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 However, over 112 the years, 58 products have been withdrawn 100 from the market following approval in one or 80 both regions, almost always for commercial 60 reasons.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).