expression construct as Bayer’s Kogenate and (EU) Withdrawn 2008 Neumega (oprelvekin), r IL-11 lacking N-terminal proline of native Pfizer (Philadelphia), Genetics Prevention of chemotherapy- 1997 (US) Helixate. Same product as Kovaltry (see below) molecule, produced in E. coli Institute induced thrombocytopenia Levemir (insulin detemir), long-acting rh insulin, produced in S. Novo Nordisk Diabetes mellitus 2005 (US) Glucagen, rh glucagon, produced in S. cerevisiae Novo Nordisk Hypoglycemia 1998 (US) Kovaltry (octocog alfa), rh coagulation factor VIII, produced Bayer Pharma Hemophilia A 2016 (EU & US) cerevisiae 2004 (EU) Glucagon (glucagon, recombinant), rh glucagon, produced in Eli Lilly (Indianapolis) Hypoglycemia 1998 (US) Proleukin (aldesleukin) r IL-2, differs from native molecule in Prometheus Laboratories (San Renal cell carcinoma 1992 (US) in BHK cells using the same expression construct as Bayer’s Bayer HealthCare (Whippany, E. coli absence of N-terminal alanine and presence of C125S substitu- Diego) Kogenate and Helixate. Same product as Iblias (see above) NJ, USA) Apidra (insulin glulisine), rapid-acting insulin analog, produced Sanofi (Frankfurt) Diabetes mellitus 2004 (EU & US) tion, produced in E. coli in E. coli Vonvendi (von Willebrand factor (recombinant)), produced in CHO Baxalta (Westlake Village, CA, von Willebrand disease 2015 (US) Recombinant growth factors cells USA) Actrapid, Velosulin, Monotard, Insulatard, Protaphane, Mixtard, Novo Nordisk Diabetes mellitus 2002 (EU) Recombinant vaccines Actraphane, Ultratard: rh insulin formulated as short-, intermedi- Monotard and Erythropoietin Nuwiq (simoctocog alfa), B-domain-deleted rh factor VIII, pro- Octapharma USA (Hoboken, NJ, Hemophilia A 2015 (US) Hepatitis B ate- or long-acting product, produced in S. cerevisiae Ultratard with- Retacrit (epoetin zeta in EU, epoetin alfa-epbx in US), rh EPO, Hospira (Royal Leamington Spa, Anemia 2018 (US) duced in HEK cells. Same product as Vihuma (see above) USA) 2014 (EU) drawn 2006 produced in CHO cells, biosimilar to Eprex and Erypo UK) 2007 (EU) HEPLISAV-B (hepatitis B vaccine (recombinant) adjuvanted), Dynavax Technologies (Berkeley, Prevention of infection caused by 2017 (US) Octapharma Velosulin with- Pfizer (Lake Forest, IL, USA) HBsAg, produced in Hansenula polymorpha yeast CA, USA) all known subtypes of hepatitis B virus Obizur (susoctocog alfa), r B-domain-deleted porcine factor VIII, Baxalta Innovations Acquired hemophilia due to 2015 (EU) drawn 2009 Biopoin (epoetin theta), rh EPO, produced in CHO cells Teva (Ulm, Germany) Anemia 2009 (EU) produced in BHK cells Baxter Healthcare (Westlake development of autoantibodies 2014 (US) Novolog (insulin aspart), short-acting rh insulin analog, produced Novo Nordisk Diabetes mellitus 2001 (US) Hexacima, also sold as Hexyon, multi-component vaccine contain- Sanofi Pasteur (Lyon, France) Immunization against several 2013 (EU) Eporatio (epoetin theta), rh EPO, produced in CHO cells Teva (Ulm, Germany) Anemia 2009 (EU) ing r HBsAg, produced in as one component pathogens and toxins Village, CA, USA) against factor VIII in S. cerevisiae H. polymorpha Abseamed (epoietin alfa), produced in CHO cells, biosimilar to Medice Arzneimittel Pütter Anemia associated with chronic 2007 (EU) Adynovate (recombinant, PEGylated antihemophilic factor), Baxalta Hemophilia A 2015 (US) Ambirix, combination vaccine containing r HBsAg, produced in GSK (Rixensart, Germany) Immunization against hepatitis 2002 (EU) Novolog mix 70/30 (contains insulin aspart, a short-acting rh insu- Novo Nordisk Diabetes mellitus 2001 (US) Eprex/Erypo (Iserlon, Germany) renal failure extended half-life PEGylated form of full-length r factor VIII prod- lin analog, in both soluble and crystalline form) (see also Novomix S. cerevisiae as one component A and B uct Advate (see below). Same product as Adynovi (see above) 30 below) Binocrit (epoetin alfa), produced in CHO cells, biosimilar to Eprex/ Sandoz Anemia associated with chronic 2007 (EU) Pediarix, combination vaccine containing r HBsAg, produced in GSK Immunization of children against 2002 (US) Erypo renal failure Elocta (efmoroctocog alfa) in EU, Eloctate (antihemophilic fac- Swedish Orphan Biovitrum Hemophilia A 2015 (EU) Novomix 30 (contains a mixture of insulin aspart, a short-acting rh Novo Nordisk Diabetes mellitus 2000 (EU) S. cerevisiae as one component various conditions inducing tor recombinant, Fc fusion protein) in US: rh coagulation factor (Stockholm) 2014 (US) insulin analog, in both soluble and crystalline form, produced in Epoetin alfa Hexal (epoietin alfa), produced in CHO cells, biosimi- Hexal (Holzkirchen, Germany) Anemia associated with chronic 2007 (EU) hepatitis B lar to Eprex/Erypo renal failure VIII–Fc fusion protein comprising B-domain-deleted human factor Biogen Idec (Cambridge, MA, S. cerevisiae) HBVAXPRO (r HBsAg), produced in S. cerevisiae Sanofi Pasteur Immunization of children and 2001 (EU) VIII covalently linked to the Fc domain of a human IgG, produced USA) Lantus (insulin glargine), long-acting rh insulin analog, produced Sanofi (Frankfurt) Diabetes mellitus 2000 (EU & US) Mircera (methoxy polyethylene glycol-epoetin beta) PEGylated rh Roche (Welwyn Garden City, UK) Anemia associated with chronic 2007 (EU & US) adolescents against hepatitis B in HEK cells EPO, produced in CHO cells kidney disease in E. coli Twinrix, combination vaccine containing r HBsAg, produced in GSK Immunization against hepatitis 2001 (US) NovoEight (turoctocog alfa), rh factor VIII analog that, when acti- Novo Nordisk (Bagsvaerd, Hemophilia A 2013 (EU & US) Optisulin (insulin glargine), long-acting rh insulin analog, pro- Sanofi (Frankfurt) Diabetes mellitus 2000 (EU) Silapo (epoetin zeta), produced in CHO cells, biosimilar to Eprex/ STADA (Bad Vilbel, Germany) Anemia associated with chronic 2007 (EU) S. cerevisiae as one component A and B 1997 (EU pedi- vated, is structurally comparable to endogenous human factor Denmark, & Plainsboro, NJ, Erypo yes renal failure atric form) VIIIa, produced in CHO cells USA) duced in E. coli (see also Lantus above) Dynepo (epoetin delta), rh EPO, produced in a human cell line Shire Pharmaceuticals Anemia 2002 (EU) 1996 (EU adult NovoRapid (insulin aspart), rh insulin analog), produced in S. Novo Nordisk Diabetes mellitus 1999 (EU) Xyntha (antihemophilic factor), rh coagulation factor VIII, pro- Pfizer/Wyeth (Philadelphia) Hemophilia A 2008 (US) (Basingstoke, UK) Withdrawn 2009 form) duced in CHO cells cerevisiae Aranesp (darbepoetin alfa), long-acting r EPO analog, produced in Amgen (Breda, the Netherlands) Anemia 2001 (EU & US) Infanrix-hexa, combination vaccine containing r HBsAg, produced GSK Immunization against diphtheria, 2000 (EU) Liprolog (insulin lispro), insulin analog, produced in E. coli Eli Lilly (Houten, the Diabetes mellitus 1997 (EU) Advate (octocog alfa), rh factor VIII, produced in CHO cells Baxter Healthcare (Vienna & Hemophilia A 2004 (EU) CHO cells (see Nespo below) in S. cerevisiae as one component tetanus, pertussis, Haemophilus Deerfield, IL, USA) 2003 (US) Netherlands) Withdrawn 2001 influenzae b, hepatitis B and Nespo (darbepoetin alfa), long-acting r EPO analog, produced in Dompé Biotec (Milan) Anemia 2001 (EU) Insuman (rh insulin), produced in E. coli Sanofi (Frankfurt) Diabetes mellitus 1997 (EU) polio Helixate NexGen (octocog alfa), rh factor VIII, produced in BHK Bayer (Berlin) Hemophilia A 2000 (EU) CHO cells (see Aranesp above) Withdrawn 2008 cells Humalog (insulin lispro), insulin analog, produced in E. coli Eli Lilly (Houten, the Diabetes mellitus 1996 (EU & US) Infanrix-penta, combination vaccine, containing r HBsAg, pro- GSK Immunization against diphtheria, 2000 (EU) Neorecormon (epoietin beta), rh EPO, produced in CHO cells Roche Anemia 1997 (EU) duced in S. cerevisiae as one component tetanus, pertussis, polio, and Withdrawn 2013 ReFacto (moroctocog alfa), B-domain-deleted rh factor VIII, pro- Pfizer/Wyeth (Sandwich, UK) Hemophilia A 2000 (US) Netherlands) Procrit (epoietin alfa), rh EPO, produced in a mammalian cell line Janssen Biotech (Horsham, PA, Anemia 1990 (US) hepatitis B duced in CHO cells Genetics Institute (Cambridge, 1999 (EU) Novolin (rh insulin), produced in S. cerevisiae Novo Nordisk Diabetes mellitus 1991 (US) USA) MA, USA) Withdrawn 2010 Hepacare (r S, pre-S & pre-S2 HBsAg), produced in a murine cell Evans Vaccines (Liverpool, UK) Immunization against hepatitis B 2000 (EU) Epogen (epoietin alfa), rh EPO, produced in CHO cells Amgen Anemia 1989 (US) line Withdrawn 2002 Kogenate, Helixate (antihemophilic factor), rh factor VIII, pro- Bayer (Leverkusen, Germany, & Hemophilia A 2000 (EU) Humulin (rh insulin), produced in E. coli Eli Lilly (Indianapolis) Diabetes mellitus 1982 (US) duced in BHK cells. Sold as Helixate by Aventis Behring through a Berkeley, CA, USA) 1993 (US) Hexavac, combination vaccine containing r HBsAg, produced in S. Sanofi Pasteur Immunization against diphtheria, 2000 (EU) license agreement Human growth hormone Colony-stimulating factors cerevisiae as one component tetanus, pertussis, hepatitis B, Withdrawn 2012 Fulphila (pegfilgrastim-jmdb), PEGylated rh G-CSF, produced in Mylan (Rockford, IL USA) Neutropenia 2018 (US) polio and H. influenzae b Bioclate (antihemophilic factor), rh factor VIII, produced in CHO Aventis Behring (King of Prussia, Hemophilia A 1993 (US) Somatropin Biopartners (somatropin), r hGH, produced in Biopartners (Reutlingen, Growth failure, growth hormone 2013 (EU) , biosimilar to Neulasta cells PA, USA) S. cerevisiae Germany) deficiency Withdrawn 2017 E. coli Procomvax, combination vaccine containing r HBsAg as one com- Sanofi Pasteur Immunization against H. influen- 1999 (EU) Nivestym (filgrastim-aafi) in US, Nivestim (filgrastim) in EU: rh Pfizer (Lake Forest, IL, USA) Neutropenia 2018 (US) ponent zae b and hepatitis B Withdrawn 2009 Recombinate (antihemophilic factor), rh factor VIII, produced in Baxter Healthcare (Deerfield, IL, Hemophilia A 1992 (US) Accretropin (somatropin), r hGH, produced in E. coli Emergent Biosolutions Growth failure or short stature 2008 (US) G-CSF, produced in , biosimilar to Neupogen Hospira (Royal Leamington Spa, 2010 (EU) CHO cells USA), Genetics Institute (Rockville, MD, USA) associated with Turner syndrome E. coli Primavax, combination vaccine containing r HBsAg, produced in Sanofi Pasteur Immunization against diphtheria, 1998 (EU) Cangene (Winnipeg, MB, in children UK) S. cerevisiae as one component tetanus and hepatitis B Withdrawn 2000 Other blood factors Canada) Ristempa (pegfilgrastim), covalent conjugate of rh G-CSF, pro- Amgen (Breda, the Netherlands) Neutropenia 2015 (EU) Engerix B, r HBsAg, produced in S. cerevisiae GSK Immunization against hepatitis B 1998 (US) duced in E. coli and conjugated to 20-kDa polyethylene glycol Withdrawn 2017 Andexxa (coagulation factor Xa recombinant inactivated-zhzo), r Portola Pharmaceuticals (South For patients treated with rivaroxa- 2018 (US) Valtropin (somatropin), r hGH, produced in S. cerevisiae, biosimi- Biopartners Certain forms of growth distur- 2007 (US) Infanrix Hep B, combination vaccine containing r HBsAg, pro- GSK Immunization against diphtheria, 1997 (EU) modified human factor Xa, produced in CHO cells San Francisco, CA, USA) ban or apixaban, when reversal of lar to Humatrope LG Life Sciences (Reutlingen, bance in children and adults 2006 (EU) Zarxio in US, Zarzio in EU (filgrastim-sndz), rh G-CSF, produced Sandoz (Princeton, NJ, USA, & Neutropenia 2015 (US) duced in S. cerevisiae as one component tetanus, pertussis and hepatitis B Withdrawn 2005 anticoagulation is needed due to Withdrawn 2012 in E. coli Kundl, Austria) 2009 (EU) Germany) Comvax, combination vaccine containing HBsAg, produced in Merck (Whitehouse Station, NJ, Immunization of infants against 1996 (US) life-threatening or uncontrolled (EU) S. Accofil (filgrastim), G-CSF, produced in E. coli, biosimilar to Accord Healthcare (Ahmedabad, Neutropenia 2014 (EU) cerevisiae as one component USA) H. influenzae b and hepatitis B bleeding Omnitrope (somatropin), r hGH, produced in E. coli, biosimilar (in Sandoz (Kundl, Austria) Certain forms of growth distur- 2006 (EU & US) Neupogen. Same product as Grastofil (see below) India) Tritanrix-Hep B, combination vaccine containing r HBsAg, pro- GSK Immunization against hepatitis B, 1996 (EU) Rebinyn (rh coagulation factor IX) in US, Refixia (nonacog beta Novo Nordisk Hemophilia B 2017 (EU & US) EU) to Genotropin Novartis (Princeton, NJ, USA) bance in children and adults Grastofil (filgrastim), rh G-CSF, produced in E. coli, biosimilar to Apotex (Leiden, the Netherlands) Neutropenia 2013 (EU) duced in S. cerevisiae as one component diphtheria, tetanus and pertussis Withdrawn 2014 pegol) in EU: rh coagulation factor IX, produced in CHO cells and Somavert (pegvisomant), PEGylated r hGH analog (antagonist), Pfizer (Brussels & New York) Acromegaly 2003 (US) Neupogen. Same product as Accofil (see above) Recombivax, r HBsAg, produced in Merck (Whitehouse Immunization against hepatitis B 1986 (US) PEGylated produced in E. coli Nektar Therapeutics (San 2002 (EU) S. cerevisiae Lonquex (lipegfilgrastim), PEGylated rh G-CSF, produced in E. coli Teva Pharma (Utrect, the Neutropenia 2013 (EU) Station, NJ, USA) Alprolix (eftrenonacog alfa), rh coagulation factor IX fused to a Biogen Idec (Maidenhead, UK, & Hemophilia B 2016 (EU) Francisco) Netherlands) human IgG1 Fc domain, produced in HEK cells Cambridge, MA, USA) 2014 (US) Nutropin AQ (somatropin), r hGH, produced in E. coli, different Ipsen Pharma (Boulogne- Growth failure, Turner syndrome 2001 (EU) Granix (tbo-filgrastim), rh G-CSF, produced in E. coli. Same prod- Teva Pharmaceuticals USA Neutropenia 2012 (US) Other Idelvion (albutrepenonacog alfa), rh factor IX–albumin fusion pro- CSL Behring Hemophilia B 2016 (EU & US) formulation of Nutropin (see below) Billancourt, France) 1994 (US) uct as Tevagrastim (see below) (Frazer, PA, USA) Shingrix (zoster vaccine recombinant, adjuvanted), recombinant GlaxoSmithKline Biologicals Prevention of herpes zoster 2018 (EU) tein, produced in CHO cells Withdrawn 2008 Cephalon (Malvern, PA, USA) (EU) varicella zoster virus surface glycoprotein E antigen component, (Rixensart, Belgium) (shingles) 2017 (US) Ixinity (coagulation factor IX (recombinant)), rh coagulation factor Aptevo BioTherapeutics (Berwyn, Hemophilia B 2015 (US) Filgrastim Hexal (filgrastim), produced in E. coli, biosimilar to Hexal Neutropenia 2009 (EU) produced in CHO cells GlaxoSmithKline (Research IX, produced in CHO cells PA, USA) Serostim (somatropin), r hGH, produced in mouse C127 cells EMD Serono (Geneva) AIDS-associated catabolism and 1996 (US) Neupogen Triangle Park, NC, USA) wasting Rixubis (nonacog gamma), rh factor IX, produced in CHO cells Baxalta Innovations (Vienna) Hemophilia B 2014 (EU) Biograstim (filgrastim), produced in E. coli, biosimilar to ABZ-Pharma (Ulm, Germany) Neutropenia 2008 (EU) Trumenba (meningococcal group B vaccine), two r Neisseria men- Pfizer (Philadelphia) Vaccine against N. meningitides 2017 (EU) Baxter Healthcare (Westlake 2013 (US) Saizen (somatropin), r hGH, produced in mouse C127 cells EMD Serono (Rockland, MA, hGH deficiency in children 1996 (US) Neupogen Withdrawn 2015 ingitides serogroup B proteins, independently expressed in E. coli serogroup B 2014 (US) Village, CA, USA) USA) Ratiograstim (filgrastim), produced in E. coli, biosimilar to Ratiopharm (Ulm, Germany) Neutropenia 2008 (EU) Pandemic influenza vaccine H5N1, vaccine derived from engi- MedImmune (Nijmegen, the Influenza vaccine 2016 (EU) Tretten in US, Novothirteen in EU (catridecog), rh factor XIII Novo Nordisk Congenital factor XIII A-subunit 2013 (US) Genotropin (somatropin), r hGH, produced in E. coli Pfizer (New York) hGH deficiency in children 1995 (US) Neupogen neered viral strain containing gene segments from appropriate viral Netherlands A-subunit, produced in S. cerevisiae deficiency 2012 (EU) influenza strains, produced in embryonated eggs Norditropin (somatropin), r hGH, produced in E. coli Novo Nordisk Growth failure in children due 1995 (US) Tevagrastim (filgrastim), produced in E. coli, biosimilar to Teva (Radebeul, Germany) Neutropenia 2008 (EU) Recothrom (thrombin), rh factor IIa, produced in CHO cells ZymoGenetics (Seattle) Control of minor bleeding during 2008 (US) to inadequate growth hormone Neupogen. Same product as Granix (see above) Bexsero (meningococcal group B vaccine), mixture of 3 N. menin- Novartis (Cambridge, MA, USA, Active immunization against N. 2015 (US) surgery secretion serogroup B proteins, produced in & Siena, Italy) serogroup B 2013 (EU) Filgrastim Ratiopharm (filgrastim), produced in E. coli, biosimilar Ratiopharm Neutropenia 2008 (EU) gitidis E. coli meningitidis NovoSeven (eptacog alfa, activated), rh factor VIIa, produced in Novo Nordisk Some forms of hemophilia 1996 (EU) Tev-Tropin, Bio-tropin (somatropin), r hGH, produced in E. coli Teva Pharmaceuticals (North hGH deficiency in children 1995 (US) to Filgrastim Withdrawn 2011 Gardasil 9, mixture of the major capsid protein (L1) of 9 strains of MSD (Lyon, France) Active immunization for those 2015 (EU) BHK cells Wales, PA, USA) 1999 (US) Neulasta in EU and US, Neupopeg in EU (pegfilgrastim), Amgen (Breda, the Netherlands) Chemotherapy-induced neutro- 2002 (EU & US) HPV, each produced in S. cerevisiae Merck (Whitehouse Station, NJ, above 9 years of age against HPV- 2014 (US) Benefix (nonacog alfa), rh factor IX, produced in CHO cells Pfizer/Wyeth Hemophilia B 1997 (EU & US) Nutropin (somatropin), r hGH, produced in E. coli Roche/Genentech hGH deficiency in children 1994 (US) PEGylated rh G-CSF penia Neupopeg with- USA) caused cancers and genital warts Humatrope (somatropin), r hGH, produced in E. coli Eli Lilly (Indianapolis) hGH deficiency in children 1987 (US) drawn 2008 Mosquirix (Plasmodium falciparum and hepatitis B vaccine), virus- GlaxoSmithKline Biologicals Vaccination against malaria 2015 (EU); Recombinant thrombolytics, anticoagulants and other blood-related products Protropin (somatrem), r hGH differing from hGH by an extra Genentech hGH deficiency in children 1985 (US) (EU) like particles comprising the RTS fusion protein of a portion of the (Rixensart, Belgium) caused by the parasite approved for use circumsporozoite protein from P. falciparum and the N- terminal Plasmodium falciparum outside the EU Tissue plasminogen activator N-terminal methionine, produced in E. coli Withdrawn 2004 Leukine (sargramostim), rh GM-CSF differing from the native pro- Sanofi-aventis U.S. (Bridgewater, Autologous bone marrow trans- 1991 (US) end of HBsAg, coexpressed in S. cerevisiae Metalyse (tenecteplase), modified rh tPA, produced in CHO cells Boehringer Ingelheim Myocardial infarction 2001 (EU) tein by an R23L substitution, produced in E. coli NJ, USA) plantation Withdrawn 2008 (Ingelheim, Germany) Withdrawn 2005 Follicle-stimulating hormone and reformu- Flublok, r hemagglutinin proteins from 3 influenza viruses, pro- Protein Sciences (Meriden, CT, Immunization against influenza 2013 (US) duced in an insect cell line USA) Rekovelle (follitropin delta), rh FSH, produced in PER.C6 cells Ferring Pharmaceuticals Anovulation 2016 (EU) lated without TNKase (tenecteplase), modified rh tPA, produced in CHO cells Roche/Genentech (South San Myocardial infarction 2000 (US) (Copenhagen) EDTA 2008 Provenge (sipuleucel-T), autologous peripheral blood mononuclear Dendreon (London) Prostate cancer 2013 (EU) Francisco, CA, USA) cells in combination with r prostatic acid phosphatase linked to 2010 (US) Bemfola (follitropin alfa), rh FSH, produced in CHO cells, biosimi- Finox Biotech (Burgdorf, Anovulation (women), failure of 2014 (EU) Neupogen (filgrastim), rh G-CSF differing from native protein by Amgen (Thousand Oaks, CA, Chemotherapy-induced neutro- 1991 (US) Ecokinase (reteplase), r tPA, produced in Escherichia coli; differs Roche (Welwyn Garden City, UK) Acute myocardial infarction 1996 (EU) GM-CSF, produced in an insect cell line Withdrawn 2015 lar to Gonal F Switzerland) spermatogenesis (men) an extra N-terminal methionine, produced in E. coli USA) penia from human tPA in that 3 of its 5 domains have been deleted Withdrawn 2000 (EU) Ovaleap (follitropin alfa), rh FSH, produced in CHO cells, biosimi- Teva Pharma (Utrect, the Infertility, subfertility 2013 (EU) Rapilysin (reteplase), r tPA (see Ecokinase above) Actavis Group PTC Acute myocardial infarction 1996 (EU) Other growth factors Cervarix, r C-terminally truncated major capsid L1 proteins from GSK Prevention of cervical cancer 2009 (US) lar to Gonal F Netherlands) (Hafnarfjordur, Iceland), Roche Oxervate (cenegermin), rh nerve growth factor, produced in E. coli Dompé Farmaceutici (Milan) Neurotophic keratitis 2017 (EU) HPV types 16 and 18, produced in a baculovirus-based expression 2007 (EU) Elonva (corifollitropin alfa), a modified rh FSH in which the Merck Sharp & Dohme Controlled ovarian stimulation 2010 (EU) system Retavase (reteplase), r tPA (see Ecokinase above) Chiesi USA (Cary, NC, USA) Acute myocardial infarction 1996 (US) Increlex (mecaserim), rh IGF-1, produced in E. coli Ipsen Pharma Growth failure in children with 2007 (EU) C-terminal peptide of the β-subunit of human chorionic gonadotro- IGF-1 deficiency or hGH gene 2005 (US) Gardasil in EU & US, Silgard in EU, r vaccine containing major Sanofi Pasteur Vaccination against diseases 2006 (EU & US) Activase (alteplase), rh tPA, produced in CHO cells Roche/Genentech Acute myocardial infarction 1987 (US) pin is fused to the FSH β-chain, produced in CHO cells deletion (long-term treatment) capsid proteins from four HPV types, produced in S. cerevisiae Merck (Whitehouse Station, NJ, caused by HPX Fertavid (follitropin beta), rh FSH, produced in CHO cells. Active Merck Sharp & Dohme Infertility 2009 (EU) Hirudin USA) substance same as that in Puregon (see below) iPlex (mecasermin rinfabate), a complex of rh IGF-1 and rh IGF Insmed (Glen Allen, VA, USA) Growth failure in children with 2005 (US) Refludan (lepirudin), r hirudin, produced in S. cerevisiae Celgene Europe (Windsor, UK) Anticoagulation therapy for hepa- 1997 (EU) binding protein-3, produced separately in E. coli severe primary IGF-1 deficiency Withdrawn 2007 Dukoral (Vibrio cholerae and r cholera toxin B subunit) Valneva Sweden (Stockholm) Immunization against disease 2004 (EU) Pergoveris (follitropin alfa/lutropin alfa) combination product Merck Serono (London) Stimulation of follicular devel- 2007 (EU) Bayer HealthCare rin-associated thrombocytopenia 1998 (US) or hGH gene deletion (long-term for IGF-1 defi- caused by V. cholerae subunit O1 containing rh FSH and rh luteinizing hormone, both produced in opment in women with severe Withdrawn 2012 treatment ciency Lymerix (r OspA), a lipoprotein found on the surface of GSK Immunization against Lyme 1998 (US) CHO cells luteinizing hormone and FSH B. burgdor- (EU) , produced in disease Withdrawn 2002 deficiency Kepivance (palifermin), rh keratinocyte growth factor, produced in Swedish Orphan Biovitrum Severe oral mucositis in selected 2005 (EU) feri E. coli Revasc (desirudin), r hirudin, produced in S. cerevisiae Canyon Pharmaceuticals Prevention of venous thrombosis 1997 (EU) E. coli patients with hematologic cancers 2004 (US) Triacelluvax, combination vaccine containing r modified pertussis Chiron (Siena, Italy) Immunization against diphtheria, 1999 (EU) Follistim (follitropin beta), rh FSH, produced in CHO cells Merck (Whitehouse Station, NJ, Infertility 1997 (US) (London) Withdrawn 2014 Withdrawn 2016 toxin as one component tetanus and pertussis Withdrawn 2002 USA) (EU) Other Puregon (follitropin beta), rh FSH, produced in CHO cells Merck Sharp & Dohme (Haarlem, Anovulation and superovulation 1996 (EU) GEM 21S: Regranex (see below) and tricalcium phosphate; BioMimetic Pharmaceuticals Periodonatally related defects 2005 (US) Monoclonal antibody–based products the Netherlands) Ruconest (conestat alfa), rh C1 esterase inhibitor, produced in the Santarus (Raleigh, NC, USA) Acute angioedema 2014 (US) growth-factor-enhanced matrix (Franklin, TN, USA) Aimovig (erenumab-aooe in USA, erenumab in EU), human IgG2 Amgen (Thousand Oaks, CA, Migraine 2018 (EU & US) milk of transgenic rabbits Pharming Group (Leiden, the 2010 (EU) Gonal F (follitropin alfa), rh FSH, produced in CHO cells Merck Serono Anovulation and superovulation 1997 (US) Regranex (becaplermin), rh platelet-derived growth factor receptor- Johnson & Johnson (Raritan, Lower extremity diabetic neuro- 1997 (US) targeting the calcitonin gene-related peptide receptor, produced USA) Netherlands) EMD Serono (Rockland, MD, 1995 (EU) BB, produced in S. cerevisiae NJ, USA) pathic ulcers 1999 (EU) in CHO cells Novartis (East Hanover, NJ, USA) USA) Jetrea (ocriplasmin), r truncated form of human plasmin, produced ThromboGenics (Leuven, Symptomatic vitreomacular adhe- 2013 (EU) Janssen-Cilag International Withdrawn 2012 Novartis Europharm (Dublin) in Pichia pastoris Belgium) sion, vitreomacular traction 2012 (US) (Beerse, Belgium) (EU) Crysvita (burosumab in EU, burosumab-twza in USA), human IgG1 Kyowa Kirin (Galashiels, UK) X-linked hypophosphatemia 2018 (EU & US) Other hormones Atryn (rh antithrombin), produced in milk of transgenic goats Laboratoire français du frac- Hereditary antithrombin defi- 2009 (US) antibody to soluble fibroblast growth factor-23, produced in CHO Ultragenyx Pharmaceutical Myalepta in EU, Myalept in US (metreleptin), rh leptin analog, Aegerion Pharmaceuticals Some forms of lipodystrophy 2018 (EU) Recombinant interferons, interleukins and tumor necrosis factor tionnement et des biotechnolo- ciency 2006 (EU) cells (Novato, CA, USA) produced in E. coli (Amsterdam & Cambridge, MA, 2014 (US) gies (Les Ulis, France), Interferon-α Fasenra (benralizumab), humanized, afucosylated IgG1 targeting AstraZeneca (Södartälje, Asthma 2018 (EU) USA) rEVO Biologics (Framingham, PEG-Intron/Rebetol combo pack (peginterferon alfa-2b/ribavirin) Schering Plough (Kenilworth, Chronic hepatitis C 2008 (US) the α subunit of the human IL-5 receptor, produced in CHO cells Sweden, & Wilmington, DE, 2017 (US) MA, USA) Ozempic (semaglutide), human GLP-1 receptor agonist, produced Novo Nordisk Diabetes mellitus type 2 2018 (EU) PEGylated rh IFN-α-2b, produced in E. coli, and ribavirin NJ, USA) USA) in yeast and covalently modified by attachment of a C18 fatty acid 2017 (US) Kalbitor (ecallantide), plasma kallikrein inhibitor, produced in P. Dyax (Cambridge, MA, USA) Hereditory angioedema 2009 (US) Pegasys (peginterferon alfa-2a), PEGylated IFN-α-2b, produced Roche/Genentech (Welwyn Hepatitis C 2002 (EU & US) Halimatoz (adalimumab), anti-TNF IgG, produced in CHO cells, Sandoz Various inflammatory conditions 2018 (EU) pastoris Movymia (teriparatide), rh parathyroid hormone fragment, pro- STADA Arzneimittel (Bad Vilbel, Osteoporosis 2017 (EU) in E. coli Garden City, UK) biosimilar to Humira. Same product as Hefiya and Hyrimoz (see mediated by TNF, including duced in E. coli, biosimilar to Fortseo. Same product as Terrosa Germany) below) rheumatoid arthritis and plaque Xigris (drotrecogin alfa), rh activated protein C, produced in a Eli Lilly (Houten, the Severe sepsis 2001 (US) PEG-Intron (peginterferon alfa-2b), PEGylated IFN-α-2b, produced Merck Sharp & Dohme Chronic hepatitis C 2001 (US) (see below) psoriasis human cell line Netherlands) 2002 (EU) in E. coli. 2000 (EU) Withdrawn 2012 Natpar (parathyroid hormone), rh parathyroid hormone, full length, Shire Pharmaceuticals Ireland Hypoparathyroidism 2017 (EU) Hefiya (adalimumab), anti-TNF IgG, produced in CHO cells, bio- Sandoz Various inflammatory conditions 2018 (EU) Viraferon (interferon alfa-2b), produced in E. coli Schering Plough (Brussels, Chronic hepatitis B, C 2000 (EU) (EU) produced in E. coli. Same product as Preotact (see below). (Dublin) Belgium) Withdrawn 2008 similar to Humira. Same product as Halimatoz and Hyrimoz (see mediated by TNF, including above and below) polyarticular juvenile idiopathic Terrosa (teriparatide), rh parathyroid hormone fragment, produced Gedeon Richter (Budapest) Osteoporosis 2017 (EU) Recombinant hormones ViraferonPeg (peginterferon alfa-2b), PEGylated IFN-α-2b, pro- Merck Sharp & Dohme Chronic hepatitis C 2000 (EU) arthritis and plaque psoriasis in E. coli, biosimilar to Fortseo. Same product as Movymia (see duced in E. coli Insulins above) Hemlibra (emicizumab in EU, emicizumab-kxwh in US), human- Roche Registration (Welwyn Hemophilia A 2018 (EU) Intron A, Alfatronol (interferon alfa-2b), produced in E. coli Merck Sharp & Dohme Cancer, genital warts, hepatitis B 2000 (EU) ized, bispecific IgG4 capable of binding factor IXa and factor X, Garden City, UK) 2017 (US) Semglee (insulin glargine), r insulin glargine, produced in Mylan (Saint-Priest, France) Diabetes mellitus 2018 (EU) Natpara (parathyroid hormone), rh parathyroid hormone, produced Shire-NPS Pharmaceuticals Hypocalcemia 2015 (US) and C, HPV 1986 (US) produced in CHO cells Roche/Genentech (South San P. pastoris, biosimilar to Lantus in E. coli (Lexington, MA, USA) Francisco, CA, USA)

NATURE BIOTECHNOLOGY VOLUME 36 NUMBER 12 DECEMBER 2018 Table 1 Continued Table 1 Continued Table 1 Continued Table 1 Continued Product Company (location) Therapeutic indication Date approved Product Company (location) Therapeutic indication Date approved Product Company (location) Therapeutic indication Date approved Product Company (location) Therapeutic indication Date approved Herzuma (trastuzumab), r humanized IgG1 against HER2, pro- Celltrion Healthcare (Budapest) Breast and gastric cancers 2018 (EU) Blincyto (blinatumomab), bispecific T-cell engager antibody con- Amgen Europe Acute lymphoblastic leukemia 2015 (EU) Humaspect (votumumab), human mAb against cytokeratin tumor- KS Biomedix (Farnham, UK) Detection of carcinoma of the 1998 (EU) Orencia (abatacept), fusion protein that links the extracellular Bristol-Myers Squibb (Uxbridge, Rheumatoid arthritis 2007 (EU) duced in CHO cells, biosimilar to Herceptin struct (BiTE), produced in CHO cells Amgen (Thousand Oaks, CA, 2014 (US) associated antigen, produced in a human lymphoblastoid cell line colon or rectum Withdrawn 2004 domain of human cytotoxic T-lymphocyte associated antigen-4 UK) 2005 (US) Hyrimoz (adalimumab), anti-TNF IgG, produced in CHO cells, Sandoz Various inflammatory conditions 2018 (EU) USA) MabThera in EU, Rituxan in US (rituximab), chimeric mAb against Roche (Welwyn Garden City, UK) Non-Hodgkin lymphoma 1998 (EU) with modified Fc region of IgG1, produced in a mammalian cell biosimilar to Humira. Same product as Halimatoz and Hefiya (see mediated by TNF, including Cosentyx (secukinumab), human IgG1 selectively binding human Novartis Europharm (Camberley, Moderate to severe plaque psoria- 2015 (EU & US) CD20 surface antigen of B lymphocytes, produced in CHO cells 1997 (US) line above) rheumatoid arthritis and plaque IL-17a, produced in CHO cells UK) sis in adults Amevive (alefacept), dimeric fusion protein consisting of the Astellas Pharma (Deerfield, IL, Moderate to severe chronic 2003 (US) Simulect (basiliximab), chimeric mAb directed against the α-chain Novartis (Horsham, UK) Prophylaxis of acute organ rejec- 1998 (EU) psoriasis Novartis (East Hanover, NJ, USA) of the IL-2 receptor, produced in a murine myeloma cell line tion in allogeneic renal trans- extracellular CD2-binding portion of human LFA-3 linked to the Fc USA) plaque psoriasis in adults Withdrawn 2011 Ilumya (tildrakizumab-asmn), humanized IgG1 that binds the p19 Merck (Whitehouse Station, NJ, Plaque psoriasis 2018 (US) Keytruda (pembrolizumab), humanized IgG4 capable of binding to Merck Sharp & Dohme Advanced (unresectable or meta- 2015 (EU) plantation region of human IgG1, produced in CHO cells subunit of IL-23, produced in CHO cells USA) the receptor PD-1, produced in CHO cells Merck (Whitehouse Station, NJ, static) melanoma in adults 2014 (US) LeukoScan (sulesomab), murine mAb Fab fragment against granu- Immunomedics (Darmstadt, Diagnostic imaging for infection 1997 (EU) Enbrel (etanercept), r TNF receptor–IgG fragment fusion protein, Amgen (Thousand Oaks, CA, Rheumatoid arthritis 2000 (EU) Kanjinti (trastuzumab), r humanized IgG1 against HER2, pro- Amgen Europe (Breda, the Breast and gastric cancers 2018 (EU) USA) locyte surface nonspecific cross-reacting antigen-90, produced in Germany) and inflammation in bone of Withdrawn 2018 produced in CHO cells. Same product as Lifmior (see above) USA) 1998 (US) duced in CHO cells, biosimilar to Herceptin Netherlands) Nivolumab BMS (nivolumab), human IgG4 against the receptor Bristol-Myers Squibb (Uxbridge, Locally advanced or metastatic July 2015 (EU) Sp2/0 cells patients with osteomyelitis Pfizer (Sandwich, UK) Mvasi (bevacizumab in EU, bevacizumab-awwb in US), humanized Amgen Europe Various cancers 2018 (EU) PD-1, produced in CHO cells. Same product as Opdivo (see below) UK) squamous non-small-cell lung Withdrawn Verluma (nofetumomab), murine mAb Fab fragment directed Boehringer Ingelheim, NeoRx Detection of small-cell lung 1996 (US) Ontak (denileukin diftitox), r IL-2–diphtheria toxin fusion protein Eisai (Tokyo), Ligand Cutaneous T-cell lymphoma 1999 (US) IgG antibody to human VEGF-A1, produced in CHO cells, biosimi- Amgen (Thousand Oaks, CA, 2017 (US) cancer after prior chemotherapy November 2015 against carcinoma-associated antigen, produced in a murine cell (Seattle) cancer Withdrawn 1999 that targets cells displaying a surface IL-2 receptor, produced in Pharmaceuticals (San Diego) lar to Avastin USA) in adults line E. coli Nucala (mepolizumab), humanized IgG1 capable of binding GlaxoSmithKline (Cork, Ireland) Add-on treatment for severe 2015 (EU & US) Mylotarg (gemtuzumab ozogamicin), antibody drug conjugate tar- Pfizer Europe (Brussels) Acute myeloid leukemia 2018 (EU) Tecnemab KI (antimelanoma Mab fragments), murine mAb frag- Amersham Sorin (Milan) Diagnosis of cutaneous mela- 1996 (EU) Gene therapy and nucleic acid–based geting the CD33 surface antigen, consisting of a humanized IgG4 Pfizer/Wyeth (Philadelphia) 2000 (US) human IL-5, produced in CHO cells GSK (Research Triangle Park, refractory eosinophilic asthma in ments (Fab/Fab mix) against HMW-MAA, produced in murine noma lesions Withdrawn 2000 NC, USA) adult patients 2 Tegsedi (inotersen), a 20-nucleotide single-stranded oligonucle- Ionis USA (London) Hereditary transthyretin amyloi- 2018 (EU) chemically conjugated to N-acetyl-γ-calicheamicin, produced in Withdrawn 2010 ascites culture otide manufactured by direct chemical synthesis dosis NS0 mouse myeloma cells (US) Opdivo (nivolumab), human IgG4 against the receptor PD-1, pro- Bristol-Myers Squibb (Uxbridge, Melanoma (as monotherapy or in 2015 (EU) ProstaScint (capromab pentetate), murine mAb against the tumor EUSA Pharma USA (Langhorne, Detection, staging and follow-up 1996 (US) Reapproved duced in CHO cells. Same product as nivolumab BMS (see above) UK, & Princeton, NJ, USA) combination with ipilimumab), 2014 (US) surface antigen PSMA, produced in a murine cell line PA, USA) of prostate adenocarcinoma Luxturna (voretigene neparvovec-rzyl), a live, nonreplicating Spark Therapeutics Retinal dystrophy 2017 (US) 2017 (US) using non-small-cell lung cancer, renal adeno-associated virus genetically modified to express the human (Philadelphia) modified dosage cell carcinoma MyoScint (imiciromab pentetate), murine mAb fragment directed Centocor Myocardial infarction imaging 1996 (US) RPE65 gene against human cardiac myosin, produced in a murine cell line Withdrawn 1999 and regimen Praluent (alirocumab), human IgG1 targeting PCSK9, produced in Sanofi-Aventis (Paris & Primary hypercholesterolemia 2015 (EU & US) Spinraza (nusinersen sodium), an 18-nucleotide antisense oligo- Biogen Idec (Maidenhead, UK) Spinal muscular atrophy 2017 (EU) Ocrevus (ocrelizumab), r humanized IgG1 targeting the CD20 sur- Roche Registration Multiple sclerosis 2018 (EU) CHO cells Bridgewater, NJ, USA) or mixed dyslipidemia, as an CEA-scan (arcitumomab), murine mAb Fab fragment against Immunomedics Detection of recurrent or meta- 1996 (EU & US) nucleotide manufactured by direct chemical synthesis Biogen (Cambridge, MA, USA) 2016 (US) face antigen, produced in CHO cells Genentech (South San 2017 (US) Regeneron Pharmaceuticals adjunct to diet human carcinoembryonic antigen (CEA), produced in mouse asci- static colorectal cancer Withdrawn 2005 tes (EU & US) Exondys 51 (eteplirsen), a chemically synthesized antisense oligo- Sarepta Therapeutics Duchenne muscular dystrophy 2016 (US) Francisco, CA, USA) (Tarrytown, NY, USA) nucleotide (Cambridge, MA, USA) Trazimera (trastuzumab), humanized IgG, produced in a CHO Pfizer (Brussels) Breast cancer, gastric or gastro- 2018 (EU) Praxbind (idarucizumab), humanized IgG1 Fab fragment capable Boehringer Ingelheim (Rhein, Rapid reversal agent for the anti- 2015 (EU & US) Indimacis 125 (igovomab), murine mAb Fab2 fragment against CIS Bio (Gif-sur-Yvette, France) Diagnosis of ovarian adenocar- 1996 (EU) the tumor-associated antigen CA125, produced in a murine cell cinoma Withdrawn 2009 Imlygic (talimogene laherparepvec), an engineered herpes simplex Amgen Europe Melanoma 2015 (EU & US) cells, biosimilar to Herceptin esophageal junction adenocar- of binding the anticoagulant drug dabigatran, produced in CHO Germany, & Ridgefield, CT, USA) coagulant drug dabigatran virus type 1 capable of producing GM-CSF Amgen cinoma cells line Kynamro (mipomersen sodium), a chemically synthesized anti- Kastle Therapeutics (Chicago) Familial hypercholesterolemia 2013 (US) TROGARZO (ibalizumab-uiyk), humanized IgG4 targeting the CD4 TaiMed Biologics (Irvine, CA, Human immunodeficiency virus 2018 (US) Repatha (evolocumab), human IgG2 capable of binding human Amgen Europe Hypercholesterolemia and mixed 2015 (EU & US) ReoPro (abciximab), Fab fragments derived from a chimeric mAb Janssen Biologics (Leiden, the Prevention of blood clots 1994 (US) against the platelet surface receptor GPII /III produced in a Netherlands), Centocor sense oligonucleotide domain, produced in NS0 cells USA) type 1 infection PCSK-9, produced in CHO cells Amgen (Thousand Oaks, CA, dyslipidemia b , mammalian cell line Glybera (alipogene tiparvovec), human LPL gene housed in an uniQure (Amsterdam) Lipoprotein lipase deficiency 2012 (EU) Theratechnologies (Montreal) USA) OncoScint CR/OV (satumomab pendetide), murine mAb against Cytogen (Princeton, NJ, USA) Detection, staging and follow-up 1992 (US) engineered AAV1 vector Withdrawn 2017 Zessly (infliximab), chimeric anti-TNF IgG1 produced in CHO Sandoz Rheumatoid arthritis and selected 2018 (EU) Unituxin (dinutuximab), chimeric IgG1 targeting human disialo- United Therapeutics (Chertsey, Neuroblastoma (administered in 2015 (EU & US) the tumor-associated glycoprotein TAG-72, produced in a murine of colorectal and ovarian cancers Withdrawn 2002 Macugen (pegaptanib sodium injection), a synthetic PEGylated Pfizer, PharmaSwiss Ceska Neovascular, age-related macular 2006 (EU) cells, biosimilar to Remicade (infliximab) additional inflammatory diseases ganglioside (GD2), produced in Sp2/0 cells UK, & Silver Spring, MD, USA) combination with GM-CSF, IL-2 Withdrawn 2017 cell line oligonucleotide that specifically binds VEGF Republika (Prague) degeneration 2004 (US) Amgevita (adalimumab), anti-TNF human IgG1, produced in Amgen Europe Rheumatoid arthritis and selected 2017 (EU) and isotretinoin) (EU) Orthoclone OKT3 (muromomab CD3), murine mAb against the Centocor Ortho Biotech Products Reversal of acute kidney trans- 1986 (US) Eyetech (Palm Beach Gardens, CHO cells, biosimilar to Humira. Same product as Solymbic and additional inflammatory diseases Cyramza (ramucirumab), human mAb that binds the VEGF-2 Eli Lilly Nederland (Utrecht, the Gastric cancer 2014 (EU & US) T-lymphocyte surface antigen CD3, produced in a murine cell line (Raritan, NJ, USA) plant rejection FL, USA), Amjevita (see below) receptor, produced in NS0 cells Netherlands) Vitravene (fomivirsen), an antisense oligonucleotide Novartis Ophthalmics Europe Cytomegalovirus retinitis in AIDS 1999 (EU) Eli Lilly (Indianapolis) Bavencio (avelumab), human IgG1 specific for programmed death Merck Europe (Amsterdam) Metastatic Merkel cell carcinoma, 2017 (EU & US) Other recombinant products (Farnborough, UK) patients 1998 (US) ligand-1 (PD-L1), produced in CHO cells Pfizer (New York) urothelial carcinoma Entyvio (vedolizumab), humanized IgG targeting the human α4β7 Takeda Pharmaceuticals Ulcerative colitis, Crohn’s disease 2014 (EU & US) Bone morphogenetic proteins Isis Pharmaceuticals (Carlsbad, Withdrawn 2002 Besponsa (inotuzumab ozogamicin), antibody-drug conjugate con- Pfizer (Sandwich, UK) Acute lymphoblastic leukemia 2017 (EU & US) integrin, produced in CHO cells (Deerfield, IL, USA) California) (EU) sisting of a humanized IgG4 specific for human CD22, produced Pfizer/Wyeth (Philadelphia) Takeda Pharma (Taastrup, Opgenra (eptotermin alfa), rh BMP-7, produced in CHO cells Olympus Biotech (Limerick, Posterolateral lumbar spinal 2009 (EU) Ireland) fusion Withdrawn 2016 in CHO cells, covalently linked to the cytotoxic agent N-acetyl-γ- Denmark) Engineered cell–based calicheamicin dimethylhydrazide Gazyva in US, Gazyvaro in EU (obinutuzumab), humanized, gly- Roche/Genentech CLL 2014 (EU) Infuse bone graft, containing dibotermin alfa, a rh BMP-2 pro- Wyeth (Madison, NJ, USA) Acute open tibial shaft fracture 2004 (US) Kymriah (tisagenlecleucel), autologous T cells genetically modified Novartis (East Hanover, NJ, USA) Acute lymphoblastic leukemia, 2017 (US) Blitzima (rituximab), chimeric IgG1 against cell surface antigen Celltrion Healthcare Hungary Non-Hodgkin lymphoma, CLL, 2017 (EU) coengineered mAb specific for B-cell antigen CD20, produced in Roche (Welwyn Garden City, UK) 2013 (US) duced in CHO cells, placed on an absorbable collagen sponge. to encode an anti-CD19 chimeric antigen receptor comprising a large B-cell lymphoma CD20, produced in CHO cells, biosimilar to MabThera (Budapest) granulomatosis CHO cells Active substance same as that in Infuse (see below) murine single-chain antibody fragment (scFv) specific for CD19, Same product as Ritemvia, Truxima and Rituzena (see below) Sylvant (siltuximab), chimeric mAb that binds human IL-6, pro- Janssen Biotech Multicentric Castleman disease 2014 (EU & US) Inductos (dibotermin alfa), rh BMP-2, produced in CHO cells Medtronic BioPharma (Heerlen, Acute tibia fractures 2002 (EU) followed by a CD8 hinge and transmembrane region that is fused Cyltezo (adalimumab in EU, adalimumab-adbm in USA), rh IgG1 Boehringer Ingelheim (Rhein, Range of inflammatory condi- 2017 (EU & US) duced in CHO cells the Netherlands) to the intracellular signaling domains for 4-1BB (CD137) and against human TNF, produced in CHO cells, biosimilar to Humira Germany) tions, including psoriasis, Wyeth Europa CD3ζ Kadcyla (trastuzumab emtansine), humanized mAb specific for Roche (Welwyn Garden City, UK) Breast cancer 2013 (EU & US) Genetics Institute Boehringer Ingelheim rheumatoid arthritis and Crohn’s HER2 antigen, produced in CHO cells and conjugated to the small Yescarta (axicabtagene ciloleucel), autologous T cells genetically Kite Pharma (Santa Monica, CA, Large B-cell lymphoma 2017 (US) (Ridgefield, CT, USA) disease molecule cytotoxin DM1 Infuse (rh BMP2), produced in CHO cells Medtronic Sofamor Danek Promotes fusion of lower spine 2002 (US) modified to express a chimeric antigen receptor comprising a USA) (Memphis, TN, USA) vertebrae murine anti-CD19 single-chain variable fragment (scFv) linked to Dinutuximab beta Apeiron (dinutuximab beta), chimeric IgG1 Apeiron Biologics (Vienna) Neuroblastoma 2017 (EU) Simponi Aria (golimumab). Active substance same as that in Janssen Biotech Rheumatoid arthritis 2013 (US) CD28 and CD3ζ co-stimulatory domains against the disialoganglioside GD2, produced in CHO cells. Same Simponi (see below); different strength and mode of administra- OP-1 implant in US, Osigraft in EU (eptotermin alfa), rh BMP-7, Olympus Biotech (Limerick, Non-union of tibia 2001 (EU & US) + product as Qarziba (see below) tion produced in CHO cells Ireland) Withdrawn 2015 Strimvelis, autologous CD34 cells transduced with an engi- GlaxoSmithKline (Cork, Ireland) Severe combined immunodefi- 2016 (EU) Stryker Biotech (Hopkinton, MA, (EU) neered retroviral vector encoding the human adenosine deaminase ciency Dupixent (dupilumab), human IgG4 that binds the IL-4α receptor Sanofi-Aventis (Paris & Atopic dermatitis 2017 (EU & US) Perjeta (pertuzumab), human mAb specific for HER2, produced Roche/Genentech Breast cancer 2013 (EU) USA) sequence subunit, produced in CHO cells Bridgewater, NJ, USA), in CHO cells 2012 (US) Regeneron Pharmaceuticals Zalmoxis, allogeneic T cells genetically modified to express the MolMed (Milan) Hematopoietic stem cell trans- 2016 (EU) Abthrax (raxibacumab), human IgG mAb against the protective GSK/Human Genome Sciences Inhalational anthrax 2012 (US) (Tarrytown, NY, USA) Recombinant enzymes herpes simplex thymidine kinase suicide gene and a truncated plantation, graft-versus-host antigen (PA) of B. anthracis, produced in NS0 cells (Rockville, MD, USA) Imfinzi (durvalumab), human IgG1 blocking the interaction of pro- AstraZeneca (Wilmington, DE, Urothelial carcinoma 2017 (US) Palynziq (pegvaliase-pqpz), r phenylalanine ammonia lyase, pro- BioMarin (Novato, CA, USA) Phenylketonuria 2018 (US) form of the human low-affinity nerve growth factor receptor gene disease grammed cell death ligand-1 (PD-L1) with its receptor PD-1 and USA) Adcetris (brentuximab vedotin), chimeric mAb conjugate specific Takeda Pharma (Roskilde, Lymphoma 2012 (EU) duced in E. coli and PEGylated for human CD30 (expressed on the surface of lymphoma cells), Denmark) 2011 (US) Data were collected from several sources (http://www.fda.gov/, https://www.ema.europa.eu/en). r, recombinant; rh, recombinant human; CHO, Chinese hamster ovary cell line; HEK, CD80, produced in CHO cells Lamzede (velmanase alfa), rh α-mannosidase, expressed in precur- Chiesi Farmaceutici (Parma, α-mannosidosis 2018 (EU) human embryo kidney cell line; BHK, baby hamster kidney cell line; PEG, polyethylene glycol; mAb, monoclonal antibody; tPA, tissue plasminogen activator; hGH, human growth produced in CHO cells Seattle Genetics Imraldi (adalimumab), produced in CHO cells, biosimilar to Samsung Bioepis UK (Chertsey, Rheumatoid arthritis, selected 2017 (EU) sor form in CHO cells Italy hormone; FSH, follicle stimulating hormone; EPO, erythropoietin; IGF, insulin-like growth factor; BMP, bone morphogenetic protein; EGF, epidermal growth factor; G-CSF, granulocyte Humira UK) additional inflammatory diseases Benlysta (belimumab), human mAb that targets human Human Genome Sciences Lupus 2011 (EU & US) Brineura (cerliponase alfa), rh serine tripeptidyl peptidase-1, BioMarin (Cork, Ireland), CLN2 disease (tripeptidyl pepti- 2017 (EU & US) colony stimulating factor; GM-CSF, granulocyte-macrophage colony stimulating factor; VEGF, vascular endothelial growth factor; IFN, interferon; IL, interleukin; HPV, human papil- B-lymphocyte stimulator (BLyS), a B cell survival factor. produced Glaxo Group (Greenford, UK) lomavirus; HBsAg, hepatitis B surface antigen; TNF, tumor necrosis factor; GLP, glucagon-like peptide; HER2, human epidermal growth factor receptor 2, CLL, chronic lymphocytic Ixifi (infliximab-qbtx), produced in a mammalian cell line, biosimi- Pfizer (New York) Various inflammatory conditions, 2017 (US) expresses in proenzyme form in CHO cells BioMarin dase-1 deficiency) leukemia. in NS0 cells lar to Remicade including rheumatoid arthritis, Mepsevii (vestronidase alfa-vjbk), r human lysosomal Ultragenyx Pharmaceutical Mucopolysaccharidosis VII 2017 (US) Crohn’s disease and psoriasis Xgeva (denosumab) (see Prolia) Amgen Europe Bone loss associated with cancer 2011 (EU) β-glucuronidase, produced in CHO cells (Novato, CA, USA) 2010 (US) Kevzara (sarilumab), human IgG1 that binds IL-6 receptors, pro- Sanofi-Aventis (Paris & Rheumatoid arthritis 2017 (EU) Oncaspar (pegaspargase), r asparaginase, produced in E. coli and Baxalta Innovations Lymphoblastic leukemia, lym- 2016 (EU) duced in CHO cells Bridgewater, NJ, USA), 2017 (US) Yervoy (ipilimumab), human mAb binding to CTLA-4 (a negative Bristol-Myers Squibb (Uxbridge, Melanoma 2011 (EU & US) conjugated to monomethoxypropylene glycol phoma regulator of T-cell activation), thereby enhancing T cell activation UK) Regeneron Pharmaceuticals Spectrila (asparaginase), r asparaginase, produced in E. coli Medac Gesellschaft für klinische Lymphoblastic leukemia, lym- 2016 (EU) and proliferation, produced in CHO cells (Tarrytown, NY, USA) Spezialpräparate (Wedel, phoma Kyntheum in EU, Siliq in US (brodalumab), human IgG2 against LEO Pharma (Ballerup, Psoriasis 2017 (EU) Actemra in US, RoActemra in EU (tocilizumab), humanized mAb Roche (Welwyn Garden City, UK) Rheumatoid arthritis 2010 (US) Germany) specific for IL-6, produced in a mammalian cell line 2009 (EU) human IL-17 receptor A, produced in CHO cells Denmark) 2017 (US) Kanuma (sebelipase alfa), rh lysosomal acid lipase, produced in Alexion Europe (Rueil- Enzyme replacement therapy 2015 (EU & US) Valeant Pharmaceuticals Arzerra (ofatumumab), human mAb specific for CD20, produced in Novartis (East Hanover, NJ, CLL 2010 (EU) the eggs of transgenic chickens Malmaison, France) in patients with lysosomal acid (Bridgewater, NJ, USA) NS0 hybridoma cells USA), 2009 (US) Alexion Pharmaceuticals lipase deficiency Ogivri (trastuzumab-dkst), produced in CHO cells, biosimilar to Mylan (Morgantown, WV, USA, Breast and gastric cancers 2017 (US) Genmab (Greenford, UK) (Cheshire, CT, USA) Herceptin & Zurich) Prolia (denosumab), human mAb specific for receptor activator of Amgen Europe Osteoporosis in postmenopausal 2010 (EU & US) Strensiq (asfotase alfa), dimeric fusion protein containing a solu- Alexion Europe (Rueil- Enzyme replacement therapy 2015 (EU & US) Ontruzant, produced in CHO cells, biosimilar to Herceptin Samsung Bioepis UK (Brentford, Breast and gastric cancers 2017 (EU) nuclear factor κB ligand (RANKL), produced in CHO cells women ble catalytic domain of human tissue nonspecific alkaline phos- Malmaison, France) in patients with pediatric-onset UK) Scintimun (besilesomab), murine mAb against nonspecific cross- CIS Bio International (Gif-sur- In vivo diagnosis or investigation 2010 (EU) phatase linked to an IgG Fc domain and a deca-aspartate peptide Alexion (Cheshire, CT, USA) hypophosphatasia Qarziba (dinutuximab beta; previously dinutuximab beta EUSA EUSA Pharma (Hemel Neuroblastoma 2017 (EU) reacting antigen-95 (found on surface of granulocytes), produced Yvette, France) of sites of inflammation or infec- domain, produced in CHO cells and dinutuximab beta Apeiron), chimeric IgG1 against carbohy- Hempstead, UK) in hybridoma cells tion via scintigraphic imaging Vimizim (elosulfase alfa), rh N-acetlygalactosamine-6-sulfatase, BioMarin (London, UK) Mucopolysaccharidosis IVA 2014 (EU & US) drate disialoganglioside GD2, which is overexpressed by cells of Cimzia (certolizumab pegol), anti-TNF-α humanized and UCB Pharma (Brussels, Belgium) Crohn’s disease, rheumatoid 2009 (EU) produced in CHO cells (Morquio A syndrome) neuroectodermal origin such as neuroblastoma cells, produced in PEGylated antibody Fabʹ fragment, produced in E. coli arthritis 2008 (US) Krystexxal (pegloticase), r urate oxidase, PEGylated after synthe- Savient Pharma Ireland (Dublin) Gout 2013 (EU) CHO cells Ilaris (canakinumab), human mAb specific for IL-1β, produced in Novartis Pharmaceuticals (East Cryopyrin-associated periodic 2009 (EU & US) sis, produced in E. coli Crealta Pharmaceuticals (Lake 2010 (US) Renflexis (infliximab-abda), chimeric IgG1 that binds TNF-α, Merck (Kenilworth, NJ, USA) Crohn’s disease and various other 2017 (US) Sp2/0 cells Hanover, NJ, USA) syndromes (CAPS) Forest, IL, USA) Withdrawn 2016 produced in CHO cells, biosimilar to Remicade. Same product as inflammatory conditions Novartis Europharm (Dublin) (EU) Flixabi (see below) Removab (catumaxomab), bispecific engineered antibody target- Neovii Biotech (Gräfelfing, Malignant ascites in patients with 2009 (EU) Elelyso (taliglucerase alfa), rh glucocerebrosidase, produced in Pfizer (New York), Protalix Gaucher disease 2012 (US) Ritemvia (rituximab), produced in CHO cells, biosimilar to Celltrion Healthcare Hungary Non-Hodgkin lymphoma, granulo- 2017 (EU) ing the human epithelial cell adhesion molecule and human CD3 Germany) carcinomas expressing epithelial Withdrawn 2017 engineered carrot root cell culture BioTherapeutics (Karmiel, Israel) MabThera. Same product as Blitzima, Rituzena and Truxima (see matosis with polyangiitis, micro- expressed on T-lymphocytes, produced in hybridoma cells cell adhesion molecule Voraxaze (glucarpidase), r carboxypeptidase, produced in E. coli BTG International (West Toxic plasma methotrexate 2012 (US) above and below) scopic polyangiitis Simponi (golimumab), human mAb specific for TNF-α, produced Janssen Biologics (Leiden, the Rheumatoid arthritis, psoriatic 2009 (EU & US) Conshohocken, PA, USA) concentrations in patients with Rituxan Hycela (rituximab and hyaluronidase human), both pro- Biogen (Cambridge, MA, USA), Follicular lymphoma, diffuse 2017 (US) in Sp2/0 cells Netherlands) arthritis, ankylosing spondylitis delayed methotrexate clearance duced in CHO cells Genentech large B-cell lymphoma, CLL Janssen Biotech (Horsham, PA, due to impaired renal function Rituzena (previously Tuxella) (rituximab), produced in CHO cells, Celltrion Healthcare Hungary Non-Hodgkin lymphoma, CLL, 2017 (EU) USA) Lumizyme (alglucosidase alfa), rh acid-α-glucosidase, produced in Sanofi Genzyme Pompe disease (glycogen storage 2010 (US) biosimilar to MabThera. Same product as Blitzima, Ritemvia and granulomatosis with polyangiitis Stelara (ustekinumab), human MAb specific for the p40 subunit of Janssen-Cilag Moderate to severe plaque pso- 2009 (EU & US) CHO cells disease type II) Truxima (see above and below) IL-12 and IL-23, produced in Sp2/0 cells riasis VPRIV (velaglucerase alfa), rh glucocerebrosidase, produced in a Shire Human Genetic Therapies Gaucher disease 2010 (EU & US) Rixathon (rituximab), chimeric IgG1 against cell surface antigen Sandoz Various conditions including 2017 (EU) Lucentis (ranibizumab), humanized IgG fragment that binds and Roche/Genentech Neovascular (wet) age-related 2007 (EU) human fibroblast cell line (Danderyd, Sweden) CD20, produced in CHO cells, biosimilar to MabThera. Same prod- non-Hodgkin lymphoma, CLL, inactivates VEGF-A, produced in E. coli macular degeneration 2006 (US) Elaprase (idursulfase), rh iduronate-2-sulfatase, produced in a Shire Human Genetic Therapies Mucopolysaccharidosis II (Hunter 2007 (EU) uct as Riximyo (see below) rheumatoid arthritis Soliris (eculizumab), humanized IgG that binds human C5 comple- Alexion Pharmaceuticals Paroxysmal nocturnal hemoglo- 2007 (EU & US) human cell line syndrome) 2006 (US) Riximyo (rituximab), chimeric IgG1 against cell surface antigen Sandoz Various conditions including non- 2017 (EU) ment protein, produced in a murine myeloma cell line (Cheshire, CT, USA, & Paris) binuria Naglazyme (galsulfase), rh N-acetylgalactosamine-4-sulfatase, BioMarin (London & Novato, Long-term enzyme replacement 2006 (EU) CD20, produced in CHO cells, biosimilar to MabThera. Same prod- Hodgkin lymphoma and rheuma- Vectibix (panitumumab), human mAb that binds to human EGF Amgen Europe EGF receptor–expressing colorec- 2007 (EU) produced in CHO cells CA, USA) therapy in mucopolysaccharido- 2005 (US) uct as Rixathon (see above) toid arthritis, but excluding CLL receptor, produced in CHO cells Abgenix tal carcinoma 2006 (US) sis VI Solymbic (adalimumab), anti-TNF human IgG1 produced in Amgen Europe Rheumatoid arthritis and selected 2017 (EU) Tysabri (natalizumab), humanized mAb against selected leukocyte Biogen Inc. (Cambridge, MA, Relapsing forms of multiple 2006 (EU) Myozyme (algulcosidase alfa), rh acid glucosidase, produced in Sanofi Genzyme (Naarden, the Pompe disease 2006 (EU & US) CHO cells, biosimilar to Humira. Same product as Amgevita and additional inflammatory diseases integrins, produced in murine myeloma cells USA) sclerosis 2004 (US) CHO cells Netherlands) Amjevita (see above and below) Biogen Netherlands Suspended Aldurazyme (laronidase), r α-l-iduronidase, produced in CHO cells BioMarin Long-term replacement in muco- 2003 (EU & US) Tecentriq (atezolizumab), humanized IgG1 specific for pro- Roche Registration (Grenzach- Urothelial carcinoma, non-small- 2017 (EU) (Badhoevedorp, the Netherlands) 2005 (US) polysaccharidosis I grammed death ligand 1 (PD-L1), engineered to lack Fc glycosyl- Wyhlen, Germany) cell lung cancer 2016 (US) Resumed 2006 Hylenex (hyaluronidase), rh hyaluronidase, produced in CHO cells Halozyme Therapeutics (San Adjuvant to increase absorption 2005 (US) ation, produced in CHO cells Genentech (South San (US) Francisco, CA, USA) Diego) and dispersion of other drugs Xolair (omalizumab), humanized mAb that binds IgE at the site of Roche/Genentech Moderate to severe persistent 2005 (EU) Fabrazyme (agalsidase beta), rh -galactosidase, produced in CHO Sanofi Genzyme (Naarden, the Fabry disease ( -galactosidase A 2003 (US) Tremfya (guselkumab), human IgG1 that selectively binds the p19 Janssen-Cilag (Beerse, Belgium) Psoriasis 2017 (EU & US) high-affinity IgE receptor binding, produced in CHO cells asthma in adults and adolescents 2003 (US) α α subunit of IL-23, produced in CHO cells Janssen Biotech (Horsham, PA, cells Netherlands) deficiency) 2001 (EU) Zevalin (ibritumomab tiuxetan), murine mAb against the CD20 Spectrum Pharmaceuticals Non-Hodgkin lymphoma 2004 (EU) USA) Replagal (agalsidase alfa), rh -galactosidase, produced in a Shire Human Genetic Therapies, Fabry disease ( -galactosidase A 2001 (EU) antigen, produced in CHO cells (Amsterdam) 2002 (US) α α Truxima (rituximab) chimeric IgG1 against cell surface antigen Celltrion Selected cancers and autoim- 2017 (EU) human cell line TKT Europe deficiency) Erbitux (cetuximab), chimeric mAb against human EGF receptor, Merck KGaA (Darmstadt, EGF receptor–expressing meta- 2004 (EU & US) CD20, produced in CHO cells, biosimilar to MabThera. Same prod- mune disorders Fasturtec in EU, Elitex in US (rasburicase), r urate oxidase, pro- Sanofi (Paris) Hyperuricemia 2002 (US) produced in Sp2/0 cells Germany) static colorectal cancer uct as Blitzima, Ritemvia, and Truxima (see above) duced in S. cerevisiae 2001 (EU) Eli Lilly (Indianapolis) Zinplava (bezlotoxumab), human IgG directed against Clostridium Merck Sharp & Dohme C. difficile infection 2017 (EU) Cerezyme (imiglucerase), rh -glucocerebrosidase, produced in Genzyme (Naarden, the Gaucher disease 1997 (EU) Raptiva (efalizumab), humanized mAb that binds to LFA-1, which Serono (London, UK) Chronic moderate to severe 2004 (EU) β difficile toxin B, produced in CHO cells Merck (Whitehouse Station, NJ, 2016 (US) CHO cells Netherlands) 1994 (US) is expressed on all leukocytes; produced in CHO cells Genentech plaque psoriasis in adults 2003 (US) USA) Withdrawn 2009 Pulmozyme (dornase alpha), r DNase, produced in CHO cells Roche/Genentech Cystic fibrosis 1993 (US) Amjevita (adalimumab-atto), rh IgG1 specific for TNF, produced in Amgen (Thousand Oaks, CA, Rheumatoid arthritis and selected 2016 (US) Avastin (bevacizumab), humanized mAb against VEGF, produced Roche/Genentech (Welwyn Metastatic colorectal cancer, 2005 (EU) CHO cells, biosimilar to Humira. Same product as Solymbic and USA) additional inflammatory diseases Fusion proteins in CHO cells Garden City, UK) glioblastoma, metastatic renal 2004 (US) Amgevita (see above) carcinoma Erelzi (etanercept in EU, etanercept-szzs in USA), r dimeric fusion Sandoz (Kundl, Austria, & Rheumatoid arthritis, selected 2017 (EU) Anthim (obiltoxaximab), chimeric IgG1 against Bacillus anthracis Elusys Therapeutics (Pine Brook, Inhalational anthrax 2016 (US) protein consisting of TNF receptor extracellular domains linked to Princeton, NJ, USA) other inflammatory diseases 2016 (US) NeutroSpec (fanolesomab), murine mAb against CD15, a surface Palatin Technologies (Cranbury, Imaging of equivocal appendicitis 2004 (US) toxin, produced in NS0 cells NJ, USA) an IgG1 Fc region, produced in CHO cells, biosimilar to Enbrel antigen of selected leukocytes, produced in hybridoma cells NJ, USA), Mallinckrodt Withdrawn 2005 Cinqair in US, Cinqaero in EU (reslizumab), humanized IgG4 Teva Respiratory (Frazer, PA Asthma 2016 (US) Pharmaceuticals (Hazelwood, Lifmior (etanercept), r dimeric fusion protein consisting of TNF Pfizer Europe (Brussels) Rheumatoid arthritis, selected 2017 (EU) against IL-5, produced in NS0 cells USA) 2016 (EU) MO, USA) receptor extracellular domains linked to an IgG1 Fc region, pro- other inflammatory diseases Teva (Haarlem, the Netherlands) duced in CHO cells. Same product as Enbrel (see below) Humira in EU & US, Trudexa in EU (adalimumab), anti-TNF AbbVie (Maidenhead, UK) Rheumatoid arthritis 2003 (EU) Darzalex (daratumumab), human IgG1 against CD-38, produced Janssen-Cilag Multiple myeloma 2016 (EU) human mAb, produced in CHO cells 2002 (US) Benepali (etanercept), rh TNF receptor–IgG Fc fusion protein, pro- Samsung Bioepis (Chertsey, UK) Arthritis, psoriasis, axial spondy- 2016 (EU) in CHO cells Janssen Biotech 2015 (US) Trudexa with- duced in CHO cells, biosimilar to Enbrel loarthritis Empliciti (elotuzumab) humanized IgG1 against the cell surface Bristol-Myers Squibb (Uxbridge, Multiple myeloma (in combina- 2016 (EU) drawn 2007 Zaltrap (aflibercept), combination drug consisting of binding Sanofi (Paris) Sanofi-aventis US Metastatic colorectal cancer 2013 (EU) receptor SLAMF7, produced in NS0 cells UK, & Princeton, NJ, USA) tion with lenalidomide and dexa- 2015 (US) (EU) domains of VEGF receptors 1 and 2 fused to an IgG Fc, produced (Bridgewater, NJ, USA) 2012 (US) methasone) Bexxar (tositumomab), radiolabeled mAb against CD20, produced GSK CD20-positive follicular non- 2003 (US) in CHO cells. Same active substance as in Eylea (see below) Flixabi (infliximab), chimeric IgG1 against TNF-α, produced in Samsung Bioepis (Chertsey, UK) Various forms of arthritis, pso- 2016 (EU) in murine hybridoma cells Hodgkin lymphoma Withdrawn 2014 Eylea (aflibercept), fusion protein consisting of extracellular ligand Bayer (Berlin) Neovascular (wet) age-related 2012 (EU) CHO cells, biosimilar to Remicade. Same product as Renflexis riasis, colitis, Crohn’s disease, Mabcampath (EU) or Campath (US) (alemtuzumab), humanized Genzyme (Naarden, the CLL 2001 (EU & US) binding domains of VEGF receptor fused to IgG Fc, produced in Regeneron Pharmaceuticals macular degeneration 2011 (US) (see above) ankylosing spondylitis mAb against CD52, a surface antigen of B lymphocytes, produced Netherlands) Withdrawn (EU) CHO cells). Same active substance as in Zaltrap (see above) (Tarrytown, NY) Inflectra in EU and US, Remsima in EU (infliximab in EU, inflix- Inflectra: Hospira (Lake Forest, Certain forms of arthritis and pso- 2016 (US) in CHO cells Millennium (Cambridge, MA, 2012 Nulojix (belatacept), fusion protein consisting of the extracellular Bristol-Myers Squibb (Uxbridge, Prophylaxis of organ rejection fol- 2011 (EU & US) imab-dyyb in US), chimeric IgG1 specific for TNF-α, produced in IL, USA), Celltrion (Incheon, riasis, Crohn’s disease, ulcerative 2013 (EU) USA) domain of human CTLA4 fused to IgG Fc; binds CD80 and CD86 UK) lowing kidney transplant murine Sp2/0 cells, biosimilar to Remicade Republic of Korea) and Hospira colitis, ankylosing spondylitis Herceptin (trastuzumab), humanized mAb against HER2, pro- Roche (Welwyn Garden City, UK) Treatment of metastatic breast 2000 (EU) on antigen-presenting cells, thereby inhibiting T cell activation, (Royal Leamington Spa, UK); duced in a murine cell line cancer overexpressing HER2 1998 (US) produced in CHO cells Remsima: Celltrion (Budapest) protein Arcalyst in US, Rilonacept Regeneron in EU (rilonacept), dimeric Regeneron Pharmaceuticals Cryopyrin-associated periodic 2009 (EU) Lartruvo (olaratumab), rh IgG1 specific for human platelet-derived Eli Lilly (Utrecht, the Sarcoma 2016 (EU & US) Remicade (infliximab), chimeric mAb against TNF-α, produced in Janssen (Leiden, the Crohn’s disease 1999 (EU) fusion protein with each monomer consisting of the ligand-binding (London, UK, & Tarrytown, NY, syndromes (CAPS) 2008 (US) growth factor receptor-α, produced in NS0 cells Netherlands, & Indianapolis) Sp2/0 cells Netherlands) 1998 (US) domains of the human IL-1 receptor and the IL-1 receptor acces- USA) Withdrawn 2012 sory protein along with the Fc region of human IgG-1, produced in (EU) Portrazza (necitumumab), human IgG1 against the ligand binding Eli Lilly (Utrecht, the Non-small-cell lung cancer (in 2016 (EU) Synagis (palivizumab) humanized mAb directed against an epitope MedImmune (Gaithersburg, MD, Prophylaxis of lower respiratory 1999 (EU) CHO cells site of human EGF receptor, produced in NS0 cells Netherlands, & Indianapolis) combination with gemcitabine 2015 (US) on the surface of respiratory syncytial virus, produced in a murine USA) tract disease caused by syncytial 1998 (US) and cisplatin) myeloma cell line AbbVie Deutschland virus in children Nplate (romiplostim), dimeric fusion protein with each monomer Amgen Europe Thrombocytopenia 2009 (EU) Taltz (ixekizumab), humanized IgG4 against hIL-17A, produced in Eli Lilly (Utrecht, the Psoriasis 2016 (EU & US) (Ludwigshafen, Germany) consisting of two thrombopoietin receptor binding domains and 2008 (US) the Fc region of human IgG-1, produced in E. coli CHO cells Netherlands, & Indianapolis) Zenapax (daclizumab), humanized mAb against the IL-2 receptor Roche (Welwyn Garden City, UK) Prevention of acute kidney trans- 1999 (EU) Zinbryta (daclizumab), humanized IgG1 against IL-2Rα, produced Biogen (Cambridge, MA US) Multiple sclerosis 2016 (EU & US) α-chain, produced in NS0 cells Biogen (Cambridge, MA, USA) plant rejection 1997 (US) in NS0 cells Biogen Idec (Maidenhead, UK) Withdrawn 2018 Withdrawn 2009 (EU & US) (EU)

NATURE BIOTECHNOLOGY VOLUME 36 NUMBER 12 DECEMBER 2018