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GLP-1 receptor ago- GSK (Carrigaline, Ireland, & Diabetes mellitus type 2 2014 (EU & US) Kadmon Pharmaceuticals Withdrawn 2006 Insulin lispro Sanofi, produced in E. coli, biosimilar to Humalog Sanofi-Aventis (Paris) Diabetes mellitus 2017 (EU) nist: two tandem copies of modified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fusion protein consisting of a GLP-1 analog Eli Lilly (Utrecht, the Diabetes mellitus type 2 2014 (EU & US) Withdrawn 2007 based and genetically engineered cell–based products.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 -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 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 (), 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 (), 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 (), 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 (), 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 , 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 (), 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