Feature

https://doi.org/10.1038/s41587-022-01582-x

Biopharmaceutical benchmarks 2022

Check for updates

Monoclonal antibodies as a group continue to lead biopharmaceuticals in numbers of

approvals and sales, although COVID-19 vaccines shot to the top of the list of highest-grossing
individual products.

T
he past few years will forever be
remembered as the years of a
pandemic, the likes of which had
Box 1
not been seen for a century. And
biopharmaceuticals took a star- Biopharmaceuticals defined
ring role, with both COVID-19 vaccines and
therapeutics dominating the news for the Biopharmaceuticals (Table 1) are defined more than one drug in the same category
speed with which they were developed and here as recombinant proteins, including was approved in a single year, they
their impact on global health. Nonetheless, recombinant antibodies, and nucleic are listed alphabetically by trade name.
regulatory agencies in both the United States acid- and genetically engineered In the case of several products that have
and EU maintained the fast pace of prior years cell-based products. They are listed in been approved for multiple indications,
in moving products through their pipelines. Table 1 consecutively from the most recent only the first indication is listed here.
This article is the latest survey of biopharma- approval in each class, with registrations Some product entries describe the
ceutical approvals, which we conduct every since 2018 indicated with boldface product as being the same as another
four years. The current survey period ( Janu- and withdrawals and discontinuations listed product. In such instances
ary 2018–June 2022) witnessed the approval with italics. Eight categories are shown: differences exist in terms of the approved
of 197 biopharmaceutical products (see Box 1 recombinant clotting factors; recombinant indication range or the company holding
for definition) in the United States and/or EU, thrombolytics, anticoagulants and other the marketing authorizations, usually
when counted by product trade name. Some blood-related products; recombinant as a result of commercial agreements.
products contain identical active ingredients hormones; recombinant growth factors; Included are (COVID-19) therapeutics
or are sold under different trade names in the recombinant interferons, interleukins authorized under emergency procedures
two regions; taking this into account, 180 dis- and tumor necrosis factor; vaccines; (Emergency Use Authorization in the
tinct biopharmaceutical active ingredients monoclonal-antibody-based products; United States and Conditional Marketing
entered the market. and other recombinant products. Where Authorisation in EU).
These new approvals bring the cumula-
tive number of individual biopharmaceuti-
cal products (by trade name) licensed in 16 vaccines (the latter two categories overlap inflammation-related conditions (15 prod-
these regions to 541, containing 435 distinct as five of the (COVID-19) vaccines are nucleic ucts), neutropenia (12 products), COVID-19
active biopharmaceutical ingredients. How- acid based). Additional notable approval cat- (11 products) and diabetes (10 products). Addi-
ever, over the years, 98 products have been egories include colony-stimulating factors tional indications, less commonly targeted
withdrawn from the market subsequent to (CSFs; 12 products, all biosimilars), cell-based by biopharmaceuticals, included ebolavirus
approval in one or both regions, almost always products (9), enzymes (8), fusion products (7) (the vaccines Mvabea, Zabdeno and Ervebo
for commercial reasons. Taking withdrawals and clotting factors (6). and the therapeutics Ebanga and Inmazeb),
into account, the number of individual biop- Here we list all biopharmaceuticals approved anthrax (the inhalation therapeutic Obiltox-
harmaceutical products with current active from January 2018 to June 2022, examining aximab SFL), weight control and weight loss
licenses is estimated to be 443 (Table 1). what types of product reached the US and EU (Wegovy) and Alzheimer’s disease (Aduhelm).
Annual approval numbers over the cur- markets as well as the indication for which they Of the 197 biopharmaceutical products
rent survey period ranged from a low of 19 in were approved. As in previous articles1–4, we approved within the survey timeframe,
Europe in 2019 to a high of 42, also in Europe, have not included tissue-engineering prod- 90 (46%) were genuinely new to the market,
in 2018 (Fig. 1a). Annual approval rates were ucts, which the US Food and Drug Administra- with the remainder representing biosimilars,
sustained or exceeded in both regions in tion (FDA) classifies as medical devices. me-too products and products previously
2020 and 2021, reflecting strong regulatory approved elsewhere. Those 90 new products
response, despite the unexpected burden In a snapshot (by trade name) contained a total of 85 dis-
on the agencies caused by the pandemic. Prod- As in previous survey periods, new approv- tinct active biopharmaceutical ingredients
ucts approved over the current period include als followed predictable lines. Cancer was by (Table 2). Looking at each region separately,
97 monoclonal antibodies, 19 hormones, 16 far the most common indication (50 prod- 121 products were licensed in the United
nucleic acid/gene-therapy-based products and ucts). Other common indications included States, of which 70 (58%) were genuinely novel;

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1722

Feature

a well as for nucleic acid-based products and

40 42 US EU
gene-engineered cells (Table 1).
35
Mammalian cell systems continue to be the
Approval numbers

30 34
32 most often used expression system during this
30
25 28 time period. Of the 159 approved products
26 26
20 made by recombinant means in cell-based sys-
19
15 tems, most (107, or 67%) are produced in mam-
10 malian cells. Nonetheless, this reverses a trend
5 seen over many decades, as it is lower than
0 the percentage of mammalian-cell-produced
2018 2019 2020 2021 biopharmaceuticals approved during the last
survey period (84%; Fig. 3). The expression
b systems used are invariably dictated by the
160 177 post-translational modification (PTM) require-
140
ments of the products. A large proportion of, in
particular, biosimilar and ‘me-too’-type prod-
Approval numbers

120
100
ucts approved over the current survey period
80
(Table 2) do not require glycosylation or other
mammalian PTMs, enabling their production
60
58 56 54 60 in nonmammalian and less expensive systems,
40
most commonly Escherichia coli. Interest-
20 9
16 ingly, when focusing solely on the genuinely
0
novel active biopharmaceutical ingredients
Up to 1990– 1995– 2000– 2005– 2010– 2015–
approved in this current period, a different
1989 1994 1999 2004 2009 2014 2019
story emerges, with 85% of these products
Fig. 1 | Product approvals profile. a, Annual product approval numbers (by product trade name) by made in mammalian systems.
individual region. b, Number of product approvals in one or both regions over the indicated periods.
As in previous surveys, the most often used
mammalian cell culture system remains Chi-
nese hamster ovary (CHO cells), which were
144 products gained marketing Authorization gaining approval in recent years. Although the used to produce 95 of those 107 individual
in the EU, of which 65 (45%) were genuinely absolute number of genuinely new biophar- products made in mammalian systems (89%).
novel. maceutical entities also continued to increase This reflects the well-known strengths of this
In the same period, US regulators approved (74 for the 2014–2018 survey, 85 for the current production platform, including the ability to
in total 244 non-biological pharmaceutical 2018–2022 period), as a proportion of total produce antibodies at titers of 3–8 g/liter at
products containing novel molecular (chemi- biopharmaceutical approvals the number of production scale5. Other mammalian systems
cal and biopharmaceutical) entities (NME); novel biopharmaceuticals has decreased over used included NS0 mouse myeloma cells (7
thus, 29% (70/244) of all genuinely novel drug this period, to 45% (85/189) as compared to the products), as well as baby hamster kidney
approvals in the US were biopharmaceuticals. previous period’s 56%. (BHK), human embryonic kidney (HEK), sp2/0
This compares to 40% for the previous survey mouse myeloma cells and PER C6 immortalized
period and 21–26% in survey periods before Monoclonal antibodies stay strong primary human embryonic retinal cells (1 prod-
2014. EU reporting formats for pharmaceu- Monoclonal antibodies (mAbs) remain domi- uct each). Moreover, a single new product (Sev-
ticals preclude calculation of an analogous nant in overall approvals, representing 53.5% enfact) is produced via transgenic means, in
figure for Europe. of all approvals in the past four years (Fig. 2a) the milk of transgenic rabbits—only the second
They also remain the most prominent category recombinant protein produced in this trans-
Overall trends of genuinely new biopharmaceuticals coming genic system. (Two existing products are also
Comparing approvals over the current survey on the market, constituting 51% of all genuinely made in transgenic systems: Atryn, approved
period to those in earlier periods or to cumu- new products approved in this survey period in 2009, in transgenic goats' milk and Kanuma,
lative approvals confirms some interesting, (Table 2) compared to 49% in the previous sur- approved in 2015, in transgenic chicken eggs.)
if predictable, trends. vey period (2014–2018). Of the nonmammalian production plat-
Since 2015, the rise in biopharmaceutical The importance of mAbs to biopharma- forms, E. coli continues to dominate, used
approval rates has been sustained. Between ceutical sales remains evident (Fig. 2b); the in the production of 36 products approved
2015 and 2019, 178 products gained approval, percentage of the total market value contrib- since 2018, with smaller numbers of prod-
approximately three times the historical uted by mAbs grew steadily during this sur- ucts produced in Pichia pastoris (5) and Sac-
five-year approval average (Fig. 1b). Moreo- vey, although COVID-19 vaccine sales affected charomyces cerevisiae (4). Also notable is the
ver, a further 117 products were approved in this trend. However, with these vaccine bacterium Pseudomonas fluorescens, used to
just the past year and a half, from January 2020 revenues excluded, mAbs still represented recombinantly produce the active ingredi-
to June 2022. Contributing to this was a sub- 80% of total protein-based global biophar- ent (teriparatide) of the biosimilar Livogiva/
stantial increase in the numbers of both bio- maceutical sales last year. Also notable is an Qutavina, as well as the active constituent of
similar and ‘me-too’-type products (Table 2) increase in approval rates for biosimilars, as Rylaze (asparaginase) and one component of

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1723

Feature

Table 2 | Biopharmaceuticals approved in the United States and/or EU during the the brain suggests that sufficient quantities of
current survey period (January 2018–June 2022) by category the antibody cross the blood–brain barrier to
have a physiological effect. This finding may
Category Products (by trade name) benefit other mAb-based therapies in develop-
Genuinely novel Amvuttra, Lunsumio, Ondexxya, Veyvondi, Voxzogo, PreHevbri/Prehevbrio, ment for diseases of the brain.
biopharmaceuticals Nuvaxovid/Novavax COVID-19 Vaccine, Spikevax, Jcovden, Vaxzevria,
(85 products) Comirnaty, Mvabea, Vaxchora, Zabdeno, Dengvaxia, Ervebo, Bebtelovimab, The impact of COVID-19
Enjaym, Evusheld, Opdualag, Padcev, Saphnelo, Uplizna, Vabysmo, Vyepti,
Adbry, Aduhelm, Bamlanivimab & eteseviman, Enspryng, Evkeeza, Minjuvi/ Clearly, COVID-19 represents the most sig-
Monjivi, Regkirona, Ronapreve/Regen-cov, Rybrevant, Tezspire, Tivdak, nificant and challenging new global threat to
Trodelvy, Vyvgart, Xevudy/Sotrovimab, Zynlonta, Adakveo, Blenrep, human health during the period of this survey.
Danyelza, Ebanga, Inmazeb, Obiltoxaximab SFL, Polivy, Tepezza, Ajovy,
Since the first reported cases in November
Cablivi, Evenity, Trogarzo, Ultomiris, Aimovig, Crysvita, Emgality, Gamifant,
Poteligeo, Takhzyro, Idefirix, Palynziq, Lamzede, Revcovi, Kimmtrak, Ngenla, 2019, 636 million confirmed cases and 6.6 mil-
Elzonris, Lumoxitib, Reblozyl, Amondys 45, Leqvio, Givlaari, Oxlumo, lion deaths have been reported globally to the
Viltepso, Zolgensma, Viondys 53, Waylivra, Onpattro, Tegsedi, Breyanzi, WHO (updated statistics available at https://
Carvykti, Abecma, Skysonab, Libmeldy, Tecartus, Zynteglo
COVID19.who.int).
Biosimilars (58 products) Inpremzia, Truvelog Mix 30, Kirsty, Rezvoglar, Semglee, Insulin aspart Development and deployment of effective
Sanofi, Sondelbay, Livogiva, Qutavinab, Retacrita, Fylnetra, Releuko,
COVID-19 vaccines and therapeutics occurred
Stimufend, Nyvepria, Cegfila, Grasustek, Ziextenzo, Fulphila, Nivestym/
Nivestima, Pelgraz, Pelmeg, Udenycab, Alymsys, Abevmy, Byooviz, Hukyndra, with unprecedented speed, thanks to indus-
Lextemyb, Libmyris, Onbevzi, Oyavas, Yuflyma, Yusimry, Amsparity, Aybintio, try action and regulatory agility. Regulators
Equidacentb, Hulio, Riabni, Ruxience, Zercepac, Abrilada, Avsola, Hadlima, shifted resources toward COVID-19-related
Idacio, Kanjinti, Kromeyab, Ontruzanta, Trazimera, Zirabev, Halimatozb,
activities and provided rapid scientific advice,
Hefiya, Herzuma, Hyrimoz, Mvasia, Ogivria, Truximaa, Zessly, Nepexto,
Benepalia compliance checks and accelerated assess-
ment and evaluation procedures to prod-
‘Me-too’ or incremental Esperoct, Adynovi, Jivi, Sevenfact, Lyumjev, Myxredlin, Lonapegsomatropin
improvement on Ascendis Pharma, Skytrofa, Sogroya, Wegovy, Besremi, Heplisav B, Vaxelis, uct developers. Rolling reviews (regulatory
existing API: for Vaxneuvance, Supemtek, Bimzelx, Enhertu, Jemperli, Kesimpta, Susvimo, assessment as data came in, rather than as
example, reformulation, Beovu, Margenza, Phesgo, Darzalex Faspro, Sarclisa, Herceptin Hylecta, part of a final marketing application) proved
PEGylation, use in Libtayo, Skyrizi, Ilumya/Ilumetri, Nexviazyme, Rylaze
particularly effective. Such agility notwith-
combination, different
indication & related (31 standing, FDA approvals of COVID-19 products
products) were made through an existing framework for
Previously approved Rybelsus, Myalepta/Myalept, Ozempic, Oxervate, Shingrix, Fasenra, authorizing new drugs in emergency circum-
elsewhere1 (15 products) Hemlibra, Imfinzi, Mylotarg, Ocrevus, Voraxaze, Mepsevii, Luxturna, stances—the Emergency Use Authorization
Kymriah, Yescarta pathway (which is not strictly an approval)—
a
Biosimilars approved in one region since 2018, but that were approved in the other region before 2018. bProducts that were whereas the EMA expedited approvals using
both approved and subsequently withdrawn from one or both regions within the survey timeframe. their pre-existing Conditional Marketing
Authorisation procedure. As a result, by Sep-
tember 2022, the FDA and EMA had, between
the multicomponent vaccine Vaxneuvance. a novel excipient (salcaprozate sodium) as an them, approved or authorized 22 different
Historically, P. fluorescens was used to produce absorption enhancer. This facilitates uptake of COVID-19 medicines (6 vaccines and 16 thera-
a single biopharmaceutical, Bonsity, a recom- semaglutide across the epithelium of the gas- peutics), of which 16 are biopharmaceuticals,
binant parathyroid hormone (PTH) initially trointestinal tract, and hence into the blood- mainly vaccines and mAbs. Updated product
approved in 1987. The yeast Hansenula poly- stream. A bioavailability of 1% was recorded in lists are available on the dedicated COVID-19
morpha is also used to produce one product humans during clinical studies. pages of both regulators’ websites.
approved in the current period (Heplisav B, Another interesting approval with chal- Vaccination has had the greatest single
a recombinant hepatitis B surface antigen). lenging delivery is the Alzheimer’s product impact on pandemic amelioration. As of
It was also used to produce the recombinant Aduhelm. This human IgG1, directed against November 2022, the World Health Organiza-
hepatitis B surface antigen active pharma- aggregated soluble and insoluble forms of tion estimates that a total of 13 billion vac-
ceutical ingredient (API) found in Hexacima/ amyloid-β in the brain (a defining pathophysi- cine doses have been administered globally.
Hexyon, initially approved in 2013. ological feature of Alzheimer’s), was approved Data from the CDC show that, for those over
As with past surveys, most products in 2021 by the FDA under its accelerated 50 years of age, full vaccination decreases
approved during the current survey period approval process. Clinical studies confirmed the risk of death by 12-fold). Approaches to
are administered parenterally. A small number that intravenous infusion of Aduhelm results vaccine API development and manufacture
are administered directly to their intended site in a reduction of amyloid-β plaques, although vary; approved vaccines include mRNA-based
of action via nonparenteral means, such as the a clear and unambiguous link between this vaccines (Comirnaty and Spikevax), inacti-
oral recombinant cholera vaccine Vaxchora effect and appreciable clinical improvement vated and adjuvanted SARS-CoV-2 virus
(Table 1). Rybelsus (semaglutide), for type 2 remains to be established. This, along with (Valneva), engineered adenovirus encod-
diabetes, represents an interesting exception: some safety concerns, led the European Medi- ing the SARS-CoV-2 spike protein (Vaxzevria
this acylated, 39-amino-acid polypeptide is cines Agency (EMA) to refuse to recommend and Jcovden) and recombinant spike protein
administered orally in tablet form, a first for approval in Europe. That an intravenous infu- (Nuvaxovid). From a technological perspec-
the biopharma sector. The tablet also contains sion of Aduhelm reduces amyloid-β plaques in tive, mRNA-based vaccines have the greatest

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1724

Feature

a 54 COVID-19 therapeutics markets is illustrated

mAb approvals as a percentage of total approvals

50 52
by Regeneron’s anti-spike-protein mAb-based
product Regen-Cov (Ronapreve). After ini-
40 tially gaining an Emergency Use Authoriza-
tion in November 2020, Regen-Cov generated
$7.6 billion in global sales in 2021, but its lack
30
of effectiveness against newer viral variants
27 caused the FDA to effectively pause its use in
24
20 22 January 2022.
20
From a commercial perspective, revenues
13 generated by biosimilar, nucleic acid (exclud-
10 11 ing COVID-19 mRNA vaccines) and engineered
cell-based products remain relative modest.
0 Collectively they generated an estimated
Up to 1990 – 1995 – 2000 – 2005 – 2010 – 2015 – 2020 –
$17.9 billion in 2021, representing some 5%
1989 1994 1999 2004 2009 2014 2019 June 2022
of the total biopharmaceutical market, and
less than sales of Humira alone. Of the 73
b 80 biopharmaceuticals recording blockbuster
mAb sales as a percentage of total sales

80.2
76.9 status (sales above $1 billion) last year, two
70 74.0
70.3 were biosimilars (Erelzi and Mvasi, record-
60 63.5 65.6
58.3 59.5 ing sales of $1.5 and $1.1 billion, respectively)
50 54.1 and two were (non-COVID) nucleic acid/gene-
49.9 51.7
40 therapy-based products (Spinraza and
Zolgensma, with sales of $1.9 and $1.3 billion,
30
respectively). mAb-based products (includ-
20
ing Fc fusion products) continue to represent
10 the most lucrative single product class. Their
0
total sales reached $217 billion last year, and
2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 they represented 15 of the top 20 products
Fig. 2 | Monoclonal antibody statistics. a, mAbs approved for the first time within the indicated periods, by sales generated (Table 4). In terms of tar-
expressed as a percentage of total biopharmaceuticals approved for the first time within the same time get indications, the vast majority of such
period. b, Global annual mAb sales value, expressed as a percentage of total protein-based biopharmaceutical antibody-based products target inflamma-
global sales for the indicated years. Financial data from LaMerie Business Intelligence. tory and autoimmune conditions (cumulative
2021 sales of $99.3 billion) and cancer (2021
cumulative sales of $68.4 billion).
Although most classes of originator biop-
novelty and are likely to pave the way toward medicinal terms, with Comirnaty and Spik- harmaceuticals continue to show strong
additional mRNA vaccines for COVID and evax cumulatively generating revenues of year-on-year growth, a notable exception
non-COVID indications (Box 2). $54.5 billion in 2021 (Table 3). Comirnaty is that of originator ‘established therapeu-
($36.8 billion) has displaced the long-time tic proteins’ (erythropoietins, interferons,
Market value best-selling biopharmaceutical Humira CSFs, human growth hormone (hGH) and
In the current survey period, the market value ($21.2 billion) as the top-selling biopharma- follicle-stimulating hormone (FSH)). Data
of biopharmaceuticals has continued to rise. ceutical product, with Spikevax ($17.7 bil- from La Merie publishing shows that this
Consolidated data from various La Merie lion) ranking third in 2021. Indeed, Humira’s product class generated total global rev-
(http://www.lamerie.com) and Fierce Pharma pre-eminence in the global biopharmaceu- enues of $11.7 billion in 2021, down 14% com-
(http://www.fiercepharma.com) financial tical market is likely over. In addition to the pared with 2020 ($13.6 billion). This mirrors
reports indicate that total global sales for advent of COVID-19 vaccines, its ‘patent wall’ a longer-term trend, in which the sales value
2021 reached US $343 billion (Table 3). Indeed has all but ended, and a number of biosimilar of this class of product has more than halved
this figure is likely an under-representation, rivals are likely to stream onto the US market in the past decade (down from $26.6 billion in
as revenues for biosimilars in some regions in particular in the next year or two. Whereas 2012) The underlying reasons for this decline
have not been publicly reported. Recombinant Comirnaty is poised to retain the top spot include competition from biosimilars and the
originator proteins, both mAb and non-mAb, globally this year, it is difficult to forecast approval of additional therapeutics targeting
collectively account for a lion’s share of this the market for COVID-19 vaccines in future the same indications.
value ($271 billion), representing an increase years. Much will depend on factors such as
of 44% over the $188 billion reported for this the course of the pandemic, the future need Biosimilars hit the big time
product category in our last survey, for 2017. for booster programs, the severity of evolv- The survey period witnessed a continued
COVID-19 vaccines had the largest impact ing viral strains and future approvals of addi- surge in biosimilar approvals, as this class of
upon the biopharmaceutical landscape in tional COVID-19 medicines, both prophylactic product gains global acceptance. When con-
commercial as well as technological and and therapeutic. The unpredictability of the sidered by product trade name, 94 biosimilars

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1725

 Feature

Percent mammalian Percent non-mammalian products must meet additional regulatory

80 requirements, as outlined by the Biologics
75 Price Competition and Innovation Act. The US
70
72 patent litigation landscape in this space can
66 also slow or stop putative biosimilar products
60
Percentage of approvals

60
58 reaching the market. Additionally, a recent
50 55
53 study found that most comparative efficacy
50 50
47 trials supporting FDA biosimilar approvals
40 45
42
40 were larger (median 504 patients), longer
30 33 (median of 52 weeks) and more costly (esti-
28 mated median cost of $20.8 million) than
20 25
pivotal trials for new molecular entities7. As
10 witnessed in Europe, however, more recent
US biosimilars are achieving faster market
0 uptake, with bevacizumab, trastuzumab
Up to 1989 1990–1994 1995–1999 2000–2004 2005–2009 2010–2014 2015–2019 2020–
June 2022 and rituximab biosimilars achieving 42%,
Fig. 3 | Expression systems. Relative use of mammalian- versus non-mammalian-based production cell lines 38% and 20% uptake within their first year on
in the manufacture of biopharmaceuticals approved over the indicated periods. Each dataset is expressed as a the market, trending toward 60% by the end
percent of total biopharmaceutical product approvals for the period indicated. of year two.

mAb approvals
have gained approval in the EU and/or the European biosimilars market to have reached Monoclonal antibodies continue to domi-
United States since 2006, although 10 have €8.8 billion in 2021, amounting to savings of nate both in approval numbers (in the case of
been subsequently withdrawn for commer- €5.7 billion (savings calculated as actual spend both originator and biosimilar categories) and
cial reasons and not all are actively marketed versus the pre-biosimilar cost of the origina- commercial value. All newly approved anti-
as yet. tor, reference product). bodies were engineered in some way: they are
By product category, the 94 biosimilar Moreover, the report finds that biosimilars either humanized or fully human, and most
approvals thus far include 2 hGHs, 5 eryth- recently launched in Europe achieved 50% were additionally engineered to enhance or
ropoietins (EPOs), 20 granulocyte CSFs penetration of the originator market in less stabilize specific functional and/or struc-
(G-CSFs; filgrastim and PEGylated filgrastim), than a year, whereas earlier biosimilars typi- tural characteristics. Jemperli and Evkeeza,
2 FSHs, 9 engineered insulins, 51 antibody- or cally took over two years to reach an equiva- both IgG4 mAbs, reportedly tend to form
antibody-fusion-based products and 5 PTHs. lent position. Biosimilars approved in the EU half-antibodies. To prevent this, each heavy
The 94 licensed products are based on 72 dis- are considered automatically interchangeable chain contains a serine-to-proline substitution
tinct active ingredients (Table 5). from a medical viewpoint, although decisions in the hinge region of the Fc domain, which
By region, 83 biosimilar products have regarding actual substitution (dispensing one stabilizes disulfide bonds between the two
received marketing Authorization in the EU, medicine instead of another medicine without heavy chains.
with 44 of these (53%) having gained Authori- consulting the prescriber) are made at indi- Skyrizi, a humanized IgG1, represents
zation within the current survey period. In vidual EU member state level. another example of engineering. Used to
the United States, a total of 37 products have According to FDA data, generic drugs treat plaque psoriasis and psoriatic arthritis,
thus far been licensed, of which 27 (73%) were account for 90% of all prescriptions in the it acts by selectively binding the p19 subunit
approved within this survey period. The accel- United States and provided savings of more of IL-23, thereby inhibiting the latter from
eration in biosimilar approval rates seen in than $1 trillion to the US health care system binding to its receptor. The framework of the
our last survey is thus maintained in this one. over a decade. The statistics for biosimilars antibody was engineered with two mutations
Notable approval trends since 2018 include are, predictably, more modest. The Phar- in the Fc region, Leu234Ala and Leu235Ala, to
the approval of a raft of polyethylene glycol maceutical Research and Manufacturers of reduce its potential effector function, which
(PEG)-filgrastims (biosimilars to Neulasta; America (PhRMA; www.phrma.org) reported does not contribute to the product’s mode
2021 global sales of $2 billion), a number of that annualized savings from biosimilars of action. The C-terminal lysine of the heavy
engineered insulins and mAbs with biosimi- reached $6.5 billion in 2020, with average chain was also deleted to reduce potential
larity to adalimumab (Humira; 2021 sales of biosimilar sales prices being as much as 45% charge heterogeneity.
$21 billion), trastuzumab (Herceptin; 2021 less than the branded biologics price at the The period also witnessed the approval
sales of $2.9 billion and bevacizumab (Avas- time of first biosimilar launch. of five glycoengineered (afucosylated or
tin; 2021 sales of $3.3 billion). US biosimilar approval and market pen- low-fucose) products: Uplizna, Rybrevant,
Despite the large number of recent biosimi- etration is influenced by regulatory, legal Blenrep, Fasenra and Poteligeo. Removal
lar approvals, both the revenues generated and developmental cost considerations. of the fucose residue in the antibody’s Fc glyco-
and the overall savings accrued to patients For example, biosimilar status in the United component can increase antibody-dependent
and healthcare systems remain relatively States does not automatically equate to inter- cellular cytotoxicity (ADCC), potentially
modest in both the EU and United States. changeability (and hence substitution for the boosting the potency of mAbs whose mode
A recent report by IQVIA6 prepared for the reference product without the involvement of of action depends on this antibody effector
European Commission, estimates the total the prescriber). Interchangeable biosimilar function.

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1726

Feature

Box 2

mRNA vaccines, COVID-19 and beyond

The first two COVID-19 vaccines approved in the United States and stability and the levels of expression. Incorporating chemically
EU were both mRNA-based, encoding the full-length SARS-CoV-2 modified nucleosides (such as 1-methylpseudouridine) reduces the
spike protein. SARS-CoV-2 was identified as the causative agent of native immune response to naked mRNA, and the development of,
COVID-19 in December 2019. The first known cases of the disease in in particular, lipid-based nanoparticles has substantially enhanced
Europe and the United States were recorded on 12 and 16 January mRNA cellular delivery.
2020, respectively. The full genome sequence of the original Wuhan Usually administered intramuscularly, either the mRNA vaccines
strain (Wuhan-Hu-1) was published in GenBank on 13 January 2020, or some locally produced antigen are taken up by antigen-presenting
and the WHO declared COVID-19 to be a global pandemic on cells, such as dendritic cells10,11. These cells then travel to lymph
11 March 2020. Pfizer-BioNTech’s mRNA COVID-19 Vaccine nodes, where they elicit adaptive immunity, incorporating both T cell
(Comirnaty) first gained Emergency Use Authorization in the and B cell immune responses.
United States on 11 December 2020 followed by conditional Compared to conventional vaccines, mRNA-based vaccines
approval in the EU on 21 December 2020. Moderna’s mRNA have been considered to have several advantages, including a
COVID-19 Vaccine (Spikevax) gained Emergency Use Authorization capacity for rapid development, relatively low cost, straightforward
status on 18 December 2020 in the United States and conditional scale-up and manufacture, a potential for high level of efficacy
approval in the EU on January 6th 2021. and a strong safety profile (no risk of infection or insertional
The Authorization or approval of two vaccines within one year of mutagenesis). The development, approval and deployment of
pathogen identification is unparalleled. Historically, for example, Comirnaty and Spikevax validated such cited advantages and
it took almost 200 years from discovery of the infectious agent provides a sound platform for further mRNA-based approvals.
to develop a measles vaccine, and over 150 years in the case of The sequence-independent flexibility of the platform is further
polio. Luckily, several technical advancements were reported underscored by the recent introduction of bivalent versions
over the previous decade in the then nascent field of mRNA of Spikevax and Comirnaty, each containing mRNA sequence
therapeutics, and several companies had already initiated vaccine combinations encoding the S proteins of both original and selected
developmental programs based on this technology, including Omicron variants of SARS-CoV-2.
BioNTech and Moderna. Several dozen such product, mainly targeting cancer and
Mimicking the native cellular transcription process, mRNA infectious disease, are at various stages of clinical development9–12.
can be produced in vitro via incubation of (usually phage) RNA The ascendancy of mRNA-based vaccines is unlikely, however,
polymerase enzymes and ribonucleotide triphosphates (NTPs) with to signal the demise of traditional vaccine modalities. Within a
template DNA (usually linearized, plasmid DNA). Although protein few months (and, in one case, within weeks) of the approval of
synthesis following administration of in-vitro-transcribed mRNA to Comirnaty and Spikevax, several additional SARS-CoV-19 vaccines
mice was reported in the 1990s, practical therapeutic application of based upon more traditional recombinant subunit and viral vector
the approach was beset by technical challenges, including mRNA modalities gained approval. Moreover, mRNA vaccines still suffer
instability, immunogenicity and inefficient in vivo delivery. More from some drawbacks, including the requirement for cold chain
recently, many of these challenges have been largely overcome9. storage and distribution (usually between –15 °C and –90 °C,
Optimization of mRNA sequences flanking the protein-coding depending on the product). mRNA-based platforms are thus likely
region (the 5′ cap and 5′ untranslated region (UTR) at one end and to broaden as opposed to replace existing vaccine production
the 3′ UTR and polyadenosine tail at the other) helps enhance both modalities in the future.

Additional engineered formats that came tissue penetration at the retina and prolong Cumulatively, ADCs generated $5.4 billion in
on stream include three bispecific full-size the therapeutic effect. 2021, with two such products achieving block-
mAbs: Vabysmo, the above-mentioned Six new antibody–drug conjugates (ADCs) buster status (Kadcyla and Adcetris).
Rybrevant and the bispecific T cell engager were approved during the survey period (Pad- The migraine therapy Vyepti, a human-
(BiTE) product Lunsumio. Cabilivi, a biva- cef, Enhertu, Tivdak, Trodelvy, Zynlonta and ized anti-calcitonin-gene-related peptide
lent nanobody, also gained approval, the Blenrep), joining five previously approved (CGRP) IgG1 antibody, is the first antibody to
first approval of a domain fragment. Three ADC products. ADCs consist of an antibody be produced in P. pastoris. Following intra-
antigen-binding fragments also entered the chemically conjugated to a cytotoxic payload. venous administration, it binds CGRP, pre-
market: Byooviz, Susvimo and Beovu. All three Antibody-mediated binding to the target venting its binding to its receptors, which
target macular degeneration and are admin- cell is followed by internalization, with sub- influence the initiation, frequency and sever-
istered by intravitreal injection. The smaller sequent intracellular cytotoxin release and ity of migraine attacks. The mAb’s heavy chain
size of antibody fragments enables delivery action. Advances in cytotoxin discovery and N-glycosylation site has been removed via pro-
of a high molar dose to the limited volume of chemical linker design have fueled increas- tein engineering, which eliminates any poten-
the eye’s vitreous body, which may enhance ing numbers of ADCs coming on stream. tial immunogenicity issues in humans due to a

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1727

Feature

Table 3 | Total reported 2021 biopharmaceuticals global sales values therapies are autologous, requiring isolation
of a patient’s T lymphocytes via leukapheresis
Biopharmaceutical category Reported sales value ($ billion) and ex vivo engineering of the cells to express
Originator recombinant proteins: mAbs
a
217.3 the CAR. The engineered T cells are expanded
in cell culture and cryopreserved until infused
Originator recombinant proteins: non-mAbs 53.6
back into the patient.
Covid vaccines (Comirnaty and Spikevax) 54.5 CAR-T cell therapies have proven most
Biosimilars 11.1 effective against B cell cancers, whereas
Nucleic acid and engineered cell based 6.8 their extension to solid tumors remains
challenging. Initial efficacy can be followed
Total value 343.3
by cancer recurrence arising from tumor
Originator’ signifies non-biosimilar.
a
evolution. The approach can also present
safety concerns, particularly cytokine
release syndrome. The autologous nature of
yeast-derived glycocomponent. Although the on the massive amplification provided by CAR-T cell therapy is inherently costly, with
lack of a glycocomponent prevents ADCC and the immune system—small doses adminis- treatment list prices typically in the region of
complement-dependent cytotoxicity (CDC) tered intramuscularly and taken up by local $400,000–$500,000.
effector functions, the product’s mode of antigen-presenting cells lead to a system-wide Genetically engineered cell-based
action does not rely on such functionality. adaptive immune response (Box 2). In con- products have also been developed for
The current period also witnessed the condi- trast, most non-vaccine nucleic acid products non-cancer indications. One example is
tional approval and emergency Authorization require substantially higher dosages, systemic Zynteglo, a hematopoietic-stem-cell-based
of several mAb-based products to treat COVID- administration, delivery to a specific tissue, gene therapy approved in the EU in 2019
19. The efficacy of mAb-based preparations prolonged therapeutic action and, in many as an orphan product for the treatment of
aimed at SARS-CoV-2 may be compromised by cases, a non-immunogenic profile that allows transfusion-dependent β-thalassemia. Zyn-
mutations affecting the viral spike protein, as chronic administration. These additional teglo consists of autologous hematopoi-
illustrated by products such as bamlanivimab technical hurdles remain largely unresolved. etic stem cells transduced with a functional
and eteseviman (which are administered β-globin gene. After infusion, the engineered
together) and REGEN-COV. This year, the FDA Engineered cell-based approvals cells repopulate the hematopoietic compart-
restricted the use of both products due to the New cell-based therapies flooded into the mar- ment, with clinical studies reporting ongoing
emergence of the Omicron variant. ket during this survey period, with nine such expression of the β-globin gene 36 months
products gaining approval in the EU and/or after treatment. However, for commercial
Nucleic acid-based approvals United States. Previously there were but two. reasons, the sponsor company, Bluebird
Two of the most technically innovative, medi- The majority of the new approvals (six prod- Bio, informed the EMA earlier this year of its
cally impactful and commercially successful ucts) are based on CAR-T cells, indicated for intention to withdraw the product from the
products coming on stream in this survey the treatment of blood-borne malignancies market. The treatment cost was in the region
period fall into this category—the COVID-19 (multiple myeloma, leukemia and, in particu- of €1.5 million per patient. In a further twist,
mRNA vaccines Spikevax and Comirnaty. An lar, lymphoma). the FDA approved Zynteglo in August of this
additional 12 nucleic acid-based products Many tumors manage to evade immune year, reportedly with an associated price tag of
were approved, adding substantially to the sur veillance by downregulating the $2.8 million per patient.
seven such products previously approved expression of major histocompatibility
(Table 1). The new approvals include five antigen class I (MHC-I) molecules. This Traditional biotech product approvals
small interfering RNA (siRNA)-based prod- prevents MHC-I-mediated presentation of The current survey period also witnessed the
ucts (Amvuttra, Leqvio, Givlaari, Oxlumo tumor-specific peptides on the cancer cell approval of 37 traditional biotech products
and Onpattro), five antisense-based products surface and recognition of the MHC-I–peptide classified as new by regulatory authorities in
(Amondys 45, Viltepso, Viondys 53, Waylivra complex by cytolytic T lymphocytes via their terms of active substance—nine fewer than in
and Tegsedi) and two gene therapy products T cell receptors (TCRs), which triggers cancer our previous survey. Traditional products refer
(Zolgensma and Luxturna), which deliver cell destruction by activated T cells. to those produced naturally or via nonrecom-
therapeutic genes in adeno-associated viral CAR-T cells harness cancer-killing T cells binant means in or by a biological source. The
vectors. Although 12 approvals signal progress independent of the MHC–TCR pathway. The profile of approvals (Supplementary Table 1)
in this field, almost all are orphan products and CAR-T cell approach is now arguably the lead- largely mirrors product types approved in
undergoing additional monitoring. ing technology in this regard, surpassing previous surveys, and include a range of
siRNA, antisense RNA and gene thera- alternatives such as T-cell-directed bispecific blood-derived products and natural extracts,
pies therefore have as yet to make a broad antibodies. CAR-T cells are genetically engi- as well as traditional (nonrecombinant) vac-
impact on the mainstream biopharma mar- neered to express on their surface a chimeric cines and un-engineered cells.
ket, particularly in regard to sales value. antigen receptor (CAR) that fuses an extracel-
These modalities may benefit from lessons lular antibody fragment (usually a single-chain Future directions
learned during the development of COVID-19 variable fragment, or scFv) specific for the Although estimates vary, data published by
mRNA vaccines, but they face steeper tech- target tumor surface antigen to intracel- PhRMA indicate that there are more than
nical challenges. mRNA vaccines capitalize lular T-cell-activating domains. CAR-T cell 7,800 biopharmaceutical products in clinical

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1728

Feature

Table 4 | The 20-top selling biopharmaceutical products in 2021

Rank Product Sales, 2021 Year first Company Patent Biosimilar version(s) approved
($ billions)a approved expiryb

1 Comirnaty (COVID-19 Vaccine, mRNA) 36.8 2020c Pfizer & BioNTech N/A
2 Humira (adalimumab) 21.2 2002 AbbVie & Eisai 2016 (US) Halimatoz/Hefiya/Hyrimoz, Amgevita/
2018 (EU) Amjevita/Solymbic, Cyltezo, Imraldi,
Kromeya, Idacio, Hadlima, Abrilada,
Hulio, Amsparity, Yusimry, Yuflyma,
Libmyris, Hukyndra
3 Spikevax (COVID-19 Vaccine, mRNA) 17.7 2020c Moderna N/A
4 Keytruda (pembrolizumab) 17.2 2014 Merck 2036 (US)
2028 (EU)
5 Stelara (ustekinumab) 9.5 2009 Janssen (Johnson & Johnson) 2023 (US)
2024 (EU)
6 Eylea (aflibercept) 9.4 2011 Regeneron, Bayer 2027 (EU
& US)
7 Opdivo (nivolumab) 8.5 2014 BMS, Ono 2027 (US)
2026 (EU)
8 Ronapreve/Regen-Cov (casirivimab & 7.6 2020 Roche, Regeneron N/A
imdevimab)
9 Trulicity (dulaglutide) 6.7 2014 Eli Lilly 2026 (US)
2024 (EU)
10 Darzalex (daratumumab) 6.0 2015 Janssen 2027 (US)
2026 (EU)
11 Dupixent (dupilumab) 5.9 2017 Sanofi-Aventis, Regeneron N/A
12/13 Prolia/Xgeva (denosumab) 5.7 2010 Amgen 2025 (US)
2022 (EU)
12/13 Gardasil 9 (human papillomavirus 5.7 2014 Merck 2028 (US
9-valent vaccine, recombinant) & EU)
14 Enbrel (etanercept) 5.6 1998 Amgen, Pfizer, Takeda 2015 (EU) Erelzi, Benepali/Eticovo, Nepexto
Pharmaceuticals 2028 (US)
15 Ocrevus (ocrelizumab) 5.5 2017 Roche/Genentech 2027 (EU)
2029 (US)
16 Cosentyx (secukinumab) 4.7 2015 Novartis 2026 (US)
N/A (EU)
17 Entyvio (vedolizumab) 4.4 2014 Takeda 2026 (US)
N/A (EU)
18 Perjeta (pertuzumab) 4.3 2012 Roche/Genentech 2024 (US)
2023 (EU)
19 Soliris (eculizumab) 4.2 2007 Alexion 2027 (US)
2020 (EU)
20 Lantus/Toujeo (insulin glargine) 3.9 2000 Sanofi 2014 (EU Semglee, Lusduna, Abasaglar,
& US) Rezoglar
a
Financial data from LaMerie Business Intelligence and Fierce Pharma. bPatent data from various sources, predominantly http://gabi-journal.net/. Note that patent landscape for biologics can
be particularly complex: issues such as follow-on patents subsequent to the main patent and patent litigation can delay biosimilar development and approval. cInitial date of Emergency Use
Authorization or Conditional Marketing Authorisation. N/A, data not available.

development globally, of which over 1,000 based, maintaining these as the single largest continue to steadily increase as a percentage
have reached phase 3 trials. Cancer remains by experimental product class. Smaller but still of overall global pharmaceutical sales, grow-
far the single most common indication, with notable numbers of gene-modified cell thera- ing from 18% in 2010 to over 30% currently.
other common target indications including pies (348) and nucleic acid- and gene-based There are more than 100 (non-COVID-19)
genetic disorders, cardiovascular disease, as therapies (546) are currently being assessed mAb-based products currently in late-stage
well as neurological, eye and blood disorders— in the clinic. On the whole, therefore, the clinical development. Antibody approvals
all leading causes of mortality or morbidity, industry retains a strong experimental prod- over the next several years will likely mirror
particularly in the West. Almost a third of prod- uct pipeline. Data from Evaluate Pharma indi- the profile of this antibody cohort. Some 60
ucts in clinical development (2,533) are mAb cates that total global biotech products sales of these experimental mAbs target cancer.

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1729

Feature

Table 5 | Biosimilar products that had gained marketing Authorization within the EU and/or the US by June 2022

Product type Trade name(s) Year (and region) Reference product Manufacturer(s) of the biologically active substance
approved

Somatropin-based
hGH-based Omnitrope 2006 (EU) Genotropin Sandoz (Kundl, Austria)
Valtropin 2006 (EU) Humatrope LG Life Sciences (Jeonbuk-do, Republic of Korea)
Withdrawn 2012
Epoetin-based
EPO-based Retacrit 2018 (US) Eprex/Erypo (EU) Norbitec (Uetersen, Germany; EU)
2007 (EU) Epogen/Procrit (US)
Binocrit 2007 (EU) Eprex/Erypo Rentschler (Laupheim, Germany) & Lek (Menges,
Slovenia)
Epoetin alfa hexal 2007 (EU) Eprex/Erypo
Abseamed 2007 (EU) Eprex/Erypo
Silapo 2007 (EU) Eprex/Erypo Norbitec
Filgrastim-based
G-CSF-based Releuko 2022 (US) Neupogen Kashiv Biosciences (Chicago)
Nivestim (EU)/Nivestym (US) 2010 (EU) Neupogen Hospira (Zagreb, Croatia)
2018 (US)
Ratiograstim 2008 (EU) Neupogen Sicor (Vilnius, Lithuania)
Filgrastim Ratiopharm 2008 (EU) Neupogen
Withdrawn 2011
Biograstim 2008 (EU) Neupogen
Withdrawn 2015
Tevagrastim 2008 (EU) Neupogen
Zarzio (EU)/Zarxio (US) 2009 (EU) Neupogen Sandoz (Kundl, Austria)
2015 (US)
Filgrastim hexal 2009 (EU) Neupogen
Grastofil 2013 (EU) Neupogen Intas Biopharmaceuticals (Gujarat, India)
Accofil 2014 (EU) Neupogen
Pegfilgrastim Fylnetra 2022 (US) Neulasta Kashiv Biosciences (Chicago)
Stimufend 2022 (EU) Neulasta Fujifilm Diosynth Biotechnologies (Billingham, UK)
Nyvepria 2020 (EU & US) Neulasta Hospira
Cegfila (previously 2019 (EU) Neulasta 3P Biopharmaceuticals, (Noain, Spain)
pegfilgrastim Mundipharma)
Pelmeg 2018 (EU) Neulasta
Grasustek 2019 (EU) Neulasta USV Private (Navi Mumbai, India)
Ziextenzo 2019 (US) Neulasta Lek & Sandoz (Kundl, Austria)
2018 (EU)
Pelgraz 2018 (EU) Neulasta Intas Pharmaceuticals (Ahmedabad, India)
Udenyca 2018 (EU & US) Neulasta KBI Biopharma (Boulder, CO, USA)
Withdrawn (EU)
Fulphila 2018 (US & EU) Neulasta Biocon Biologics (Bangalore, India)
FSH-based
FSH-based Ovaleap 2013 (EU) Gonal F Merckle Biotech (Ulm, Germany)
Bemfola 2014 (EU) Gonal F Polymun Scientific Immunbiologische Forschung
(Klosterneuburg, Austria)
Insulin-based
Insulin-based Inpremzia 2022 (EU) Actrapid Biocon (Bangalore, India)

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1730

Feature

Table 5 (continued) | Biosimilar products that had gained marketing authorization within the EU and/or the US by June 2022

Product type Trade name(s) Year (and region) Reference product Manufacturer(s) of the biologically active substance
approved

Insulin glargine-based Rezvoglar 2021 (US) Lantus Eli Lilly (Indianapolis, IN, USA), Lilly del Caribe
(Carolina, Puerto Rico, USA) & Lilly France
(Fegersheim, France)
Semglee 2021 (US) Lantus Biocon (Johor, Malaysia)
2018 (EU)
Abasaglar 2014 (EU) Lantus Lilly del Caribe Eli Lilly
Lusduna 2017 (EU) Lantus Merck Sharp & Dohme (Elkton, VA, USA)
Withdrawn 2018
2017 (tentative, US)
Withdrawn 2018
Insulin lispro-based Insulin lispro Sanofi 2017 (EU) Humalog Sanofi-Aventis (Frankfurt)
Insulin aspart-based Truvelog Mix 30 2022 (EU) NovoMix Sanofi-Aventis
Kirsty 2021 (EU) NovoRapid Biocon
Insulin aspart Sanofi 2020 (EU) NovoRapid Sanofi-Aventis
Mab-based and related
Infliximab-based Avsola 2019 (US) Remicade R*
Inflectra 2013 (EU) Remicade Celltrion (Incheon, Republic of Korea)
2016 (US)
Remsima 2014 (EU) Remicade
Flixabi 2016 (EU) Remicade Biogen (Hillerod, Denmark) & Samsung Bioepis
(Incheon, Republic of Korea)
Renflexis 2017 (US) Remicade
Ixifi 2017 (US) Remicade Pfizer
Zessly 2018 (EU) Remicade Boehringer Ingelheim (Biberach an der Riss,
Germany)
Adalimumab-based Hukyndra 2021 (EU) Humira Alvotech (Reykjavik)
Libmyris 2021 (EU) Humira
Yuflyma 2021 (EU) Humira Celltrion
Yusimry 2021 (US) Humira R*
Amsparity 2020 (EU) Humira Wyeth BioPharma (Andover, MA, USA)
Hulio 2020 (US) Humira Kyowa Kirin, Takasaki (Gunma, Japan)
2018 (EU)
Abrilada 2019 (US) Humira R*
Hadlima 2019 (US) Humira Samsung Bioepis
Imraldi 2017 (EU) Humira
Idacio 2019 (EU) Humira Merck Serono (Corsier-sur-Vevey, Switzerland)
Kromeya 2019 (EU) Humira
Withdrawn 2019
Amgevita (EU)/Amjevita (US) 2016 (US) Humira Amgen (Thousand Oaks, CA, USA)
2017 (EU)
Solymbic 2017 (EU) Humira
Cyltezo 2017 (EU & US) Humira Boehringer Ingelheim (Fremont, CA, USA)
Halimatoz 2018 (EU) Humira Catalent Biologics (Bloomington, IN, USA) &
Withdrawn 2020 Sandoz (Langkampfen, Austria)
Hefiya 2018 (EU) Humira
Hyrimoz 2018 (EU & US) Humira

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1731

Feature

Table 5 (continued) | Biosimilar products that had gained marketing authorization within the EU and/or the US by June 2022

Product type Trade name(s) Year (and region) Reference product Manufacturer(s) of the biologically active substance
approved

Rituximab-based Riabni 2020 (US) Rituxan Immunex (West Greenwich, RI, USA)
Ruxience 2020 (EU) MabThera Boehringer Ingelheim (Biberach an der Riss, Germany)
2019 (US)
Truxima 2018 (US) MabThera Celltrion
2017 (EU)
Blitzima 2017 (EU) MabThera
Ritemvia 2017 (EU) MabThera
Rituzena 2017 (EU) MabThera
Rixathon 2017 (EU) MabThera Sandoz (Langkampfen, Austria)
Riximyo 2017 (EU) MabThera
Trastuzumab-based Zercepac 2020 (EU) Herceptin Shanghai Henlius Biopharmaceutical (Shanghai,
China) & WuXi Biologics (WuXi, China)
Kanjinti 2019 (US) Herceptin Patheon Biologics (Groningen, the Netherlands) &
2018 (EU) Immunex
Ontruzant 2019 (US) Herceptin Fujifilm Diosynth (Hillerød, Denmark) & Samsung
2017 (EU) Biologics (Incheon, Republic of Korea)
Trazimera 2019 (US) Herceptin Boehringer Ingelheim (Biberach an der Riss, Germany)
2018 (EU)
Herzuma 2018 (EU & US) Herceptin Celltrion
Ogivri 2018 (EU) Herceptin Biocon (Bangalore, India)
2017 (US)
Bevacizumab-based Alymsys 2022 (US) Avastin GH GENHELIX (Armunia, Spain)
Oyavas 2021 (EU) Avastin
Abevmy 2021 (EU) Avastin Biocon Biologics (Bangalore, India)
Lextemy 2021 (EU) Avastin
Withdrawn 2021
Onbevzi 2021 (EU) Avastin Biogen (Hillerød, Denmark)
Aybintio 2020 (EU) Avastin Fujifilm Diosynth Biotechnologies (Hillerød, Denmark)
Equidacent 2020 (EU) Avastin Kyowa Kirin (Takasaki, Japan)
Withdrawn 2020
Zirabev 2019 (EU & US) Avastin Wyeth (Andover, MA, USA)
Mvasi 2018 (EU) Avastin Amgen
2017 (US)
Ranibizumab-based Byooviz 2021 (EU & US) Lucentis Wacker Biotech (Jena, Germany)
Etanercept-based Nepexto 2020 (EU) Enbrel Lupin (Taluka Mulshi, India)
Benepali/Eticovo 2019 (US) Enbrel Fujifilm Diosynth & Samsung (Incheon, Republic
2016 (EU) of Korea)
Erelzi 2016 (US) Enbrel Sandoz (Langkampfen, Austria) & Novartis (Singapore)
2017 (EU)
Teriparatide
Teriparatide-based Sondelbay 2022 (EU) Forsteo Intas Pharmaceuticals (Ahmedabad, India)
Livogiva 2020 (EU) Forsteo Cytovance Biologics (Oklahoma City, OK, USA)
Qutavina 2020 (EU) Forsteo Cytovance Biologics
Withdrawn 2020
Movymia 2017 (EU) Forsteo Richter-Helm BioLogics (Bovenau, Germany)
Terrosa 2017 (EU) Forsteo
R*, manufacturing site details of biological active substance redacted in FDA documentation.

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1732

Feature

Although 18 target liquid malignancies, the trials. Indeed, one additional such product subunit based, 40 (23%) are RNA based, and 23
majority target a range of solid tumor types (BioMarin’s hemophilia A product Rocta- (13%) are (nonreplicating) viral vector based.
including ovarian, prostate, melanoma, vian) has recently gained approval in Europe, The biopharmaceutical sector’s impressive
breast, small-cell lung cancer and renal can- and a biological license application (BLA) is response to the global COVID-19 pandemic is
cer. Almost a third (18 products) are bispecific, currently being considered by the FDA. Roc- likely to inform and accelerate broader inno-
and one-fifth (12 products) are antibody con- tavian’s active substance, valoctocogene vation in the sector, particularly within the
jugates. The remaining 54 non-cancer mAbs roxaparvovec, comprises a nonreplicating vaccine space. Finally, regulatory experience
target a wide range of conditions; almost all recombinant adeno-associated viral vector accrued in the last survey period should accel-
are human or humanized monospecific prod- housing a functional human factor VIII cDNA erate the speed of the drug development and
ucts. In addition to this cohort of experimental under the control of a liver-specific promoter. approval processes for future medicines.
products, over a dozen anti-COVID-19 mAbs Clinical studies show that increased factor VIII
remain in clinical studies, although the impact expression was sustained for (so far) at least Gary Walsh1 & Eithne Walsh2
of these products will ultimately depend upon two years, with the need for additional factor 1
The Industrial Biochemistry Program at the
their efficacy against current and future VIII replacement treatment dropping by 97.5%. Department of Chemical Sciences and Bernal
SARS-CoV-2 variants. Reports from industry sources indicate that Institute University of Limerick, Limerick,
Earlier stages in the mAb developmental Biomarin anticipates Roctavian’s list price in Ireland. 2County Clare, Ireland.
pipeline display a greater diversity of antibody Europe to be on the order of €1.5 million euros, e-mail: [email protected];
formats (ADCs, bispecific and fragments) and net of all discounts. [email protected]
a larger proportion of products targeting Biosimilars will also continue to feature with
solid as opposed to hematological malignan- increasing prominence on the biopharma- Published online: 5 December 2022
cies. For example, 80% of ADCs in oncology ceutical landscape. Various US-facing reports
clinical trials target solid tumor types8. Solid indicate that almost 100 biosimilars targeting References
1. Walsh, G. Nat. Biotechnol. 36, 1136–1145 (2018).
tumors were the most common global causes the American market are in clinical develop- 2. Walsh, G. Nat. Biotechnol. 32, 992–1000 (2014).
of cancer death in 2020 according to the WHO, ment and that cumulative sales of biosimilars 3. Walsh, G. Nat. Biotechnol. 28, 917–924 (2010).
including lung (1.80 million deaths), colon over the next five years could total $80 bil- 4. Walsh, G. Nat. Biotechnol. 24, 769–776 (2006).
5. Kelley, B., Kiss, R. & Laird, M. (2018). in New Bioprocessing
and rectum (916,000 deaths), liver (830,000 lion. A recent report by Allied Market Research Strategies: Development and Manufacturing of
deaths), stomach (769,000 deaths) and breast forecasts the global biosimilars market to Recombinant Antibodies and Proteins (eds Kiss, B.,
(685.000 deaths). reach as much as $143 billion by 2031, fuelled Gottschalk, U. & Pohlscheidt, M.) 443–462 (Springer,
2018).
Nucleic acid and engineered cell-based by sales of biosimilar mAbs, CSFs, EPO, insu- 6. Troein, P. et al. The impact of biosimilar competition in
therapies continue to represent a vibrant lins and hGH. Forecasts can vary, however. A Europe. IQVIA (2021); https://www.iqvia.com/library/
and growing sector of experimental as well report from Research & Markets predicts that white-papers/the-impact-of-biosimilar-competition-
in-europe-2021
as approved biopharmaceuticals. Recent vali- global biosimilar sales will reach $88 billion by 7. Moore, T. J., Mouslim, M. C., Blunt, J. L., Alexander, G. C. &
dation by COVID-19 is providing particular 2030, whereas Global Market Insights put the Shermock, K. M. JAMA Intern. Med. 181, 52–60 (2021).
impetus to the field of mRNA vaccines, and value at $100 billion. 8. Dean, A. Q., Luo, S., Twomey, J. D. & Zhang, B. MAbs 13,
1951427 (2021).
advances in CAR-T-cell-based therapeutic COVID-19 is likely to feature on the biop- 9. Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. Nat.
approaches will continue to drive the devel- harmaceutical landscape over the foresee- Rev. Drug Discov. 17, 261–279 (2018).
opmental pipeline in this field, particularly able future. mRNA and other vaccines are 10. Bettini, E. & Locci, M. Vaccines (Basel) 9, 147 (2021).
11. Cagigi, A. & Loré, K. Vaccines (Basel) 9, 61 (2021).
against solid tumors. Although only two gene expected to require updating to match 12. Wang, Y. et al. Mol. Cancer 20, 33 (2021).
therapy products based upon viral delivery novel SARS-CoV-2 variants. Tracking data
were approved in the current survey period maintained by the WHO estimates there are Additional information
Supplementary information The online version
(Zolgensma and Luxturna), several such currently 172 Covid vaccines in clinical devel- contains supplementary material available at
products are showing success in clinical opment globally, of which 55 (32%) are protein https://doi.org/10.1038/s41587-022-01582-x.

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1733

Feature

Table 1 | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Recombinant clotting factors

Factor VIII
Esperoct (turoctocog alfa pegol), rh coagulation factor VIII, Novo Nordisk (Bagsvaerd, Hemophilia A 2019 (EU & US)
produced in a CHO cell line. PEGylated form of NovoEight Denmark)
(see later entry). Novo Nordisk (Plainsboro,
NJ, USA)
Adynovi (rurioctocog alfa pegol), extended-half-life Baxalta Innovations (Vienna) Hemophilia A 2018 (EU)
PEGylated form of full-length r factor VIII product Advate (see
below). Same product as Adynovate (see below).
Jivi (damoctocog alfa pegol (EU), antihemophilic Bayer (Leverkusen, Germany) Hemophilia A 2018 (EU & US)
factor (recombinant), PEGylated-aucl (US)), PEGylated Bayer HealthCare (Whippany,
B-domain-deleted rh coagulation factor VIII, produced in BHK NJ, USA)
cells.
Afstyla (lonoctocog alfa), B-domain-truncated rh coagulation CSL Behring (Marburg, Germany, & Hemophilia A 2017 (EU) 2016 (US)
factor VIII, produced in CHO cells. Kankakee, IL, USA)
Vihuma (simoctocog alfa), rh B-domain-deleted factor VIII, Octapharma (Stockholm) Hemophilia A 2017 (EU)
produced in HEK cells. Same product as Nuwiq (see below).
Iblias (octocog alfa), rh coagulation factor VIII, produced in BHK Bayer Pharma (Berlin) Hemophilia A 2016 (EU)
cells using the same expression construct as Bayer’s Kogenate Withdrawn 2020
and Helixate. Same product as Kovaltry (see below).
Kovaltry (octocog alfa), rh coagulation factor VIII, produced Bayer Pharma (Leverkusen, Hemophilia A 2016 (EU & US)
in BHK cells using the same expression construct as Bayer’s Germany)
Kogenate and Helixate. Same product as Iblias (see above). Bayer HealthCare (Whippany,
NJ, USA)
Vonvendi (von Willebrand factor (recombinant)), produced in Baxalta (Westlake Village, CA, USA) von Willebrand disease 2015 (US)
CHO cells.
Nuwiq (simoctocog alfa), B-domain-deleted rh factor VIII, Octapharma USA (Hoboken, Hemophilia A 2015 (US)
produced in HEK cells. Same product as Vihuma (see above). NJ, USA) 2014 (EU)
Octapharma (Stockholm)
Obizur (susoctocog alfa), r B-domain-deleted porcine factor VIII, Baxalta Innovations (Vienna) Acquired hemophilia 2015 (EU)
produced in BHK cells. Baxter Healthcare (Westlake due to development of 2014 (US)
Village, CA, USA) autoantibodies against
factor VIII
Adynovate (recombinant, PEGylated antihemophilic factor), Baxalta Hemophilia A 2015 (US)
extended-half-life PEGylated form of full-length r factor VIII
product Advate (see below). Same product as Adynovi (see
above).
Elocta (efmoroctocog alfa; EU), Eloctate (antihemophilic factor Swedish Orphan Biovitrum Hemophilia A 2015 (EU)
recombinant, Fc fusion protein; US), rh coagulation factor (Stockholm) 2014 (US)
VIII–Fc fusion protein comprising B-domain-deleted human Biogen Idec (Cambridge, MA, USA)
factor VIII covalently linked to the Fc domain of a human IgG,
produced in HEK cells.
NovoEight (turoctocog alfa), rh factor VIII analog that, when Novo Nordisk (Bagsvaerd, Hemophilia A 2013 (EU & US)
activated, is structurally comparable to endogenous human Denmark, & Plainsboro, NJ, USA)
factor VIIIa, produced in CHO cells.
Xyntha (antihemophilic factor), rh coagulation factor VIII, Pfizer/Wyeth (Philadelphia) Hemophilia A 2008 (US)
produced in CHO cells.
Advate (octocog alfa), rh factor VIII, produced in CHO cells. Takeda (Vienna) Hemophilia A 2004 (EU)
Baxter Healthcare 2003 (US)
(Westlake Village, CA, USA)
Helixate NexGen (octocog alfa), rh factor VIII, produced in Bayer (Berlin) Hemophilia A 2000 (EU)
BHK cells. Withdrawn 2019
ReFacto (moroctocog alfa), B-domain-deleted rh factor VIII, Pfizer (Brussels) Hemophilia A 2000 (US)
produced in CHO cells. Genetics Institute (Cambridge, 1999 (EU)
MA, USA)
Kogenate, Helixate (antihemophilic factor), rh factor VIII, Bayer (Leverkusen, Germany, & Hemophilia A 2000 (EU)
produced in BHK cells. Sold as Helixate by Aventis Behring Berkeley, CA, USA) 1993 (US)
through a license agreement.

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1734

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Bioclate (antihemophilic factor), rh factor VIII, produced in Aventis Behring (King of Prussia, Hemophilia A 1993 (US)
CHO cells. PA, USA)
Recombinate (antihemophilic factor), rh factor VIII, produced Baxter Healthcare (Westlake Hemophilia A 1992 (US)
in CHO cells. Village, CA, USA)
Other blood factors
Sevenfact (coagulation factor VIIa (recombinant)-jncw; rh HEMA Biologics (Louisville, Hemophilia A or B 2020 (US)
activated factor VII, produced in milk of transgenic rabbits. KY, USA)
Ondexxya (andexanet alfa (EU), Andexxa (US)), engineered AstraZeneca (Sodertalje, Stopping life-threatening 2019 (EU)
rh factor Xa lacking the coagulation activity of native FXa Sweden) or uncontrolled bleeding 2018 (US)
but retaining binding ability to FXa inhibitors, produced in Portola Pharmaceuticals (South in adults taking the
CHO cells. San Francisco, CA, USA) anticoagulant medicines
Alexion Pharmaceuticals apixaban or rivaroxaban
(Boston)
Veyvondi (vonicog alfa), rh von Willebrand factor, produced Baxalta Innovations (Vienna) von Willebrand disease 2018 (EU)
in CHO cells.
Rebinyn (rh coagulation factor IX; US), Refixia (nonacog beta Novo Nordisk (Plainsboro, NJ, Hemophilia B 2017 (EU & US)
pegol; EU), rh coagulation factor IX, produced in CHO cells and USA & Bagsvaerd, Denmark)
PEGylated.
Alprolix (eftrenonacog alfa), rh coagulation factor IX fused to a Swedish Orphan Biovitrum Hemophilia B 2016 (EU)
human IgG1 Fc domain, produced in HEK cells. (Stockholm) 2014 (US)
Bioverativ Therapeutics (Waltham,
MA, USA)
Idelvion (albutrepenonacog alfa), rh factor IX–albumin fusion CSL Behring Hemophilia B 2016 (EU & US)
protein, produced in CHO cells.
Ixinity (coagulation factor IX, recombinant)), rh coagulation Aptevo BioTherapeutics (Berwyn, Hemophilia B 2015 (US)
factor IX, produced in CHO cells. PA, USA)
Rixubis (nonacog gamma), rh factor IX, produced in CHO cells. Baxalta Innovations (Vienna) Hemophilia B 2014 (EU)
Baxter Healthcare (Lexington, 2013 (US)
MA, USA)
Tretten (US), Novothirteen (EU) (catridecog), rh factor XIII Novo Nordisk Congenital factor XIII 2013 (US)
A-subunit, produced in S. cerevisiae. A-subunit deficiency 2012 (EU)
Recothrom (thrombin), rh factor Iia, produced in CHO cells. Baxter Healthcare (Deerfield, Control of minor bleeding 2008 (US)
IL, USA) during surgery
NovoSeven (eptacog alfa, activated), rh factor VIIa, produced in Novo Nordisk Some forms of hemophilia 1996 (EU)
BHK cells. 1999 (US)
Benefix (nonacog alfa), rh factor IX, produced in CHO cells. Pfizer/Wyeth Hemophilia B 1997 (EU & US)
Recombinant thrombolytics, anticoagulants and other blood-related products
Tissue plasminogen activator (tPA)
Metalyse (tenecteplase), modified rh tPA, produced in CHO cells. Boehringer Ingelheim (Ingelheim, Myocardial infarction 2001 (EU)
Germany) Withdrawn 2005
TNKase (tenecteplase), modified rh tPA, produced in CHO cells. Roche/Genentech (South San Myocardial infarction 2000 (US)
Francisco, CA, USA)
Ecokinase (reteplase), r tPA, produced in E. coli; differs from Roche (Welwyn Garden City, UK) Acute myocardial infarction 1996 (EU)
human tPA in the deletion of 3 of its 5 domains. Withdrawn 2000
Rapilysin (reteplase), r tPA (see Ecokinase, above). Actavis Group PTC (Hafnarfjordur, Acute myocardial infarction 1996 (EU)
Iceland), Roche
Retavase (reteplase), r tPA (see Ecokinase, above). Chiesi USA (Cary, NC, USA) Acute myocardial infarction 1996 (US)
Activase (alteplase), rh tPA, produced in CHO cells. Roche/Genentech Acute myocardial infarction 1987 (US)
Hirudin
Refludan (lepirudin), r hirudin, produced in S. cerevisiae. Bayer HealthCare (Leverkusen, Anticoagulation therapy 1997 (EU)
Germany) for heparin-associated 1998 (US)
thrombocytopenia Withdrawn 2012
Revasc (desirudin), r hirudin, produced in S. cerevisiae. Canyon Pharmaceuticals (London) Prevention of venous 1997 (EU)
thrombosis Withdrawn 2014

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1735

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Other
Ruconest (conestat alfa), rh C1 esterase inhibitor, produced in Pharming Healthcare (Warren, Acute angioedema 2014 (US)
the milk of transgenic rabbits. NJ, USA) 2010 (EU)
Pharming Group (Leiden, the
Netherlands)
Jetrea (ocriplasmin), r truncated form of human plasmin, Inceptua (Bromma, Sweden) Symptomatic vitreomacular 2013 (EU)
produced in Pichia pastoris. ThromboGenics (Iselin, NJ, USA) adhesion, vitreomacular 2012 (US)
traction
Atryn (rh antithrombin), produced in milk of transgenic goats. Laboratoire français du Hereditary antithrombin 2009 (US)
fractionnement et des deficiency 2006 (EU)
biotechnologies (Les Ulis, France) Withdrawn 2018 (EU)
rEVO Biologics (Framingham,
MA, USA)
Kalbitor (ecallantide), plasma kallikrein inhibitor, produced in Dyax (Cambridge, MA, USA) Hereditary angioedema 2009 (US
P. pastoris.
Xigris (drotrecogin alfa), rh activated protein C, produced in a Eli Lilly (Houten, the Netherlands) Severe sepsis 2001 (US)
human cell line. 2002 (EU)
Withdrawn 2012
Recombinant hormones
Insulins
Inpremzia (rh insulin), produced in P. pastoris. Biosimilar Baxter Holding (Utrecht, Diabetes mellitus 2022 (EU)
to Actrapid. the Netherlands)
Truvelog Mix 30 (insulin aspart, produced in E. coli. Sanofi-Aventis (Paris) Diabetes mellitus 2022 (EU)
Biosimilar to NovoMix.
Kirsty (previously Kixelle) insulin aspart; fast-acting insulin Mylan Ireland (Dublin, Ireland) Diabetes mellitus 2021 (EU)
analog, produced in P. pastoris. Biosimilar to NovoRapid.
Rezvoglar (insulin glargine-aglr, long-acting human insulin Eli Lilly Diabetes mellitus 2021 (US)
analog, biosimilar to Lantus, produced in E. coli.
Semglee (insulin glargine (EU), insulin glargine-yfgn (US)); Mylan (Saint-Priest, France) Diabetes mellitus 2021 (US)
r insulin glargine, produced in P. pastoris. Biosimilar to Mylan Pharmaceuticals 2018 (EU)
Lantus. (Morgantown, WV, USA)
Insulin aspart Sanofi (insulin aspart, r fast-acting insulin Sanofi-Aventis (Paris) Diabetes mellitus 2020 (EU)
analog, produced in E. coli. Biosimilar to NovoRapid.
Lyumjev (previously Liumjev; insulin lispro (EU), insulin Eli Lilly Nederland (Utrecht, Diabetes mellitus 2020 (EU & US)
lispro-aabc (US)); rh rapid-acting insulin analog, produced the Netherlands)
in E. coli. Same active ingredient as in Humalog, but new
formulation.
Myxredlin (rh insulin, produced in P. pastoris). Baxter Healthcare (Deerfield, Diabetes mellitus 2019 (US)
IL, USA)
Admelog (insulin lispro injection), rapid-acting human insulin Sanofi (Bridgewater, NJ, USA) Diabetes mellitus 2017 (US)
analog, produced in E. coli.
Fiasp (insulin aspart injection), rapid-acting insulin analog, Novo Nordisk Diabetes mellitus 2017 (US & EU)
produced in S. cerevisiae.
Insulin lispro Sanofi, produced in E. coli. Biosimilar to Humalog. Sanofi-Aventis (Paris) Diabetes mellitus 2017 (EU)
Lusduna (insulin glargine), engineered insulin, produced Merck Sharp & Dohme Diabetes mellitus 2017 (EU)
in E. coli. Biosimilar to Lantus. (Hoddesdon, UK) Withdrawn 2018 (EU)
2017 (US, tentative)
Withdrawn 2018 (US)
Suliqua (EU), Soliqua (US) (insulin glargine/lixisenatide), Sanofi-Aventis (Paris) Diabetes mellitus type 2 2017 (EU)
combination of long-acting insulin glargine, produced in E. coli, Sanofi (Bridgewater, NJ, USA) 2016 (US)
and a synthetically produced human GLP-1 analog.
Xultophy (insulin degludec/liraglutide), a combination Novo Nordisk Diabetes mellitus type 2 2016 (US)
of 2 previously approved products, Victoza and Tresiba. 2014 (EU)
Abasaglar (previously Abasria; EU), Basaglar (US) (insulin Eli Lilly (Utrecht, the Netherlands) Diabetes mellitus 2015 (US)
glargine), produced in E. coli. Biosimilar (in EU) to Lantus. Eli Lilly (Indianapolis, IN USA) 2014 (EU)

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1736

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Ryzodeg 70/30 (US), Ryzodeg (EU) (insulin degludec/insulin Novo Nordisk Diabetes mellitus type 1 2015 (US)
aspart), combination of two engineered insulins, produced and 2 2013 (EU)
in S. cerevisiae.
Toujeo (insulin glargine, long-acting rh insulin analog), produced Sanofi-Aventis Deutschland Diabetes mellitus 2000 (EU)
in E. coli (see also Lantus, below). Previously Optisulin in EU. (Frankfurt) 2015 (US)
Sanofi (Bridgewater, NJ, USA)
Tresiba (insulin degludec), engineered long-acting human Novo Nordisk Diabetes mellitus type 1 2015 (US)
insulin analog, produced in S. cerevisiae (see also Ryzodeg, and 2 2013 (EU)
above).
Afrezza (rh insulin), produced in E. coli). MannKind (Danbury, CT, USA) Diabetes mellitus 2014 (US)
Novolog mix (insulin aspart mix), 50:50 mixture of engineered Novo Nordisk Diabetes mellitus 2008 (US)
rh insulins, produced in S. cerevisiae in soluble and protamine
suspension forms.
Insulin Human Winthrop (rh insulin), produced in E. coli. Sanofi (Frankfurt) Diabetes mellitus 2007 (EU)
Withdrawn 2018
Exubera (inhalable rh insulin), produced in E. coli. Pfizer (Sandwich, UK) Diabetes mellitus 2006 (EU & US)
Withdrawn 2008
Levemir (insulin detemir), long-acting rh insulin, produced Novo Nordisk Diabetes mellitus 2005 (US)
in S. cerevisiae. 2004 (EU)
Apidra (insulin glulisine), rapid-acting insulin analog, produced Sanofi (Frankfurt) Diabetes mellitus 2004 (EU & US)
in E. coli.
Actrapid, Velosulin, Monotard, Insulatard, Protaphane, Novo Nordisk Diabetes mellitus 2002 (EU)
Mixtard, Actraphane, Ultratard, rh insulin formulated as short-, Monotard and Ultratard
intermediate- or long-acting products. withdrawn 2006
Velosulin withdrawn
2009
Novolog (insulin aspart), short-acting rh insulin analog, Novo Nordisk Diabetes mellitus 2001 (US)
produced in S. cerevisiae.
Novolog mix 70/30 (contains insulin aspart, a short-acting rh Novo Nordisk Diabetes mellitus 2001 (US)
insulin analog, as one ingredient).
Novomix 30 (contains a mixture of insulin aspart, a short-acting Novo Nordisk Diabetes mellitus 2000 (EU)
rh insulin analog, produced in S. cerevisiae, in both soluble
and crystalline forms).
Lantus (insulin glargine), long-acting rh insulin analog, Sanofi (Frankfurt) Diabetes mellitus 2000 (EU & US)
produced in E. coli.
NovoRapid (insulin aspart), rh insulin analog), produced Novo Nordisk Diabetes mellitus 1999 (EU)
in S. cerevisiae.
Liprolog (insulin lispro), insulin analog, produced in E. coli. Eli Lilly (Houten, the Netherlands) Diabetes mellitus 1997 (EU)
Withdrawn 2001
Insuman (rh insulin), produced in E. coli. Sanofi (Frankfurt) Diabetes mellitus 1997 (EU)
Humalog (insulin lispro), insulin analog, produced in E. coli. Eli Lilly (Houten, the Netherlands) Diabetes mellitus 1996 (EU & US)
Novolin (rh insulin), produced in S. cerevisiae. Novo Nordisk Diabetes mellitus 1991 (US)
Withdrawn 2010
Humulin (rh insulin), produced in E. coli. Eli Lilly (Indianapolis, IN, USA) Diabetes mellitus 1982 (US)
Human growth hormone
Lonapegsomatropin Ascendis Pharma (lonapegsomatropin), Ascendis Pharma (Hellerup, Growth hormone 2022 (EU)
rhGH, produced in E. coli and PEGylated. Denmark) deficiency
Skytrofa (lonapegsomatropin-tcgd; r hGH, produced Ascendis Pharma Endocrinology Growth hormone 2021 (US)
in E. coli and PEGylated. Same API as Lonapegsomatropin Division deficiency
Ascendis Pharma.
Sogroya (somapacitan (EU, somapacitan-beco (US)), long Novo Nordisk Growth hormone 2021 (EU)
acting r hGH with L101C substitution and an albumin-binding deficiency 2020 (US)
C-16 fatty acid derivative attached, produced in E. coli.
Somatropin Biopartners (somatropin), r hGH, produced Biopartners (Reutlingen, Germany) Growth failure, growth 2013 (EU)
in S. cerevisiae. hormone deficiency Withdrawn 2017

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1737

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Accretropin (somatropin), r hGH, produced in E. coli. Emergent Biosolutions (Rockville, Growth failure or short 2008 (US)
MD, USA) stature associated with
Cangene (Winnipeg, Canada) Turner syndrome in
children
Valtropin (somatropin), r hGH, produced in S. cerevisiae. Biopartners, LG Life Sciences Certain forms of growth 2007 (US)
Biosimilar to Humatrope. (Republic of Korea & Reutlingen, disturbance in children and 2006 (EU)
Germany) adults Withdrawn 2012 (EU),
2019 (US)
Omnitrope (somatropin), biosimilar to Genotropin (in EU) r hGH, Sandoz (Kundl, Austria) Certain forms of growth 2006 (EU & US)
produced in E. coli. Sandoz (Princeton, NJ, USA) disturbance in children and
adults
Somavert (pegvisomant), r hGH analog (antagonist), produced Pfizer Acromegaly 2003 (US)
in E. coli and PEGylated. 2002 (EU)
Nutropin AQ (somatropin), r hGH, produced in E. coli. Different Ipsen Pharma Growth failure, Turner 2001 (EU)
formulation of Nutropin (see below). (Boulogne-Billancourt, France) syndrome 1994 (US)
Withdrawn 2008 (EU)
Serostim (somatropin), r hGH, produced in mouse C127 cells. EMD Serono (Rockland, MA, USA) AIDS-associated catabolism 1996 (US)
and wasting
Saizen (somatropin), r hGH, produced in mouse C127 cells. EMD Serono (Rockland, MA, USA) hGH deficiency in children 1996 (US)
Genotropin (somatropin), r hGH, produced in E. coli. Pfizer (New York) hGH deficiency in children 1995 (US)
Norditropin (somatropin), r hGH, produced in E. coli. Novo Nordisk Growth failure in children 1995 (US)
due to inadequate growth
hormone secretion
Tev-Tropin, Bio-tropin (somatropin), r hGH, produced in E. coli. Teva Pharmaceuticals (North hGH deficiency in children 1995 (US)
Wales, PA, USA)
Nutropin (somatropin), r hGH, produced in E. coli. Roche/Genentech hGH deficiency in children 1994 (US)
Humatrope (somatropin), r hGH, produced in E. coli. Eli Lilly (Indianapolis) hGH deficiency in children 1987 (US)
Protropin (somatrem), r hGH differing from hGH by an extra Genentech (South San Francisco, hGH deficiency in children 1985 (US)
N-terminal methionine, produced in E. coli. CA, USA) Withdrawn 2004
Follicle-stimulating hormone
Rekovelle (follitropin delta), rh FSH, produced in PER.C6 cells Ferring Pharmaceuticals Anovulation 2016 (EU)
(Copenhagen)
Bemfola (follitropin alfa), rh FSH, produced in CHO cells. Gedeon Richter (Budapest) Anovulation (women), 2014 (EU)
Biosimilar to Gonal F. failure of spermatogenesis
(men)
Ovaleap (follitropin alfa), rh FSH, produced in CHO cells. Theramex Ireland (Dublin) Infertility, subfertility 2013 (EU)
Biosimilar to Gonal F.
Elonva (corifollitropin alfa), modified rh FSH with the C-terminal N.V. Organon (Oss, the Controlled ovarian 2010 (EU)
peptide of the β-subunit of hCG fused to the FSH β-chain, Netherlands) stimulation
produced in CHO cells.
Fertavid (follitropin beta), rh FSH, produced in CHO cells. Merck Sharp & Dohme Infertility 2009 (EU)
Active substance same as in Puregon (see below). Withdrawn 2020
Pergoveris (follitropin alfa/lutropin alfa) combination product Merck (Amsterdam) Stimulation of follicular 2007 (EU)
containing rh FSH and rh luteinizing hormone, both produced development in women with
in CHO cells. severe luteinizing hormone
and FSH deficiency
Follistim (follitropin beta), rh FSH, produced in CHO cells. Merck (Whitehouse Station, NJ, Infertility 1997 (US)
USA)
Puregon (follitropin beta), rh FSH, produced in CHO cells. N.V. Organon Anovulation and 1996 (EU)
superovulation
Gonal F (follitropin alfa), rh FSH, produced in CHO cells. Merck Serono, EMD Serono Anovulation and 1997 (US)
(Rockland, MD, USA) superovulation 1995 (EU)
Other hormones
Sondelbay (teriparatide), the active N-terminal fragment of Accord Healthcare (Barcelona, Osteoporosis 2022 (EU)
human PTH, produced in E. coli. Biosimilar to Forsteo. Spain)

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1738

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Wegovy (semaglutide), r glucagon-like peptide-1 (GLP-1) Novo Nordisk (Bagsvaerd, Weight loss and weight 2022 (EU)
analog with a linker and a fatty acid side chain, produced in Denmark) control
Saccharomyces cerevisiae and then chemically modified.
Same active substance as in Ozempic.
Voxzogo (vosoritide), truncated (39-amino-acid) modified BioMarin International (Cork, Achondroplasia 2021 (EU & US)
analog of the native human C-type natriuretic peptide, Ireland)
expressed in E. coli. BioMarin Pharmaceutical
(Novato, CA, USA)
Livogiva (teriparatide; r 1-34 N-terminal fragment of Theramex Ireland (Dublin) Osteoporosis 2020 (EU)
endogenous human PTH, produced in Pseudomonas
fluorescens. Biosimilar to Forsteo.
Qutavina (teriparatide; r 1-34 N-terminal fragment of endogenous EuroGenerics (Amsterdam, the Osteoporosis 2020 (EU)
human PTH, produced in P. fluorescens. Biosimilar to Forsteo. Netherlands) Withdrawn 2020
Rybelsus (semaglutide; long-acting hGLP 1 analog (receptor Novo Nordisk Type 2 diabetes 2020 (EU)
agonist), produced in S. cerevisiae and chemically modified 2017 (US)
via fatty acid attachment (acylation). Same active substance
as Ozempic, but developed for oral use. Oral bioavailability
improved via inclusion of a novel absorption-enhancer
excipient (salcaprozate sodium (SNAC), a fatty acid derivative).
Myalepta (EU), Myalept (US) (metreleptin), rh leptin analog, Amryt Pharmaceuticals (Dublin) Some forms of 2018 (EU)
produced in E. coli. Aegerion Pharmaceuticals lipodystrophy 2014 (US)
(Cambridge, MA, USA)
Ozempic (semaglutide), human GLP-1 receptor agonist, Novo Nordisk Diabetes mellitus type 2 2018 (EU)
produced in S. cerevisiae and covalently modified by 2017 (US)
attachment of a C18 fatty acid.
Movymia (teriparatide), rh PTH fragment, produced in E. coli. Stada Arzneimittel (Bad Vilbel, Osteoporosis 2017 (EU)
Biosimilar to Fortseo. Same product as Terrosa (see below). Germany)
Natpar (parathyroid hormone), rh PTH, full length, produced in Takeda Pharmaceuticals (Dublin) Hypoparathyroidism 2017 (EU)
E. coli. Same product as Preotact (see below).
Terrosa (teriparatide), rh PTH fragment, produced in E. coli. Gedeon Richter (Budapest) Osteoporosis 2017 (EU)
Biosimilar to Fortseo. Same product as Movymia (see above).
Natpara (parathyroid hormone), rh PTH, produced in E. coli. Shire-NPS Pharmaceuticals Hypocalcemia 2015 (US)
(Lexington, MA, USA)
Saxenda (liraglutide), human GLP-1 analog, produced in Novo Nordisk Obesity 2015 (EU)
S. cerevisiae and covalently modified by palmitic acid.
Active substance same as in Victoza (see below).
Eperzan (EU), Tanzeum (US) (albiglutide), GLP-1 receptor agonist: GSK (Carrigaline, Ireland) Diabetes mellitus type 2 2014 (EU & US)
two tandem copies of modified human GLP-1 fused to human GSK (Research Triangle Park, NC, Withdrawn 2018
albumin, produced in S. cerevisiae. USA)
Trulicity (dulaglutide), fusion protein consisting of a GLP-1 Eli Lilly (Utrecht, the Netherlands, Diabetes mellitus type 2 2014 (EU & US)
analog linked to a human IgG Fc domain, produced in a & Indianapolis)
mammalian cell line.
Gattex (US), Revestive (EU) (teduglutide), rh GLP-2 analog, Takeda (Dublin) Short bowel syndrome 2012 (EU & US)
produced in E. coli. Shire (Lexington, MA, USA)
Victoza (liraglutide), GLP-1 analog with attached fatty acid, Novo Nordisk Diabetes mellitus type 2 2010 (US)
produced in S. cerevisiae. 2009 (EU)
Preotact, rh PTH, produced in E. coli. NPS Pharma Osteoporosis 2006 (EU)
Withdrawn 2014
Fortical, r salmon calcitonin, produced in E. coli. Upsher-Smith Laboratories Postmenopausal 2005 (US)
(Minneapolis, MN, USA) osteoporosis
Unigene Laboratories (Fairfield,
NJ, USA)
Luveris (lutropin alfa), rh luteinizing hormone, produced in CHO Merck (Amsterdam) Some forms of infertility 2004 (US)
cells. 2000 (EU)
Withdrawn 2007 (US)
Forsteo (EU), Forteo (US) (teriparatide), r shortened human PTH, Eli Lilly (Utrecht, the Netherlands) Established osteoporosis 2003 (EU)
produced in E. coli. Lilly (Indianapolis) in some postmenopausal 1987 (US)
women

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1739

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Natrecor (nesiritide), rh natriuretic peptide, produced in E. coli. Johnson & Johnson/Scios Acutely decompensated 2001 (US)
(Titusville, NJ, USA) congestive heart failure
Ovitrelle (EU), Ovidrel (US) (choriogonadotropin alfa) rh Merck (Amsterdam) Selected assisted 2001 (EU)
chorionic gonadotropin, produced in CHO cells. EMD Serono (Rockville, MD, USA) reproductive techniques 2000 (US)
Thyrogen (thyrotropin alfa), rh thyroid-stimulating hormone, Genzyme (Amsterdam & Thyroid cancer (detection 1998 (US)
produced in CHO cells. Cambridge, MA, USA) and treatment) 2000 (EU)
Forcaltonin, r salmon calcitonin, produced in E. coli. Unigene UK (Bushey Heath, UK) Paget disease 1999 (EU)
Withdrawn 2008
Glucagen, rh glucagon, produced in S. cerevisiae. Novo Nordisk Hypoglycemia 1998 (US)
Glucagon (glucagon, recombinant), rh glucagon, produced in Eli Lilly (Indianapolis) Hypoglycemia 1998 (US)
E. coli.
Bonsity. r PTH analog, expressed in P. fluorescens. Pfenex (San Diego, CA, USA) Osteoporosis 1987 (US)
Recombinant growth factors
Erythropoietin
Retacrit (epoetin zeta (EU), epoetin alfa-epbx (US)), Pfizer (Brussles, Belgium & Anemia 2018 (US)
rh EPO, produced in CHO cells. Biosimilar to Eprex and Lake Forest, IL, USA) 2007 (EU)
Erypo.
Biopoin (epoetin theta), rh EPO, produced in CHO cells. Teva (Ulm, Germany) Anemia 2009 (EU)
Eporatio (epoetin theta), rh EPO, produced in CHO cells. Ratiopharm (Ulm, Germany) Anemia 2009 (EU)
Abseamed (epoietin alfa), biosimilar to Eprex/Erypo, produced in Medice Arzneimittel Pütter (Iserlon, Anemia associated with 2007 (EU)
CHO cells. Biosimilar to rh EPO. Germany) chronic renal failure
Binocrit (epoetin alfa), biosimilar to Eprex/Erypo, produced in Sandoz (Kundl, Austria) Anemia associated with 2007 (EU)
CHO cells. Biosimilar to rh EPO. chronic renal failure
Epoetin alfa Hexal (epoietin alfa), biosimilar to Eprex/Erypo Hexal (Holzkirchen, Germany) Anemia associated with 2007 (EU)
produced in CHO cells. Biosimilar to rh EPO. chronic renal failure
Mircera (methoxy polyethylene glycol-epoetin beta), rh EPO, Roche (Grenzach-Wyhlen, Anemia associated with 2007 (EU & US)
produced in CHO cells and PEGylated. Germany) chronic kidney disease
Silapo (epoetin zeta), biosimilar toEprex/Erypo, produced in Stada (Bad Vilbel, Germany) Anemia associated with 2007 (EU)
CHO cells. Biosimilar to rh EPO. chronic renal failure
Dynepo (epoetin delta), rh EPO, produced in a human cell line. Shire Pharmaceuticals (Hampshire, Anemia 2002 (EU)
UK) Withdrawn 2009
Aranesp (darbepoetin alfa), long-acting r EPO analog, produced Amgen (Breda, the Netherlands) Anemia 2001 (EU & US)
in CHO cells (see Nespo, below) Amgen (Thousand Oaks, CA, USA)
Nespo (darbepoetin alfa), long-acting r EPO analog, produced in Dompé Biotec (Milan) Anemia 2001 (EU)
CHO cells (see Aranesp above) Withdrawn 2008
Neorecormon (epoietin beta), rh EPO, produced in CHO cells. Roche Anemia 1997 (EU)
Procrit (epoietin alfa), rh EPO, produced in a mammalian Janssen Biotech (Horsham, Anemia 1990 (US)
cell line. PA, USA)
Epogen (epoietin alfa), rh EPO, produced in CHO cells. Amgen Anemia 1989 (US)
Colony-stimulating factors
Fylnetra (pegfilgrastim-pbbk; rh G-CSF, produced in E. coli Amneal Pharmaceuticals Neutropenia 2022 (US)
and PEGylated. Biosimilar to Neulasta. (Bridgewater, NJ, USA)
Releuko (filgrastim-ayow; rh G-CSF, produced in E. coli. Kashiv BioSciences (Piscataway, Neutropenia 2022 (US)
Biosimilar to Neupogen. NJ, USA)
Stimufend (pegfilgrastim), rh G-CSFr produced in E. coli. Fresenius Kabi Deutschland Neutropenia 2022 (EU)
Biosimilar to Neulasta. (Höhe, Germany)
Nyvepria (pegfilgrastim (EU), pegfilgrastim-apgf (US)), Pfizer Europe MA EEIG (Brussels, Neutropenia 2020 (EU & US)
rh G-CSF, expressed in E. coli and PEGylated. Biosimilar to Belgium)
Neulasta. Pfizer (New York).
Cegfila (previously Pegfilgrastim Mundipharma; Mundipharma (Dublin) Neutropenia 2019 (EU)
pegfilgrastim), rh G-CSF, produced in E. coli and PEGylated
Biosimilar to Neulasta.

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1740

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Grasustek (pegfilgrastim), rh-G-CSF, produced in E. coli and Juta Pharma (Flensburg, Neutropenia 2019 (EU)
PEGylated. Biosimilar to Neulasta. Germany, USA)
Ziextenzo (pegfilgrastim (EU), pegfilgrastim-bmez (US)), Sandoz (Kundl, Austria) Neutropenia 2019 (US)
rh G-CSF, produced in E. coli and PEGylated. Biosimilar to 2018 (EU)
Neulasta.
Fulphila (pegfilgrastim-jmdb), rh G-CSF, produced in E. coli Mylan (Rockford, IL USA) Neutropenia 2018 (US and EU)
and PEGylated. Biosimilar to Neulasta. Mylan (Saint-Priest, France)
Nivestym (filgrastim-aafi; US), Nivestim (filgrastim; EU), Pfizer Neutropenia 2018 (US)
rh G-CSF, produced in E. coli. Biosimilar to Neupogen. 2010 (EU)
Pelgraz (pegfilgrastim), rh G-CSF, produced in E. coli and Accord Healthcare (Barcelona, Neutropenia 2018 (EU)
pEGylated. Biosimilar to Neulasta. Spain)
Pelmeg (pegfilgrastim), rh G-CSF, produced in E. coli and Cinfa Biotech (Olloki, Spain) Neutropenia 2018 (EU)
PEGylated. Biosimilar to Neulasta.
Udenyca (pegfilgrastim (EU), pegfilgrastim-cbqv (US)), ERA Consulting (Walsrode, Neutropenia 2018 (EU & US)
rh G-CSF, produced in E. coli and PEGylated Biosimilar Germany) Withdrawn (EU)
to Neulasta. Coherus BioSciences (Redwood
City, CA, USA)
Ristempa (pegfilgrastim), covalent conjugate of rh G-CSF, Amgen (Breda, the Netherlands) Neutropenia 2015 (EU)
produced in E. coli and conjugated to 20-kDa PEG. Withdrawn 2017
Zarxio (US), Zarzio (EU) (filgrastim-sndz), rh G-CSF, produced Sandoz (Princeton, NJ, USA, & Neutropenia 2015 (US)
in E. coli. Kundl, Austria) 2009 (EU)
Accofil (filgrastim), G-CSF, produced in E. coli. Biosimilar to Accord Healthcare (Barcelona, Neutropenia 2014 (EU)
Neupogen. Same product as Grastofil (see below). Spain)
Grastofil (filgrastim), rh G-CSF, produced in E. coli. Biosimilar to Accord Healthcare (Barcelona, Neutropenia 2013 (EU)
Neupogen. Same product as Accofil (see above). Spain)
Lonquex (lipegfilgrastim), rh G-CSF, produced in E. coli and Teva Pharmaceuticals (Utrecht, Neutropenia 2013 (EU)
PEGylated. the Netherlands)
Granix (tbo-filgrastim), rh G-CSF, produced in E. coli. Same Teva Pharmaceuticals (North Neutropenia 2012 (US)
product as Tevagrastim (see below). Wales, PA, USA)
Filgrastim Hexal (filgrastim), biosimilar to Neupogen, produced Hexal Neutropenia 2009 (EU)
in E. coli. Biosimilar rh G-CSF.
Biograstim (filgrastim), biosimilar to Neupogen produced ABZ-Pharma (Ulm, Germany) Neutropenia 2008 (EU)
in E. coli. Biosimilar rh G-CSF. Withdrawn 2015
Ratiograstim (filgrastim), biosimilar to Neupogen, produced Ratiopharm (Ulm, Germany) Neutropenia 2008 (EU)
in E. coli. Biosimilar rh G-CSF.
Tevagrastim (filgrastim), rh G-CS, produced in E. coli. Biosimilar Teva (Radebeul, Germany) Neutropenia 2008 (EU)
to Neupogen. Same product as Granix (see above).
Filgrastim Ratiopharm (filgrastim), produced in E. coli. Biosimilar Ratiopharm Neutropenia 2008 (EU)
to Filgrastim. Withdrawn 2011
Neulasta (EU and US), Neupopeg (EU) (pegfilgrastim), PEGylated Amgen (Breda, the Netherlands) Chemotherapy-induced 2002 (EU & US)
rh G-CSF. neutropenia Neupopeg withdrawn
2008 (EU)
Leukine (sargramostim), rh GM-CSF differing from the native Partner Therapeutics (Lexington, Autologous bone marrow 1991 (US)
protein by an R23L substitution, produced in E. coli. MA, USA) transplantation Withdrawn 2008 and
reformulated without
EDTA 2008
Neupogen (filgrastim), rh G-CSF differing from native protein Amgen (Thousand Oaks, CA, USA) Chemotherapy-induced 1991 (US)
by an extra N-terminal methionine, produced in E. coli. neutropenia
Other growth factors
Oxervate (cenegermin (EU), cenegermin-bkbj (US)), Dompé Farmaceutici (Milan) Neurotophic keratitis 2018 (US)
ophthalmic solution, rh nerve growth factor, produced Dompé U.S. (Boston) 2017 (EU)
in E. coli.
Increlex (mecaserim), rh IGF-1, produced in E. coli. Ipsen Pharma Growth failure in children 2007 (EU)
with IGF-1 deficiency 2005 (US)
or hGH gene deletion
(long-term treatment)

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1741

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

iPlex (mecasermin rinfabate), a complex of rh IGF-1 and rh IGF Insmed (Glen Allen, VA, USA) Growth failure in children 2005 (US)
binding protein-3, produced separately in E. coli. with severe primary IGF-1 Withdrawn 2007 for
deficiency or hGH gene IGF-1 deficiency
deletion (long-term treatment)
Kepivance (palifermin), rh keratinocyte growth factor, produced Swedish Orphan Biovitrum Severe oral mucositis in 2005 (EU)
in E. coli. selected patients with 2004 (US)
hematologic cancers Withdrawn 2016 (EU)
GEM 21S: Regranex (see below) and tricalcium phosphate; BioMimetic Pharmaceuticals Periodontally related 2005 (US)
growth-factor-enhanced matrix. (Franklin, TN, USA) defects
Regranex (becaplermin), rh platelet-derived growth factor Janssen-Cilag International (Beerse, Lower-extremity diabetic 1997 (US)
receptor-BB, produced in S. cerevisiae. Belgium) neuropathic ulcers 1999 (EU)
Johnson & Johnson (Raritan, NJ, USA) Withdrawn 2012 (EU)
Recombinant interferons, interleukins and tumor necrosis factor
Interferon-α
Besremi (ropeginterferon alfa-2b (EU), ropeginterferon AOP Orphan Pharmaceuticals Polycythemia vera 2021 (US)
alfa-2b-njft (US); rh-interferon alfa-2b with an additional (Vienna) 2019 (EU)
N-terminal proline conjugated to a 40-kDa two-arm PEG PharmaEssentia (Burlington,
moiety, produced in E . coli. MA, USA)
PEG-Intron/Rebetol combo pack (peginterferon alfa-2b/ Schering Plough (Kenilworth, Chronic hepatitis C 2008 (US)
ribavirin), rh IFN-α-2b, produced in E. coli and PEGylated, NJ, USA)
and ribavirin.
Pegasys (peginterferon alfa-2a), IFN-α-2b, produced in E. coli zr pharma (Vienna) Hepatitis C 2002 (EU & US)
and PEGylated. Roche/Genentech
PEG-Intron (peginterferon alfa-2b), IFN-α-2b, produced in E. coli Merck Sharp & Dohme Chronic hepatitis C 2001 (US)
and PEGylated. 2000 (EU)
Withdrawn 2021 (EU)
Viraferon (interferon alfa-2b), produced in E. coli. Schering Plough (Brussels) Chronic hepatitis B, C 2000 (EU)
Withdrawn 2008
ViraferonPeg (peginterferon alfa-2b), IFN-α-2b, produced Merck Sharp & Dohme Chronic hepatitis C 2000 (EU)
in E. coli and PEGylated. Withdrawn 2021
Intron A, Alfatronol (interferon alfa-2b), produced in E. coli. Merck Sharp & Dohme Cancer, genital warts, 2000 (EU)
hepatitis B and C, HPV 1986 (US)
Rebetron (ribavirin/interferon alfa-2b), produced in E. coli. Schering Plough Chronic hepatitis C 1999 (US)
Infergen (interferon alficon-1), r IFN-α, synthetic type I, produced Astellas Pharma Europe Chronic hepatitis C 1999 (EU)
in E. coli. (Leiderdorp, the Netherlands) 1997 (US)
Kadmon Pharmaceuticals Withdrawn 2006 (EU),
(Warrendale, PA, USA) 2013 (US)
Roferon A (interferon alfa-2a), produced in E. coli. Roche Hairy cell leukemia 1986 (US)
Withdrawn 2007
Interferon-β and interferon-γ
Plegridy (peginterferon beta-1a), rh IFN-β-1a, produced in CHO Biogen (Badhoevedorp, the Multiple sclerosis 2014 (EU & US)
cells and PEGylated. Netherlands)
Extavia (interferon beta-1b), rh IFN-β-1b, produced in E. coli. Novartis (Dublin) Multiple sclerosis 2009 (US)
Novartis Pharmaceuticals (East 2008 (EU)
Hanover, NJ USA)
Rebif (interferon beta-1a), rh IFN-β-1a, produced in CHO cells. Merck (Amsterdam) Relapsing/remitting 2002 (US)
EMD Serono (Rockland, MA, USA) multiple sclerosis 1998 (EU)
Avonex (interferon beta-1a), rh IFN-β-1a, produced in CHO cells. Biogen (Badhoevedorp, the Relapsing multiple sclerosis 1997 (EU)
Netherlands) 1996 (US)
Betaferon (interferon beta-1b), r IFN-β-1b differing from native Bayer Pharma Multiple sclerosis 1995 (EU)
protein by C17S, produced in E. coli.
Betaseron (interferon β-1b), differing from human protein by Berlex Laboratories (Richmond, Relapsing/remitting 1993 (US)
C17S, produced in E. coli. CA, USA) multiple sclerosis
Chiron (Emeryville, CA, USA)
Actimmune (interferon gamma-1b), produced in E. coli. Vidara Therapeutics (Dublin) Chronic granulomatous 1990 (US)
disease

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1742

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Others
Kineret (anakinra), rh IL-1 receptor antagonist, produced Swedish Orphan Biovitrum Rheumatoid arthritis 2001 (US)
in E. coli. (Stockholm)
Beromun (tasonermin), rh TNF-α, produced in E. coli. Belpharma (Luxembourg) Adjunct to surgery for 1999 (EU)
subsequent tumor removal,
to prevent or delay
amputation
Neumega (oprelvekin), r IL-11 lacking N-terminal proline of native Pfizer (Philadelphia), Genetics Prevention of chemotherapy- 1997 (US)
molecule, produced in E. coli. Institute induced thrombocytopenia
Proleukin (aldesleukin) r IL-2, differs from native molecule Prometheus Laboratories Renal cell carcinoma 1992 (US)
in absence of N-terminal alanine and presence of C125S (San Diego)
substitution, produced in E. coli.
Vaccines
Hepatitis B
PreHevbri (EU), Prehevbrio (US), r hepatitis B surface antigen VBI Vaccines (Amsterdam) Hepatitis B vaccine 2022 (EU)
produced in CHO cells genetically modified to produce the VBI Vaccines (Cambridge, 2021 (US)
hepatitis B virus envelope proteins, which include the small MA, USA)
(S), middle (pre-S2) and large (pre-S1) hepatitis B surface
antigens (HBsAg), representing the active substance.
Heplisav B, r-hepatitis B surface antigen, produced in Dynavax (Dusseldorf, Germany) Hepatitis B vaccine 2021 (EU)
Hansenula polymorpha Dynavax Technologies (Berkeley, 2017 (US)
CA, USA)
Vaxelis, multi-component vaccine containing r HBsAg, MCM Vaccine (Swiftwater PA, Immunization against 2018 (US)
produced in S. cerevisiae as one component. USA) diphtheria, tetanus,
Merck (Whitehouse Station, pertussis, poliomyelitis,
NJ, USA) hepatitis B and invasive
Sanofi Pasteur (Swiftwater PA, disease due to Haemophilus
USA) influenzae type b
Hexacima (also sold as Hexyon), multi-component vaccine Sanofi Pasteur (Lyon, France) Immunization against 2013 (EU)
containing r HBsAg, produced in H. polymorpha as one several pathogens and
component. toxins
Ambirix, combination vaccine containing r HBsAg, produced in GSK (Rixensart, Belgium) Immunization against 2002 (EU)
S. cerevisiae as one component. hepatitis A and B
Pediarix, combination vaccine containing r HBsAg, produced in GSK Immunization of children 2002 (US)
S. cerevisiae as one component. against various conditions
inducing hepatitis B
HBVAXPRO (r HBsAg), produced in S. cerevisiae. Merck Sharp & Dohme (Haarlem, Immunization of children 2001 (EU)
the Netherlands) and adolescents against
hepatitis B
Twinrix, combination vaccine containing r HBsAg, produced in GSK Immunization against 2001 (US)
S. cerevisiae as one component. hepatitis A and B 1997 (EU pediatric form)
1996 (EU adult form)
Infanrix-hexa, combination vaccine containing r HbsAg, GSK Immunization against 2000 (EU)
produced in S. cerevisiae as one component. diphtheria, tetanus, pertussis,
Haemophilus influenzae b,
hepatitis B and polio
Infanrix-penta, combination vaccine, containing r HbsAg, GSK Immunization against 2000 (EU)
produced in S. cerevisiae as one component. diphtheria, tetanus, Withdrawn 2013
pertussis, polio, and
hepatitis B
Hepacare (r S, pre-S & pre-S2 HBsAg), produced in a murine Evans Vaccines (Liverpool, UK) Immunization against 2000 (EU)
cell line. hepatitis B Withdrawn 2002
Hexavac, combination vaccine containing r HBsAg, produced Sanofi Pasteur Immunization against 2000 (EU)
in S. cerevisiae as one component. diphtheria, tetanus, Withdrawn 2012
pertussis, hepatitis B, polio
and H. influenzae b
Procomvax, combination vaccine containing r HBsAg as one Sanofi Pasteur Immunization against H. 1999 (EU)
component. influenzae b and hepatitis B Withdrawn 2009

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1743

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Primavax, combination vaccine containing r HBsAg, produced Sanofi Pasteur Immunization against 1998 (EU)
in S. cerevisiae as one component. diphtheria, tetanus and Withdrawn 2000
hepatitis B
Engerix B, r HbsAg, produced in S. cerevisiae. GSK Immunization against 1998 (US)
hepatitis B
Infanrix Hep B, combination vaccine containing r HbsAg, GSK Immunization against 1997 (EU)
produced in S. cerevisiae as one component. diphtheria, tetanus, Withdrawn 2005
pertussis and hepatitis B
Comvax, combination vaccine containing HBsAg, produced Merck (Whitehouse Station, Immunization of infants 1996 (US)
in S. cerevisiae as one component. NJ, USA) against H. influenzae b and
hepatitis B
Tritanrix-Hep B, combination vaccine containing r HBsAg, GSK Immunization against 1996 (EU)
produced in S. cerevisiae as one component. hepatitis B, diphtheria, Withdrawn 2014
tetanus and pertussis
Recombivax, r HBsAg, produced in S. cerevisiae. Merck (Whitehouse Station, Immunization against 1986 (US)
NJ, USA) hepatitis B
COVID-19
Nuvaxovid/Novavax COVID-19, vaccine directed at Novavax CZ (Jevany, Czechia) Vaccine (COVID-19) 2022 (US; Emergency
SARS-CoV-2 r (full-length) spike protein, produced in Use Authorization)
Spodoptera frugiperda (Sf9) insect cells using r baculovirus 2021 (EU; Conditional
system. Marketing
Authorisation)
Spikevax (previously COVID-19 Vaccine Moderna; Moderna Biotech Spain (Madrid) Vaccine (COVID-19) 2021 (EU; Conditional
elasomeran), ss mRNA produced by cell-free in vitro ModernaTX (Cambridge, MA, Marketing
transcription from DNA templates encoding (full-length) viral USA) Authorization)
spike (S) protein of SARS-CoV-2. 2020 (US; Emergency
Use Authorisation)
Jcovden (COVID-19 vaccine Janssen), r replication-deficient Janssen-Cilag International Vaccine (COVID-19) 2021 (EU; Conditional
(E1- and partially E3-gene-deleted) adenovirus type 26 (Beerse, Belgium) Marketing
encoding SARS-CoV-2 spike glycoprotein, propagated in a Authorization)
PER.C6 cell line (derived from human embryonal retina cells). 2021 (US; Emergency
Use Authorisation)
Vaxzevria, r replication-deficient (E1- and E3-deleted) AstraZeneca (Sodertalje, Vaccine (COVID-19) 2021 (EU; Conditional
chimpanzee adenovirus encoding SARS-CoV-2 spike protein Sweden) Marketing
combined with a tPA leader sequence, propagated in T-REx- Authorisation)
293 cells (derivative of HEK293).
Comirnaty (Pfizer BioNTech COVID-19 vaccine; tozinameran; BioNTech Manufacturing (Mainz, Vaccine (COVID-19) 2020 (US; Emergency
COVID-19 mRNA vaccine, nucleoside modified), ss, 5′-capped Germany) Use Authorization)
mRNA produced by cell-free in vitro transcription from DNA Pfizer (New York) 2020 (EU; Conditional
templates, encoding SARS-CoV-2 spike (S) protein. Marketing
Authorisation)
Other
Vaxneuvance (Pneumococcal 15-valent Conjugate Vaccine), Merck Vaccine against 2021 (US)
containing one r element, expressed in P. fluorescens. Streptococcus pneumonia
Mvabea (ebolavirus vaccine MVA-BN-Filo), engineered Janssen-Cilag International Ebolavirus vaccine 2020 (EU)
vaccinia strain encoding proteins from different viral strains. (Beerse, Belgium)
Supemtek (Quadrivalent influenza vaccine), consisting of Sanofi Pasteur (Lyon, France) Influenza vaccine 2020 (EU)
4 r hemagglutinin (rHA) proteins, each expressed separately
in Sf9 insect cells using a baculovirus protein expression
vector.
Vaxchora, live, attenuated Vibrio cholerae O1 strain Classical Emergent Netherlands Cholera vaccine 2020 (EU)
biotype genetically engineered via deletion of part of the (Amsterdam)
enterotoxin catalytic subunit A gene and inclusion of a
mercury resistance marker (allowing it to be distinguished
from wild-type V. cholerae).
Zabdeno (Ebola vaccine; Ad26.ZEBOV-GP), r Janssen-Cilag International Ebolavirus vaccine 2020 (EU)
replication-incompetent, adenovirus type 26 (Ad26) (Beerse, Belgium)
encoding full-length glycoprotein (GP) of Ebola virus Zaire
(ZEBOV) Mayinga strain.

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1744

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Dengvaxia, dengue tetravalent vaccine (live, attenuated) Sanofi Pasteur (Lyon, France) Dengue vaccine 2019 (US)
based upon r engineered yellow fever virus–dengue virus. Sanofi Pasteur (Swiftwater PA, 2018 (EU)
USA)
Ervebo (Ebola Zaire Vaccine), live, r vesicular stomatitis virus Merck Sharp & Dohme (Haarlem, Ebolavirus vaccine 2019 (EU & US)
with its envelope glycoprotein, replaced with ebolavirus Zaire the Netherlands)
surface glycoprotein, cultured in Vero cells. Merck (Whitehouse Station,
NJ, USA)
Shingrix (zoster vaccine recombinant, adjuvanted), r Varicella GlaxoSmithKline Biologicals Herpes zoster (shingles) 2018 (EU)
zoster virus surface glycoprotein E antigen component, (Rixensart, Belgium) prevention 2017 (US)
produced in CHO cells. GlaxoSmithKline (Research
Triangle Park, NC, USA)
Trumenba (meningococcal group B vaccine), two r Neisseria Pfizer (Brussels) Vaccine against N. 2017 (EU)
meningitides serogroup B proteins independently expressed Pfizer (Philadelphia) meningitides serogroup B 2014 (US)
in E. coli.
Pandemic influenza vaccine H5N1, vaccine derived MedImmune (Nijmegen, the Influenza vaccine 2016 (EU)
from engineered viral strain containing gene segments Netherlands)
from appropriate influenzavirus strains, produced in
embryonated eggs.
Bexsero (meningococcal group B vaccine), mixture of 3 GSK (Siena, Italy) Active immunization 2015 (US)
N. meningitidis serogroup B proteins, produced in E. coli. GlaxoSmithKline (Research against N. meningitidis 2013 (EU)
Triangle Park, NC, USA) serogroup B
Gardasil 9, mixture of the major capsid protein (L1) of 9 strains of MSD (Haarlem, the Netherlands) Active immunization for 2015 (EU)
HPV, each produced in S. cerevisiae. Merck (Whitehouse Station, those above 9 years of 2014 (US)
NJ, USA) age against HPV-caused
cancers and genital warts
Flublok, r hemagglutinin proteins from 3 influenza viruses, Protein Sciences (Meriden, Immunization against 2013 (US)
produced in an insect cell line. CT, USA) influenza
Provenge (sipuleucel-T), autologous peripheral blood Dendreon (Seal Beach, CA, USA) Prostate cancer 2013 (EU)
mononuclear cells in combination with r prostatic acid 2010 (US)
phosphatase linked to GM-CSF, produced in an insect cell line. Withdrawn 2015 (EU)
Cervarix, r C-terminally truncated major capsid L1 proteins GSK Prevention of cervical 2009 (US)
from HPV types 16 and 18, produced in a baculovirus-based cancer 2007 (EU)
expression system
Gardasil (EU & US), Silgard (EU), r vaccine containing major Merck Sharp & Dohme (Haarlem, Vaccination against 2006 (EU & US)
capsid proteins from four HPV types, produced in S. cerevisiae. the Netherlands) diseases caused by HPX
Merck (Whitehouse Station,
NJ, USA)
Dukoral, Vibrio cholerae and r cholera toxin B subunit. Valneva Sweden (Stockholm) Immunization against 2004 (EU)
disease caused by
V. cholerae subunit O1
Lymerix (r OspA), Borrelia burgdorferi surface lipoprotein, GSK Immunization against Lyme 1998 (US)
produced in E. coli. disease Withdrawn 2002
Triacelluvax, combination vaccine with r modified pertussis toxin Chiron (Siena, Italy) Immunization against 1999 (EU)
as one component. diphtheria, tetanus and Withdrawn 2002
pertussis
Monoclonal-antibody-based products
Alymsys (bevacizumab-maly (US), bevacizumab (EU)), Amneal Pharmaceuticals Colorectal & various other 2022 (US)
humanized IgG1 targeting VEGF, produced in a CHO cell line. (Bridgewater, NJ, USA) cancers 2021 (EU)
Biosimilar to avastin. Same product as Oyavas. Mabxience Research (Madrid)
Bebtelovimab, rh IgG1 that binds an epitope of the Eli Lilly (Indianapolis) COVID-19 2022 (US; Emergency
SARS-CoV-2 spike protein RBD, expressed in CHO cell line. Use Authorization)
Enjaym (sutimlimab-jome), humanized IgG4 targeting Bioverativ USA (Waltham, Cold agglutinin disease 2022 (US)
complement protein component 1s, produced in a CHO MA, USA)
cell line.
Evusheld (tixagevimab & cilgavimab), combination of 2 human AstraZeneca (Sodertalje, COVID -19 prevention. 2022 (EU)
IgG1κ mAbs directed against 2 (non-overlapping) epitopes Sweden) 2021 (US; Emergency
on the SARS-CoV-2 spike protein RBD, produced in CHO Use Authorization)
cell lines.

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1745

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Lunsumio (mosunetuzumab), humanized full-length Roche (Grenzach-Wyhlen, Relapsed or refractory 2022 (EU)
anti-CD20/CD3 T-cell-engaging bispecific IgG1, produced in Germany) follicular lymphoma
a CHO cell line.
Opdualag (nivolumab and relatlimab-rmbw), combination of Bristol-Myers Squibb (Princeton, Unresectable or 2022 (US)
two IgG4κ mAbs targeting PD-1 and lymphocyte activation NJ, USA) metastatic melanoma
gene-3, both produced in CHO cells.
Padcev (enfortumab vedotin (EU), enfortumab vedotin-ejfv Astellas Pharma Europe (Leiden, Urothelial cancer 2022 (EU)
(US)), antibody–drug conjugate (ADC) targeting nectin-4 the Netherlands) 2019 (US)
(an adhesion protein highly expressed in urothelial cancer). Astellas Pharma US (Northbrook,
Fully human IG1κ (produced in a CHO cell line) conjugated to Illinois, USA)
monomethyl auristatin E (MMAE).
Saphnelo (anifrolumab (EU), anifrolumab-fnia (US)), human AstraZeneca (Sodertalje, Sweden) Systemic lupus 2022 (EU)
IgG1κ directed against type I IFN subunit 1 receptor, produced AstraZeneca (Wilmington, erythematosus 2021 (US)
in mouse myeloma cells (NS0). DE, USA)
Uplizna (inebilizumab (EU), inebilizumab-cdon (US)), Viela Bio (Schiphol, the Neuromyelitis optica 2022 (EU)
humanized, affinity-optimized, afucosylated (IgG1κ specific Netherlands) spectrum disorders 2020 (US)
for the B-cell-specific surface antigen CD19, produced in Viela Bio (Gaithersburg,
fucosyltransferase-deficient CHO cells. MD, USA)
Vabysmo (faricimab-svoa), humanized bispecific IgG1, Genentech Neovascular (wet) 2022 (US)
targeting VEGF-A and angiopoietin-2, produced in a CHO age-related macular
cell line. degeneration and diabetic
macular edema
Vyepti (eptinezumab (EU), eptinezumab-jjmr (US)), humanized H. Lundbeck (Valby, Denmark) Migraine prevention 2022 (EU)
anti-CGRP IgG1 mAb, produced in P. pastoris. Lundbeck Seattle 2020 (US)
BioPharmaceuticals
Abevmy (bevacizumab), r humanized, anti-VEGF-A IgG1κ, Mylan (Dublin) Cancer (various) 2021 (EU)
produced in a CHO cell line. Biosimilar to Avastin.
Adbry (tralokinumab-ldrm; US), Adtralza (tralokinumab; LEO Pharma (Madison, NJ, USA) Atopic dermatitis 2021 (US & EU)
EU), anti-IL-13 human IgG4λ, manufactured in an NS0 murine LEO Pharma (Ballerup, Denmark) (eczema)
cell line.
Aduhelm (aducanumab-avwa), human IgG1 directed against Biogen (Cambridge, MA, USA) Alzheimer’s disease 2021 (US)
aggregated soluble and insoluble forms of amyloid-β,
produced in a CHO cell line.
Bamlanivimab & eteseviman, rh IgG1 mAbs that bind Eli Lilly (Indianapolis) COVID 19 2021 (US; Emergency
distinct but overlapping epitopes in the SARS-CoV-2 spike Use Authorization;
protein RBD. Authorization paused
in 2022 as product not
sufficiently effective
against Omicron
variant)
Bimzelx (bimekizumab), humanized IgG1κ mAb targeting UCB Pharma (Brussels) Psoriasis 2021 (EU)
human IL-17A and 17F, produced in a CHO cell line.
Byooviz (ranibizumab-nuna (US), ranibizumab (EU)), r Samsung Bioepis NL (Delft, Age-related macular 2021 (EU & US)
humanized IgG1κ Fab fragment targeting VEGF-A, produced the Netherlands) degeneration (wet) and
in E. coli. Biosimilar to Lucentis. Biogen (Cambridge, MA, USA) some additional retinal
conditions
Enhertu (trastuzumab deruxtecan), ADC comprising Daiichi Sankyo Europe (Munich, Metastatic breast cancer 2021 (EU)
humanized anti-HER2 IgG1κ (trastuzumab sequence), Germany) 2019 (US)
produced in CHO cells, conjugated to a topoisomerase I Daiichi Sankyo (Basking Ridge,
inhibitor derivative of exatecan. NJ, USA)
Enspryng (satralizumab (EU), satralizumab-mwge (US)), Roche (Grenzach-Wyhlen, Neuromyelitis optica 2021(EU)
r humanized IgG2 targeting soluble and membrane-bound Germany) spectrum disorders 2020 (US)
IL-6 receptor, produced in a CHO cell line. Genentech
Evkeeza (evinacumab-dgnb (US), evinacumab (EU)), Regeneron (Dublin) Homozygous familial 2021 (EU & US)
rh-IgG4 mAb targeting angiopoietin-like 3, produced in a Regeneron (Tarrytown, NY, USA) hypercholesterolemia
CHO cell line.
Hukyndra (adalimumab), human IgG1κ targeting TNF, Stada Arzneimittel (Bad Vilbel, Various inflammatory 2021 (EU)
produced in a CHO cell line. Biosimilar to Humira. Same Germany) conditions
as Libmyris.

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1746

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Jemperli (dostarlimab-gxly (US), dostarlimab (EU)), GlaxoSmithKline (Dublin) Endometrial cancer 2021 (EU & US)
humanized IgG4 mAb against programmed cell death GlaxoSmithKline (Research
protein 1 (PD-1), produced in CHO cells. Triangle Park, NC, USA)
Kesimpta (ofatumumab), rh IgG1 targeting B cell surface Novartis (Dublin) Multiple sclerosis 2021 (EU)
CD20, expressed in a mouse NS0 cell line.
Lextemy (bevacizumab), r humanized anti-VEGF-A IgG1κ, Mylan (Dublin) Cancer (various) 2021 (EU)
produced in a CHO cell line. Biosimilar to Avastin. Same Withdrawn 2021
product as Abevmy.
Libmyris (adalimumab), human IgG1κ targeting TNF, Stada Arzneimittel (Bad Vilbel, Various inflammatory 2021 (EU)
produced in a CHO cell line. Biosimilar to Humira. Germany) conditions
Minjuvi (EU), Monjivi (US) (tafasitamab (EU), tafasitamab-cxix Incyte Biosciences Distribution Diffuse large B cell 2021(EU)
(US)), humanized, Fc-engineered CD19-specific mAb, (Amsterdam) lymphoma 2020 (US)
produced in a CHO cell line. Morphosys US (Boston)
Onbevzi (bevacizumab), humanized, anti-VEGF mAb, Samsung Bioepis (Delft, the Cancers (various) 2021 (EU)
produced in CHO cells. Biosimilar to Avastin. Netherlands)
Oyavas (bevacizumab), r humanized, anti-VEGF-A IgG1κ, Stada Arzneimittel (Hessen, Cancer (various) 2021 (EU)
produced in a CHO cell line. Biosimilar to Avastin. Germany)
Regkirona (regdanvimab), human IgG1 targeting the Celltrion (Budapest) COVID 19 (treatment) 2021 (EU)
SARS-CoV-2 spike protein, produced in a CHO cell line.
Ronapreve (EU), Regen-cov (US)) (casirivimab & imdevimab), Roche (Grenzach-Wyhlen, COVID-19 (prevention & 2021 (EU)
combination of two human IgGs (IgG1κ and IgG1λ) targeting Germany) treatment) 2020 (US; Emergency
distinct epitopes of SARS-CoV-2 spike protein, both produced Regeneron (US) Use Authorization;
in CHO cell lines. Authorization paused
in 2022 as product
not sufficiently
effective against
Omicron variant)
Rybrevant (amivantamab-vmjw (US), amivantamab (EU)), Janssen-Cilag (Beerse, Belgium) Advanced non-small-cell 2021 (EU & US)
human low-fucose IgG1 bispecific antibody that binds the Janssen Biotech (Horsham, PA, lung cancer
extracellular domains of EGF and MET receptors, produced in USA)
CHO cell lines.
Susvimo (ranibizumab), humanized IgG1κ antibody fragment Genentech Neovascular (wet) 2021 (US)
specific for VEGF-A, produced in E. coli. age-related macular
degeneration
Tezspire (tezepelumab-ekko), human IgG2λ specific for thymic Amgen & AstraZeneca Severe asthma 2021 (US)
stromal lymphopoietin (TSLP), produced in a CHO cell line.
Tivdak (tisotumab vedotin-tftv), tissue factor (TF)-directed Seagen (Bothell, WA, USA) Cervical cancer 2021 (US)
ADC comprising a human anti-TF IgG1κ antibody conjugated
to monomethyl auristatin E (MMAE), produced in a CHO cell
line.
Trodelvy (sacituzumab govitecan (EU), sacituzumab Gilead Sciences (Cork, Ireland) Breast cancer 2021 (EU)
govitecan-hziy (US)), ADC comprising an anti-Trop-2 Immunomedics (Morris Plains, (triple-negative) 2020 (US)
humanized IgG1κ, produced in Sp2/0 cells, conjugated to NJ, USA)
camptothecin-derived topoisomerase I inhibitor SN-38.
Vyvgart (efgartigimod alfa-fcab), human IgG1-derived Fc Argenx (Boston) Myasthenia gravis 2021 (US)
fragment that binds the neonatal Fc receptor (FcRn), leading
to reduced circulating IgG, produced in a CHO cell line.
Xevudy (sotrovimab in US), human IgG1 targeting the GlaxoSmithKline (Dublin) Treating COVID-19 2021 (EU)
COVID-19 spike protein RBD, produced in a CHO cell line. GSK (Durham, NC, USA) 2021 (US; Emergency
Use Authorization;
Authorization paused
in 2022 as product not
sufficiently effective
against Omicron
variant)
Yuflyma (adalimumab), anti-TNF human IgG1, produced in a Celltrion (Budapest) Various inflammatory 2021 (EU)
CHO cell line. Biosimilar to Humira. conditions
Yusimry (adalimumab-aqvh), anti-TNF human IgG1, produced Coherus BioSciences (Redwood Various inflammatory 2021 (US)
in a CHO cell line. Biosimilar to Humira. City, CA, USA) conditions

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1747

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Zynlonta (loncastuximab tesirine-lpyl), CD19-directed ADC Therapeutics (Murray Hill, Lymphoma 2021 (US)
humanized IgG1κ produced in a CHO cell line, conjugated to NJ, USA)
SG3199 (alkylating agent).
Adakveo (crizanlizumab (EU), crizanlizumab-tmca (US)), Novartis (Dublin) Prevention of recurrent 2020 (EU)
r humanized IgG2aκ mAb targeting human P-selectin, Novartis (East Hanover, NJ, USA) vaso-occlusive crises 2019 (US)
produced in a CHO cell line. (VOCs) in sickle cell anemia
Amsparity (adalimumab), human IgG1 targeting TNF-α, Pfizer (Brussels) Various inflammatory 2020 (EU)
produced in a CHO cell line. Biosimilar to Humira. conditions
Aybintio (bevacizumab), humanized anti-VEGF mAb, Samsung Bioepis (Delft, the Various cancers 2020 (EU)
produced in a CHO cell line. Biosimilar to Avastin. Netherlands)
Beovu (brolucizumab (EU), brolucizumab-dbll (US)), humanized Novartis (Dublin) Wet age-related macular 2020 (EU)
single-chain Fv (scFv) antibody fragment targeting vascular Novartis (East Hanover, NJ, USA) degeneration, macular 2019 (US)
endothelial growth factor-A (VEGF-A), produced in E . coli. oedema
Blenrep (belantamab mafodotin (EU), belantamab GlaxoSmithKline (Dublin) Multiple myeloma 2020 (EU & US)
mafodotin-blmf (US)), ADC comprising monomethyl GlaxoSmithKline (Research
auristatin F conjugated to an afucosylated humanized IgG1κ, Triangle Park, NC, USA)
produced in a CHO cell line, targeting B cell maturation
antigen (BCMA).
Danyelza (naxitamab-gqgk), humanized IgG1 specific Y-mABs Therapeutics (New York, Neuroblastoma 2020 (US)
for glycolipid disialoganglioside (GD2), produced in a NY, USA)
CHO cell line.
Darzalex Faspro (daratumumab and hyaluronidase-fihj), Janssen Biotech (Horsham, Multiple myeloma 2020 (US)
IgG1κ specific for the CD38 antigen in combination with rh PA, USA)
hyaluronidase (which increases drug dispersion and absorption
upon SC administration), both produced in CHO cell lines.
Ebanga (ansuvimab-zykl), Zaire ebolavirus glycoprotein Ridgeback Biotherapeutics Infection by Zaire 2020 (US)
(EBOV GP)-directed human IgG1, produced in a CHO cell line. (Miami, FL, USA) ebolavirus
Equidacent (bevacizumab), humanized IgG1 targeting VEGF, Centus Biotherapeutics (Dublin) Cancers, various 2020 (EU)
produced in a CHO cell line. Biosimilar to Avastin. Withdrawn 2020
Hulio (adalimumab (EU), adalimumab-fkjp (US)), human IgG1 Mylan (Saint-Priest, France) Various inflammatory 2020 (US)
targeting TNF-α, expressed in CHO cells. Biosimilar Mylan Pharmaceuticals conditions mediated by 2018 (EU)
to Humira. (Morgantown, WV, USA) TNF
Inmazeb (atoltivimab, maftivimab and odesivimab-ebgn), Regeneron (Tarrytown, NY, USA) Infection by Zaire 2020 (US)
combination of Zaire ebolavirus glycoprotein-directed human ebolavirus
IgG1s, produced in CHO cell lines.
Margenza (margetuximab-cmkb), chimeric Fc-engineered MacroGenics (Rockville, MD, HER2 positive breast 2020 (US)
IgG1κ specific for the extracellular domain of the human USA) cancer
epidermal growth factor receptor 2 protein (HER2), produced
in a CHO cell line.
Obiltoxaximab SFL (EU), Anthim (US) (obiltoxaximab), SFL Pharmaceuticals Inhalational anthrax 2020 (EU)
chimeric IgG1 targeting the B. anthracis protective antigen Deutschland (Lörrach, Germany) 2016 (US)
(PA), the cell-binding component of anthrax toxin. Produced Elusys Therapeutics (Pine Brook,
in an NS0 cell line. NJ, USA)
Phesgo (pertuzumab, trastuzumab), combination of 2 r Roche (Grenzach-Wyhlen, HER2-positive breast 2020 (EU & US)
humanized IgG1 mAbs targeting the human epidermal growth Germany; EU) cancer
factor receptor 2 (HER2), both produced in CHO cells, along Genentech (South San Francisco,
with rh hyaluronidase (vorhyaluronidase alfa) as an excipient. CA, USA; US)
Polivy (polatuzumab vedotin), ADC comprising a humanized Roche (Grenzach-Wyhlen, Diffuse large B cell 2020 (EU)
IgG1, produced in CHO cells, targeting a component of the B Germany) lymphoma 2019 (US)
cell receptor (CD79b) conjugated to monomethyl auristatin Genentech (South San Francisco,
E (MMAE). CA, USA)
Riabni (rituximab-arrx), chimeric IgG1κ directed against the Amgen (Thousand Oaks, CA, Non-Hodgkin’s lymphoma, 2020 (US)
CD20 antigen, produced in a CHO cell line. Biosimilar to USA) chronic lymphocytic
Rituxan. leukemia, Wegener’s
granulomatosis and
microscopic polyangiitis
Ruxience (rituximab (EU), rituximab-pvvr (US)), chimeric Pfizer (Brussels) Various cancers and 2020 (EU)
mouse/human IgG1 targeting B lymphocyte CD20, produced Pfizer (New York) inflammatory conditions 2019 (US)
in a CHO cell line. Biosimilar to MabThera/Rituxan.

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1748

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Sarclisa (isatuximab (EU), isatuximab-irfc (US)), chimeric Sanofi-Aventis (Paris) Multiple myeloma 2020 (EU & US)
anti-CD 38 IgG1, produced in a CHO cell line. Sanofi-Aventis (Bridgewater,
NJ, USA)
Tepezza (teprotumumab-trbw), human IgG1 that binds IGF-1 Horizon Therapeutics (Lake Thyroid eye disease 2020 (US)
receptor, produced in a CHO cell line. Forest, IL, USA)
Zercepac (trastuzumab), humanized anti-HER2 mAb, Accord Healthcare (Barcelona) Breast and stomach 2020 (EU)
produced in a CHO cell line. Biosimilar to Herceptin. cancers
Abrilada (adalimumab-afzb), human IgG1 specific for TNF, Pfizer (New York) Various inflammatory 2019 (US)
produced in a CHO cell line. Biosimilar to Humira. conditions
Ajovy (fremanezumab (EU), fremanezumab-vfrm (US)), Teva (Ulm, Germany) Migraine 2019 (EU)
humanized IgG2 targeting both isoforms of CGRP, produced Teva Pharmaceuticals USA 2018 (US)
in a CHO cell line. (North Wales, PA, USA)
Avsola (infliximab-axxq), anti-TNF chimeric IgG1κ, produced Amgen (Thousand Oaks, Various inflammatory 2019 (US)
in a CHO cell line. Biosimilar to Remicade. CA, USA) conditions
Cablivi (Caplacizumab (EU), caplacizumab-yhdp (US)), Ablynx (Zwijnaarde, Belgium) Acquired thrombotic 2019 (US)
humanized bivalent nanobody comprising two identical Genzyme (Cambridge, MA, USA) thrombocytopenic 2018 (EU)
building blocks joined by a tri-alanine linker and targeting the purpura
A1 domain of von Willebrand factor, produced in E. coli.
Evenity (romosozumab (EU), romosozumab-aqqg (US)), UCB Pharma (Brussels) Osteoporosis 2019 (EU & US)
humanized IgG2 targeting sclerostin, produced in a CHO cell Amgen (Thousand Oaks,
line. CA, USA)
Hadlima (adalimumab-bwwd), anti-TNF human IgG1 produced Merck (Whitehouse Station, Various inflammatory 2019 (US)
in a CHO cell line. Biosimilar to Humira. Same product as NJ, USA) conditions
Imraldi.
Herceptin Hylecta (trastuzumab and hyaluronidase-oysk). Genentech Breast cancer 2019 (US)
Idacio (adalimumab), rh-IgG1 targeting TNF, produced Fresenius Kabi Deutschland (Bad Various inflammatory 2019 (EU)
in a CHO cell line. Biosimilar to Humira. Same as Kromeya Homburg v.d. Höhe, Germany) conditions
(see below).
Kanjinti (trastuzumab (EU), trastuzumab-anns (US)), r Amgen Europe (Breda, the Breast and gastric cancers 2019 (US)
humanized IgG1 against HER2, produced in CHO cells. Netherlands) 2018 (EU)
Biosimilar to Herceptin.
Kromeya (adalimumab, rh-IgG1 targeting TNF, produced Fresenius Kabi Deutschland (Bad Various inflammatory 2019 (EU)
in a CHO cell line. Biosimilar to Humira. Same as Idacio Homburg v.d. Höhe, Germany) conditions Withdrawn 2019
(see above).
Libtayo (cemiplimab-rwlc (US), cemiplimab (EU), human IgG4 Regeneron Pharmaceuticals Cutaneous squamous cell 2019 (EU)
specific for PD-1, produced in CHO cells. (Tarrytown, NY, USA) carcinoma 2018 (US)
Regeneron Ireland (Dublin)
Ontruzant (trastuzumab (EU), trastuzminjmab-dttb USA), Samsung Bioepis (Delft, the Breast and gastric cancers 2019 (EU)
produced in CHO cells. Biosimilar to Herceptin. Netherlands) 2017 (EU)
Organon (Jersey City, NJ, USA)
Skyrizi (risankizumab (EU), risankizumab-rzaa (US)), AbbVie Deutschland (Rhein, Plaque psoriasis and 2019 (US & EU)
humanized IgG1 targeting IL-23, produced in a CHO cell line. Germany) psoriatic arthritis
AbbVie (North Chicago, IL, USA)
Trazimera (trastuzumab (EU), trastuzumab-qyyp, US)), Pfizer (Brussels) Breast cancer, gastric 2019 (US)
humanized IgG, produced in a CHO cells. Biosimilar to Pfizer (New York) or gastroesophageal 2018 (EU)
Herceptin. junction adenocarcinoma
Trogarzo (ibalizumab (EU), ibalizumab-uiyk (US)), humanized Theratechnologies Europe Treatment of human 2019 (EU)
IgG-4, targeting T-helper cells CD4 receptor, produced in an (Dublin) immunodeficiency virus 2018 (US)
NS0 cell line. TaiMed Biologics (Irvine, type 1 infection
CA, USA) & Theratechnologies
(Montreal)
Ultomiris (ravulizumab (EU), ravulizumab-cwvz (US)), r Alexion Europe (LevallPerret, Paroxysmal nocturnal 2019 (EU)
humanized IgG2/4 targeting complement component 5, France) hemoglobinuria and 2018 (US)
produced in a CHO cell line. Alexion Pharmaceuticals atypical hemolytic uremic
(Boston) syndrome
Zirabev (bevacizumab (EU), bevacizumab-bvzr (US)), Pfizer Europe (Brussels) Cancer (various) 2019 (EU & US)
humanized IgG1κ targeting VEGF, produced in CHO cell line. Pfizer (New York)
Biosimilar to Avastin.

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1749

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Aimovig (erenumab-aooe (US), erenumab (EU)), human IgG2 Amgen (Thousand Oaks, CA, USA) Migraine 2018 (EU & US)
targeting the CGRP receptor, produced in CHO cells. Novartis (East Hanover, NJ, USA)
Novartis Europharm (Dublin)
Crysvita (burosumab (EU), burosumab-twza (US)), human Kyowa Kirin (Hoofddorp, the X-linked 2018 (EU & US)
IgG1 antibody to soluble fibroblast growth factor-23, Netherlands) hypophosphatemia
produced in CHO cells. Ultragenyx Pharmaceutical
(Novato, CA, USA)
Emgality (galcanezumab (EU), galcanezumab-gnlm (US)), Eli Lilly Nederland (Utrecht, the Migraine 2018 (EU & US)
humanized IgG4 that binds CGRP, produced in CHO cells. Netherlands)
Eli Lilly (Indianapolis)
Fasenra (benralizumab), humanized, afucosylated IgG1 AstraZeneca (Södartälje, Asthma 2018 (EU)
targeting the α subunit of the human IL-5 receptor, produced Sweden, & Wilmington, DE, USA) 2017 (US)
in CHO cells.
Gamifant (emapalumab-lzsg), r IgG1 targeting IFN-γ, Sobi (Waltham, MA, USA) Primary hemophagocytic 2018 (US)
produced in CHO cells. lymphohistiocytosis (HLH)
Halimatoz (adalimumab), anti-TNF IgG, produced in CHO Sandoz Various inflammatory 2018 (EU)
cells. Biosimilar to Humira. Same product as Hefiya and conditions mediated Withdrawn 2020
Hyrimoz (see below). by TNF, including
rheumatoid arthritis and
plaque psoriasis
Hefiya (adalimumab), anti-TNF IgG, produced in CHO cells. Sandoz Various inflammatory 2018 (EU)
Biosimilar to Humira. Same product as Halimatoz and Hyrimoz conditions mediated
(see above and below). by TNF, including
polyarticular juvenile
idiopathic arthritis and
plaque psoriasis
Hemlibra (emicizumab (EU), emicizumab-kxwh (US)), Roche Registration (Welwyn Hemophilia A 2018 (EU)
humanized, bispecific IgG4 capable of binding factors IXa Garden City, UK) 2017 (US)
and X, produced in CHO cells. Roche/Genentech (South
San Francisco, CA, USA)
Herzuma (trastuzumab (EU), trastuzumab-pkrb (US)), r Celltrion Healthcare (Budapest), Breast and gastric 2018 (EU & US)
humanized IgG1 against HER2, produced in CHO cells. Celltrion (Incheon, Republic cancers (EU)
Biosimilar to Herceptin. of Korea) Breast cancer (US)
Teva Pharmaceuticals USA
(North Wales, PA, USA)
Hyrimoz (adalimumab (EU), adalimumab-adaz (US)), Sandoz Various inflammatory 2018 (EU & US)
anti-TNF IgG, produced in CHO cells. Biosimilar to Humira. conditions mediated by
Same product as Halimatoz and Hefiya (see above). TNF, including rheumatoid
arthritis and plaque
psoriasis
Ilumya (tildrakizumab-asmn; US), Ilumetri (tildrakizumab; Merck (Whitehouse Station, Psoriasis 2018 (US & EU)
EU), humanized IgG1 that binds the p19 subunit of IL-23, NJ, USA)
produced in CHO cells. Almirall (Barcelona)
Imfinzi (durvalumab), human IgG1 blocking the interaction of AstraZeneca (Sodertalje, Non-small-cell lung 2018 (EU)
programmed cell death ligand-1 (PD-L1) with its receptor PD-1 Sweden) cancer 2017 (US)
and CD80, produced in CHO cells. AstraZeneca (Wilmington, Urothelial carcinoma
DE, USA)
Mvasi (bevacizumab (EU), bevacizumab-awwb (US)), Amgen Europe Amgen (Thousand Various cancers 2018 (EU)
humanized IgG antibody to human VEGF-A1, produced in CHO Oaks, CA, USA) 2017 (US)
cells. Biosimilar to Avastin.
Mylotarg (gemtuzumab ozogamicin), ADC targeting the CD33 Pfizer (Brussels) Acute myeloid leukemia 2018 (EU)
surface antigen, consisting of a humanized IgG4 chemically Pfizer/Wyeth (Philadelphia) 2000 (US)
conjugated to N-acetyl-γ-calicheamicin, produced in NS0 Withdrawn 2010 (US)
mouse myeloma cells. Reapproved 2017 (US)
using modified dosage
and regimen
Ocrevus (ocrelizumab), r humanized IgG1 targeting the CD20 Roche/Genentech (South San Multiple sclerosis 2018 (EU)
surface antigen, produced in CHO cells. Francisco, CA, USA) 2017 (US)
Ogivri (trastuzumab-dkst (US), trastuzumab (EU)), IgG Viatris (Dublin) Breast and gastric cancers 2018 (EU)
produced in CHO cells. Biosimilar to Herceptin. Mylan (Morgantown, WV, USA) 2017 (US)

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1750

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Poteligeo (mogamulizumab (EU), mogamulizumab-kpkc Kyowa Kirin (Hoofddorp, Sezary syndrome, mycosis 2018 (EU & US)
(US)), defucosylated, humanized IgG1 that binds C-C the Netherlands) fungoides
chemokine receptor type 4 (CCR4), produced in CHO cells. Kyowa Kirin (Bedminster,
NJ, USA)
Takhzyro (lanadelumab (EU), lanadelumab-flyo (US)), Shire (Dublin) Hereditary angioedemas 2018 (EU & US)
human IgG1 targeting active plasma kallikrein, produced Dyax (Lexington, MA, USA)
in CHO cells.
Truxima (rituximab (EU), rituximab-abbs (US)), chimeric IgG1 Celltrion (Torony, Hungary) Selected cancers and 2018 (US)
against cell surface antigen CD20, produced in CHO cells. Teva Pharmaceuticals USA autoimmune disorders 2017 (EU)
Biosimilar to MabThera. Same product as Blitzima, Ritemvia (North Wales, PA, USA) (EU), non-Hodgkin’s
(see above). lymphoma (US)
Zessly (infliximab), chimeric anti-TNF IgG1 produced in CHO Sandoz Rheumatoid arthritis 2018 (EU)
cells. Biosimilar to Remicade. and selected additional
inflammatory diseases
Amgevita (adalimumab), anti-TNF human IgG1, produced in Amgen Europe Rheumatoid arthritis 2017 (EU)
CHO cells. Biosimilar to Humira. Same product as Solymbic and selected additional Withdrawn 2019
(see below). inflammatory diseases
Bavencio (avelumab), human IgG1 specific for programmed Merck Europe (Amsterdam) Metastatic Merkel cell 2017 (EU & US)
death ligand-1 (PD-L1), produced in CHO cells. Pfizer (New York) carcinoma, urothelial
carcinoma
Besponsa (inotuzumab ozogamicin), ADC comprising Pfizer (Brussels) Acute lymphoblastic 2017 (EU & US)
a humanized IgG4 specific for human CD22, produced Pfizer/Wyeth (Philadelphia) leukemia
in CHO cells, covalently linked to the cytotoxic agent
N-acetyl-γ-calicheamicin dimethylhydrazide.
Blitzima (rituximab), chimeric IgG1 against cell surface antigen Celltrion Healthcare (Budapest) Non-Hodgkin’s lymphoma, 2017 (EU)
CD20, produced in CHO cells. Biosimilar to MabThera. Same CLL, granulomatosis
product as Ritemvia, Truxima and Rituzena (see below).
Rixiamgelusd zarz ezo (adalimumab (EU), adalimumab-adbm Boehringer Ingelheim (Rhein, Range of inflammatory 2017 (EU & US)
(US)), rh IgG1 against human TNF, produced in CHO cells. Germany) conditions, including Withdrawn 2019 (EU)
Biosimilar to Humira. Boehringer Ingelheim (Ridgefield, psoriasis, rheumatoid
CT, USA) arthritis and Crohn’s
disease
Dupixent (dupilumab), human IgG4 that binds the IL-4α receptor Sanofi-Aventis (Paris & Atopic dermatitis 2017 (EU & US)
subunit, produced in CHO cells Bridgewater, NJ, USA)
Regeneron Pharmaceuticals
(Tarrytown, NY, USA)
Imraldi (adalimumab), produced in CHO cells. Biosimilar to Samsung Bioepis (Delft, the Rheumatoid arthritis, 2017 (EU)
Humira. Netherlands) selected additional
inflammatory diseases
Ixifi (infliximab-qbtx), produced in mammalian cells. Biosimilar Pfizer (New York) Various inflammatory 2017 (US)
to Remicade. conditions, including
rheumatoid arthritis,
Crohn’s disease, and
psoriasis
Kevzara (sarilumab), human IgG1 that binds IL-6 receptors, Sanofi-Aventis (Paris & Rheumatoid arthritis 2017 (EU)
produced in CHO cells. Bridgewater, NJ, USA) 2017 (US)
Regeneron Pharmaceuticals
(Tarrytown, NY, USA)
Kyntheum (EU), Siliq (US) (brodalumab), human IgG2 against LEO Pharma (Ballerup, Denmark) Psoriasis 2017 (EU)
human IL-17 receptor A, produced in CHO cells. Valeant Pharmaceuticals 2017 (US)
(Bridgewater, NJ, USA)
Qarziba (dinutuximab beta; previously dinutuximab beta EUSA Pharma (Schiphol-Rijk, the Neuroblastoma 2017 (EU)
EUSA and dinutuximab beta Apeiron), chimeric IgG1 against Netherlands)
carbohydrate disialoganglioside GD2 that is overexpressed by
cells of neuroectodermal origin such as neuroblastoma cells,
produced in a CHO cell line.
Renflexis (infliximab-abda), chimeric IgG1 that binds TNF-α, Merck (Kenilworth, NJ, USA) Crohn’s disease and 2017 (US)
produced in CHO cells. Biosimilar to Remicade. Same product various other inflammatory
as Flixabi (see below). conditions

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1751

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Ritemvia (rituximab), produced in CHO cells. Biosimilar to Celltrion Healthcare (Budapest) Non-Hodgkin’s lymphoma, 2017 (EU)
MabThera. Same product as Blitzima, Rituzena and Truxima granulomatosis with Withdrawn 2021
(see above and below). polyangiitis, microscopic
polyangiitis
Rituxan Hycela, rituximab and hyaluronidase human, both Biogen (Cambridge, MA, USA), Follicular lymphoma, 2017 (US)
produced in CHO cells. Genentech diffuse large B cell
lymphoma, CLL
Rituzena (previously Tuxella) (rituximab), produced in CHO cells. Celltrion Healthcare (Budapest) Non-Hodgkin’s lymphoma, 2017 (EU)
Biosimilar to MabThera. Same product as Blitzima, Ritemvia and CLL, granulomatosis with Withdrawn 2019
Truxima (see above and below). polyangiitis
Rixathon (rituximab), chimeric IgG1 against cell surface antigen Sandoz Various conditions 2017 (EU)
CD20, produced in CHO cells. Biosimilar to MabThera. Same including non-Hodgkin’s
product as Riximyo (see below). lymphoma, CLL,
rheumatoid arthritis
Riximyo (rituximab), chimeric IgG1 against cell surface Sandoz Various conditions 2017 (EU)
antigen CD20, produced in CHO cells. Biosimilar to MabThera. including non-Hodgkin’s
Same product as Rixathon (see above). lymphoma and rheumatoid
arthritis, but excluding CLL
Solymbic (adalimumab), anti-TNF human IgG1 produced in Amgen Europe Rheumatoid arthritis 2017 (EU)
CHO cells. Biosimilar to Humira. Same product as Amgevita and and selected additional Withdrawn 2018
Amjevita (see above and below). inflammatory diseases
Tecentriq (atezolizumab), humanized IgG1 specific for Roche Registration Urothelial carcinoma, 2017 (EU)
programmed death ligand 1 (PD-L1), engineered to lack Fc (Grenzach-Wyhlen, Germany) non-small-cell lung cancer 2016 (US)
glycosylation, produced in CHO cells. Genentech (South San Francisco,
CA, USA)
Tremfya (guselkumab), human IgG1 that selectively binds the Janssen-Cilag (Beerse, Belgium) Psoriasis 2017 (EU & US)
p19 subunit of IL-23, produced in CHO cells. Janssen Biotech (Horsham,
PA, USA)
Zinplava (bezlotoxumab), human IgG directed against Merck Sharp & Dohme C. difficile infection 2017 (EU)
Clostridium difficile toxin B, produced in CHO cells. Merck (Whitehouse Station, 2016 (US)
NJ, USA)
Amjevita (adalimumab-atto), rh IgG1 specific for TNF, produced Amgen (Thousand Oaks, CA, USA) Rheumatoid arthritis 2016 (US)
in CHO cells. Biosimilar to Humira. Same product as Solymbic and selected additional
and Amgevita (see above). inflammatory diseases
Cinqair (US), Cinqaero (EU) (reslizumab), humanized IgG4 Teva Respiratory (Frazer, PA USA) Asthma 2016 (US)
against IL-5, produced in NS0 cells. Teva (Haarlem, the Netherlands) 2016 (EU)
Darzalex (daratumumab), human IgG1 against CD-38, produced Janssen-Cilag Multiple myeloma 2016 (EU)
in CHO cells. Janssen Biotech 2015 (US)
Empliciti (elotuzumab) humanized IgG1 against the cell surface Bristol-Myers Squibb (Dublin & Multiple myeloma 2016 (EU)
receptor SLAMF7, produced in NS0 cells. Princeton, NJ, USA) (in combination with 2015 (US)
lenalidomide and
dexamethasone)
Flixabi (infliximab), chimeric IgG1 against TNF-α, produced in Samsung Bioepis (Delft, the Various forms of arthritis, 2016 (EU)
CHO cells. Biosimilar to Remicade. Same product as Renflexis Netherlands) psoriasis, colitis, Crohn’s
(see above). disease, ankylosing
spondylitis
Inflectra (EU & US), Remsima (EU) (infliximab (EU), Inflectra: Hospira (Lake Forest, Certain forms of arthritis 2016 (US)
infliximab-dyyb (US)), chimeric IgG1 specific for TNF-α, IL, USA) and psoriasis, Crohn’s 2013 (EU)
produced in murine Sp2/0 cells. Biosimilar to Remicade. Pfizer (Brussels) disease, ulcerative colitis,
Remsima: Celltrion (Budapest) ankylosing spondylitis
Lartruvo (olaratumab), rh IgG1 specific for human Eli Lilly (Utrecht, the Netherlands, & Sarcoma 2016 (EU & US)
platelet-derived growth factor receptor-α, produced in NS0 cells. Indianapolis) Withdrawn 2019
Portrazza (necitumumab), human IgG1 against the ligand- Eli Lilly (Utrecht, the Netherlands, Non-small-cell lung cancer 2016 (EU)
binding site of human EGF receptor, produced in NS0 cells. & Indianapolis) (in combination with 2015 (US)
gemcitabine and cisplatin) Withdrawn 2021 (EU)
Taltz (ixekizumab), humanized IgG4 against hIL-17A, produced Eli Lilly (Utrecht, the Netherlands, Psoriasis 2016 (EU & US)
in CHO cells. & Indianapolis)
Zinbryta (daclizumab), humanized IgG1 against IL-2Rα, produced Biogen (Cambridge, MA, US) Multiple sclerosis 2016 (EU & US)
in NS0 cells. Biogen Idec (Maidenhead, UK) Withdrawn 2018

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1752

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Blincyto (blinatumomab), bispecific T cell engager antibody Amgen Europe Acute lymphoblastic 2015 (EU)
construct (BiTE), produced in CHO cells. Amgen (Thousand Oaks, CA, USA) leukemia 2014 (US)
Cosentyx (secukinumab), human IgG1 selectively binding Novartis (Dublin) Moderate to severe plaque 2015 (EU & US)
human IL-17a, produced in CHO cells. Novartis (East Hanover, NJ, USA) psoriasis in adults
Keytruda (pembrolizumab), humanized IgG4 capable of binding Merck Sharp & Dohme Advanced (unresectable 2015 (EU)
to the receptor PD-1, produced in CHO cells. Merck (Whitehouse Station, or metastatic) melanoma 2014 (US)
NJ, USA) in adults
Nivolumab BMS (nivolumab), human IgG4 against the receptor Bristol-Myers Squibb (Uxbridge, Locally advanced or July 2015 (EU)
PD-1, produced in CHO cells. Same product as Opdivo UK) metastatic squamous Withdrawn November
(see below). non-small-cell lung cancer 2015
after prior chemotherapy
in adults
Nucala (mepolizumab), humanized IgG1 capable of binding GlaxoSmithKline (Cork, Ireland) Add-on treatment 2015 (EU & US)
human IL-5, produced in CHO cells. GSK (Research Triangle Park, for severe refractory
NC, USA) eosinophilic asthma in
adult patients
Opdivo (nivolumab), human IgG4 against the receptor PD-1, Bristol-Myers Squibb (Dublin, & Melanoma (as monotherapy 2015 (EU)
produced in CHO cells. Same product as nivolumab BMS Princeton, NJ, USA) or in combination with 2014 (US)
(see above). ipilimumab), non-small-cell
lung cancer, renal cell
carcinoma
Praluent (alirocumab), human IgG1 targeting PCSK9, produced Sanofi-Aventis (Paris & Primary 2015 (EU & US)
in CHO cells Bridgewater, NJ, USA) hypercholesterolemia or
Regeneron Pharmaceuticals mixed dyslipidemia, as an
(Tarrytown, NY, USA) adjunct to diet
Praxbind (idarucizumab), humanized IgG1 Fab fragment capable Boehringer Ingelheim (Rhein, Rapid reversal agent for 2015 (EU & US)
of binding the anticoagulant drug dabigatran, produced in Germany, & Ridgefield, CT, USA) the anticoagulant drug
CHO cells. dabigatran
Repatha (evolocumab), human IgG2 capable of binding human Amgen Europe Hypercholesterolemia and 2015 (EU & US)
PCSK-9, produced in CHO cells. Amgen (Thousand Oaks, CA, USA) mixed dyslipidemia
Unituxin (dinutuximab), chimeric IgG1 targeting human United Therapeutics Chertsey Neuroblastoma 2015 (EU & US)
disialoganglioside (GD2), produced in Sp2/0 cells (Surrey, UK, & Silver Spring, (administered in Withdrawn 2017 (EU)
MD, USA) combination with GM-CSF,
IL-2 and isotretinoin)
Cyramza (ramucirumab), human mAb that binds the VEGF-2 Eli Lilly Nederland (Utrecht, the Gastric cancer 2014 (EU & US)
receptor, produced in NS0 cells. Netherlands)
Eli Lilly (Indianapolis)
Entyvio (vedolizumab), humanized IgG targeting the human Takeda Pharmaceuticals (Deerfield, Ulcerative colitis, Crohn’s 2014 (EU & US)
α4β7 integrin, produced in CHO cells. IL, USA) disease
Takeda Pharma (Taastrup, Denmark)
Gazyva (US), Gazyvaro (EU) (obinutuzumab), humanized, Roche/Genentech CLL 2014 (EU)
glycoengineered mAb specific for B cell antigen CD20, 2013 (US)
produced in CHO cells.
Sylvant (siltuximab), chimeric mAb that binds human IL-6, Janssen Biotech Multicentric Castleman 2014 (EU & US)
produced in CHO cells. disease
Kadcyla (trastuzumab emtansine), humanized mAb specific for Roche Breast cancer 2013 (EU & US)
HER2 antigen, produced in CHO cells and conjugated to the
small-molecule cytotoxin DM1.
Simponi Aria (golimumab). Active substance same as that Janssen Biotech Rheumatoid arthritis 2013 (US)
in Simponi (see below); different strength and mode of
administration.
Perjeta (pertuzumab), human mAb specific for HER2, produced Roche/Genentech Breast cancer 2013 (EU)
in CHO cells. 2012 (US)
Abthrax (raxibacumab), human IgG mAb against the protective GSK/Human Genome Sciences Inhalational anthrax 2012 (US)
antigen (PA) of B. anthracis, produced in NS0 cells. (Rockville, MD, USA)
Adcetris (brentuximab vedotin), chimeric mAb conjugate Takeda Pharma (Roskilde, Denmark) Lymphoma 2012 (EU)
specific for human CD30 (expressed on the surface of Seattle Genetics 2011 (US)
lymphoma cells), produced in CHO cells.

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1753

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Benlysta (belimumab), human mAb that targets human Human Genome Sciences, Lupus 2011 (EU & US)
B-lymphocyte stimulator (BLyS), a B cell survival factor. GSK (Dublin)
Produced in NS0 cells.
Xgeva (denosumab) (see Prolia). Amgen Europe Bone loss associated with 2011 (EU)
cancer 2010 (US)
Yervoy (ipilimumab), human mAb binding to CTLA-4 (a negative Bristol-Myers Squibb (Dublin) Melanoma 2011 (EU & US)
regulator of T cell activation), thereby enhancing T cell Bristol-Myers Squibb (Princeton,
activation and proliferation, produced in CHO cells. NJ, USA)
Actemra (US), RoActemra (EU) (tocilizumab), humanized mAb Roche (Grenzach-Wyhlen Rheumatoid arthritis 2010 (US)
specific for IL-6, produced in a mammalian cell line. Germany) 2009 (EU)
Genentech (South San Francisco,
CA, USA)
Arzerra (ofatumumab), human mAb specific for CD20, produced Novartis, Genmab (Greenford, UK) CLL 2010 (EU)
in NS0 hybridoma cells. 2009 (US)
Withdrawn 2019 (EU)
Prolia (denosumab), human mAb specific for receptor activator Amgen Osteoporosis in 2010 (EU & US)
of nuclear factor-κB ligand (RANKL), produced in CHO cells. postmenopausal women
Scintimun (besilesomab), murine mAb against nonspecific CIS Bio International In vivo diagnosis or 2010 (EU)
cross-reacting antigen-95 (found on surface of granulocytes), (Gif-sur-Yvette, France) investigation of sites of
produced in hybridoma cells. inflammation or infection
via scintigraphic imaging
Cimzia (certolizumab pegol), anti-TNF-α humanized antibody UCB Pharma (Brussels) Crohn’s disease, 2009 (EU)
Fab′ fragment, produced in E. coli and PEGylated. UCB (Smyrna, GA, USA) rheumatoid arthritis 2008 (US)
Ilaris (canakinumab), human mAb specific for IL-1β, produced Novartis Pharmaceuticals (East Cryopyrin-associated 2009 (EU & US)
in Sp2/0 cells. Hanover, New Jersey, USA) periodic syndromes (CAPS)
Novartis Europharm (Dublin)
Removab (catumaxomab), bispecific engineered antibody Neovii Biotech (Gräfelfing, Malignant ascites in patients 2009 (EU)
targeting the human epithelial cell adhesion molecule (EpCAM) Germany) with carcinomas expressing Withdrawn 2017
and human CD3 expressed on T lymphocytes, respectively, epithelial cell adhesion
produced in hybridoma cells. molecule
Simponi (golimumab), human mAb specific for TNF-α, produced Janssen Biologics (Leiden, Rheumatoid arthritis, 2009 (EU & US)
in Sp2/0 cells. the Netherlands) psoriatic arthritis,
Janssen Biotech (Horsham, ankylosing spondylitis
PA, USA)
Stelara (ustekinumab), human MAb specific for the p40 subunit Janssen-Cilag Moderate to severe plaque 2009 (EU & US)
of IL-12 and IL-23, produced in Sp2/0 cells. psoriasis
Lucentis (ranibizumab), humanized IgG fragment that binds and Novartis (Dublin) Neovascular (wet) 2007 (EU)
inactivates VEGF-A, produced in E. coli. Genentech age-related macular 2006 (US)
degeneration
Soliris (eculizumab), humanized IgG that binds human C5 Alexion Pharmaceuticals Paroxysmal nocturnal 2007 (EU & US)
complement protein, produced in a murine myeloma cell line. (Cheshire, CT, USA, & Paris) hemoglobinuria
Vectibix (panitumumab), human mAb that binds human EGF Amgen EGF-receptor-expressing 2007 (EU)
receptor, produced in CHO cells. colorectal carcinoma 2006 (US)
Tysabri (natalizumab), humanized mAb against selected Biogen (Cambridge, MA, USA) Relapsing forms of multiple 2006 (EU) 2004 (US)
leukocyte integrins, produced in murine myeloma cells. Biogen Netherlands sclerosis Suspended 2005 (US)
(Badhoevedorp, the Netherlands) Resumed 2006 (US)
Xolair (omalizumab), humanized mAb that binds IgE at the site Roche/Genentech Moderate to severe 2005 (EU)
of high-affinity IgE receptor binding, produced in CHO cells. persistent asthma in adults 2003 (US)
and adolescents
Zevalin (ibritumomab tiuxetan), murine mAb against the CD20 Ceft Biopharma (Prague) Non-Hodgkin’s lymphoma 2004 (EU)
antigen, produced in CHO cells. Spectrum Pharmaceuticals 2002 (US)
(Irvine, CA, USA)
Erbitux (cetuximab), chimeric mAb against human EGF receptor, Merck (Amsterdam) EGF-receptor-expressing 2004 (EU & US)
produced in Sp2/0 cells. Eli Lilly (Indianapolis) metastatic colorectal cancer
Raptiva (efalizumab), humanized mAb that binds LFA-1, which is Serono (London, UK) Chronic moderate to severe 2004 (EU)
expressed on all leukocytes; produced in CHO cells. Genentech plaque psoriasis in adults 2003 (US)
Withdrawn 2009

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1754

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Avastin (bevacizumab), humanized mAb against VEGF, produced Roche/Genentech Metastatic colorectal 2005 (EU)
in CHO cells. cancer, glioblastoma, 2004 (US)
metastatic renal carcinoma
NeutroSpec (fanolesomab), murine mAb against CD15, a surface Palatin Technologies (Cranbury, NJ, Imaging of equivocal 2004 (US)
antigen of selected leukocytes, produced in hybridoma cells. USA), Mallinckrodt Pharmaceuticals appendicitis Withdrawn 2005
(Hazelwood, MO, USA)
Humira (EU & US), Trudexa (EU) (adalimumab), anti-TNF human AbbVie (Maidenhead, UK) Rheumatoid arthritis 2003 (EU)
mAb, produced in CHO cells. 2002 (US)
Trudexa withdrawn
2007 (EU)
Bexxar (tositumomab), radiolabeled mAb against CD20, GSK CD20-positive follicular 2003 (US)
produced in murine hybridoma cells. non-Hodgkin’s lymphoma Withdrawn 2014
Mabcampath (EU), Campath (US) (alemtuzumab), humanized Genzyme (Naarden, the CLL 2001 (EU & US)
mAb against CD52, a surface antigen of B lymphocytes, Netherlands) Withdrawn 2012 (EU)
produced in CHO cells. Millennium (Cambridge, MA, USA)
Mylotarg (gemtuzumab zogamicin), a humanized antibody–toxic Wyeth (Madison, NJ, USA) Acute myeloid leukemia 2000 (US)
antibiotic conjugate targeted against the CD33 antigen found Withdrawn 2010
on leukemic blast cells, produced in NS0 cells. Reintroduced in 2017
Herceptin (trastuzumab), humanized mAb against HER2, Roche (Grenzach-Wyhlen, Treatment of metastatic 2000 (EU)
produced in a murine cell line. Germany) breast cancer 1998 (US)
overexpressing HER2
protein
Remicade (infliximab), chimeric mAb against TNF-α, produced Janssen (Leiden, the Netherlands) Crohn’s disease 1999 (EU)
in Sp2/0 cells. 1998 (US)
Synagis (palivizumab) humanized mAb directed against an AstraZeneca (Sodertalje, Sweden) Prophylaxis of lower 1999 (EU)
epitope on the surface of respiratory syncytial virus, produced respiratory tract disease 1998 (US)
in a murine myeloma cell line caused by syncytial virus in
children
Zenapax (daclizumab), humanized mAb against the IL-2 receptor Roche (Welwyn Garden City, UK) Prevention of acute kidney 1999 (EU)
α-chain, produced in NS0 cells. Biogen (Cambridge, MA, USA) transplant rejection 1997 (US)
Withdrawn 2009 (EU)
Humaspect (votumumab), human mAb against cytokeratin KS Biomedix (Farnham, UK) Detection of carcinoma of 1998 (EU)
tumor-associated antigen, produced in a human lymphoblastoid the colon or rectum Withdrawn 2004
cell line.
MabThera (EU), Rituxan (US) (rituximab), chimeric mAb against Genentech/Roche Non-Hodgkin’s lymphoma 1998 (EU)
CD20 surface antigen of B lymphocytes, produced in CHO cells. 1997 (US)
Simulect (basiliximab), chimeric mAb directed against the Novartis (Dublin) Prophylaxis of acute organ 1998 (EU)
α-chain of the IL-2 receptor, produced in a murine myeloma rejection in allogeneic renal
cell line. transplantation
LeukoScan (sulesomab), murine mAb Fab fragment against Immunomedics (Darmstadt, Diagnostic imaging for 1997 (EU)
granulocyte surface nonspecific cross-reacting antigen-90, Germany) infection and inflammation Withdrawn 2018
produced in Sp2/0 cells. in bone of patients with
osteomyelitis
Verluma (nofetumomab), murine mAb Fab fragment directed Boehringer Ingelheim, NeoRx Detection of small-cell lung 1996 (US)
against carcinoma-associated antigen, produced in a murine (Seattle) cancer Withdrawn 1999
cell line.
Tecnemab KI (anti-melanoma mAb fragments), murine mAb Amersham Sorin (Milan) Diagnosis of cutaneous 1996 (EU)
fragments (Fab/Fab2 mix) against HMW-MAA, produced in murine melanoma lesions Withdrawn 2000
ascites culture.
ProstaScint (capromab pentetate), murine mAb against the tumor EUSA Pharma (Langhorne, PA, USA) Detection, staging and 1996 (US)
surface antigen PSMA, produced in a murine cell line. follow-up of prostate Discontinued 2018
adenocarcinoma
MyoScint (imiciromab pentetate), murine mAb fragment directed Centocor Myocardial infarction 1996 (US)
against human cardiac myosin, produced in a murine cell line. imaging Withdrawn 1999
CEA-scan (arcitumomab), murine mAb Fab fragment against Immunomedics Detection of recurrent or 1996 (EU & US)
human carcinoembryonic antigen (CEA), produced in mouse metastatic colorectal cancer Withdrawn 2005
ascites. (EU & US)

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1755

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Indimacis 125 (igovomab), murine mAb Fab2 fragment against the CIS Bio (Gif-sur-Yvette, France) Diagnosis of ovarian 1996 (EU)
tumor-associated antigen CA125, produced in a murine cell line. adenocarcinoma Withdrawn 2009
ReoPro (abciximab), Fab fragments derived from a chimeric mAb Janssen Biologics (Leiden, Prevention of blood clots 1994 (US)
against the platelet surface receptor GPIIb/III, produced in a the Netherlands) Withdrawn 2019
mammalian cell line. Centocor
OncoScint CR/OV (satumomab pendetide), murine mAb against Cytogen (Princeton, NJ, USA) Detection, staging and 1992 (US)
the tumor-associated glycoprotein TAG-72, produced in a murine follow-up of colorectal and Withdrawn 2002
cell line. ovarian cancers
Orthoclone OKT3 (muromomab CD3), murine mAb against the Centocor Ortho Biotech Products Reversal of acute kidney 1986 (US)
T-lymphocyte surface antigen CD3, produced in a murine cell line. (Raritan, NJ, USA) transplant rejection Withdrawn 2010
Other recombinant products
Bone morphogenetic proteins
Opgenra (eptotermin alfa), rh BMP-7, produced in CHO cells Olympus Biotech (Limerick, Posterolateral lumbar spinal 2009 (EU)
Ireland) fusion Withdrawn 2016
Infuse bone graft, containing dibotermin alfa, a rh BMP-2 Wyeth (Madison, NJ, USA) Acute open tibial shaft 2004 (US)
produced in CHO cells, placed on an absorbable collagen fracture
sponge. Active substance same as that in Infuse (see below).
Inductos (dibotermin alfa), rh BMP-2, produced in CHO cells. Medtronic BioPharma (Heerlen, the Acute tibia fractures 2002 (EU)
Netherlands)
Infuse (rh BMP2), produced in CHO cells. Medtronic Sofamor Danek Promotes fusion of lower 2002 (US)
(Memphis, TN, USA) spine vertebrae
OP-1 implant (US), Osigraft (EU) (eptotermin alfa), rh BMP-7, Olympus Biotech (Limerick, Ireland) Non-union of tibia 2001 (EU & US)
produced in CHO cells. Stryker Biotech (Hopkinton, Withdrawn 2015 (EU)
MA, USA)
Recombinant enzymes
Voraxaze (glucarpidase), Pseudomonas-derived exopeptidase SERB SAS (Paris) Reduce toxic plasma 2022 (EU)
enzyme capable of hydrolyzing the carboxy terminal BTG International (West methotrexate 2012 (US)
glutamate residue from folic acid and its analogs, including Conshohocken, PA, USA) concentrations
methotrexate (MTX); produced recombinantly in E. coli.
Nexviazyme (avalglucosidase alfa-ngpt), rh α-glucosidase Genzyme (Cambridge, MA, USA) Late-onset Pompe disease 2021 (US)
produced in a CHO cell line, conjugated with multiple synthetic
bis-mannose-6-phosphate (bis-M6P)-tetra-mannose glycans.
Rylaze (asparaginase erwinia chrysanthemi Jazz Pharmaceuticals (Palo Alto, Acute lymphoblastic 2021 (US)
(recombinant)-rywn), Erwinia chrystanthemi-derived CA, USA) leukemia and
asparaginase, produced recombinantly in P. fluorescens. lymphoblastic lymphoma
Idefirix (imlifidase; r Streptococcus pyogenes–derived Hansa Biopharma (Lund, Sweden) Preventing kidney 2020 (EU)
protease that degrades IgG in the lower hinge region, transplant rejection
produced in E. coli.
Palynziq (pegvaliase (EU), pegvaliase-pqpz (US)), BioMarin International (Cork, Phenylketonuria 2019 (EU)
r phenylalanine ammonia lyase derived from the Ireland) 2018 (US)
cyanobacterium Anabaena variabilis, produced in E. coli and BioMarin (Novato, CA, USA)
PEGylated.
Lamzede (velmanase alfa), rh α-mannosidase, expressed in Chiesi Farmaceutici (Parma, Italy) α-mannosidosis 2018 (EU)
precursor form in CHO cells.
Mepsevii (vestronidase alfa-vjbk (US), vestronidase alfa (EU)), Ultragenyx Germany (Berlin) Mucopolysaccharidosis 2018 (EU)
r human lysosomal β-glucuronidase, produced in CHO cells. Ultragenyx Pharmaceutical VII 2017 (US)
(Novato, CA, USA)
Revcovi (elapegademase-lvlr), PEG-conjugated r bovine Leadiant Biosciences Adenosine deaminase 2018 (US)
adenosine deaminase, produced in E. coli. (Gaithersburg, MD, USA) severe combined immune
deficiency (ADA-SCID)
Brineura (cerliponase alfa), rh serine tripeptidyl peptidase-1, BioMarin (Cork, Ireland) CLN2 disease (tripeptidyl 2017 (EU & US)
expressed in proenzyme form in CHO cells. BioMarin peptidase-1 deficiency)
Oncaspar (pegaspargase), r asparaginase, produced in E. coli Les Laboratoires Servier (Suresnes, Lymphoblastic leukemia, 2016 (EU)
and conjugated to monomethoxypropylene glycol. France) lymphoma
Spectrila (asparaginase), r asparaginase, produced in E. coli. Medac Gesellschaft für klinische Lymphoblastic leukemia, 2016 (EU)
Spezialpräparate (Wedel, Germany) lymphoma

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1756

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Kanuma (sebelipase alfa), rh lysosomal acid lipase, produced in Enzyme replacement 2015 (EU & US)
the eggs of transgenic chickens.Alexion Europe (Rueil-Malmaison, therapy in patients with
France), Alexion Pharmaceuticals (Cheshire, CT, USA) lysosomal acid lipase
deficiency
Strensiq (asfotase alfa), dimeric fusion protein containing Alexion Europe (Rueil-Malmaison, Enzyme replacement 2015 (EU & US)
a soluble catalytic domain of human tissue-nonspecific France) therapy in patients
alkaline phosphatase linked to an IgG Fc domain and Alexion (Cheshire, CT, USA) with pediatric-onset
a deca-aspartate peptide domain, produced in CHO hypophosphatasia
cells.
Vimizim (elosulfase alfa), rh N-acetlygalactosamine-6-sulfatase, BioMarin (Cork, Ireland) Mucopolysaccharidosis IVA 2014 (EU & US)
produced in CHO cells. (Morquio A syndrome)
Krystexxa (pegloticase), r urate oxidase, produced in E. coli and Savient Pharma (Dublin) Gout 2013 (EU)
PEGylated. Crealta Pharmaceuticals 2010 (US)
(Lake Forest, IL, USA) Withdrawn 2016 (EU)
Elelyso (taliglucerase alfa), rh glucocerebrosidase, produced in Pfizer (New York, NY, USA) Gaucher disease 2012 (US)
engineered carrot root cell culture.
Lumizyme (alglucosidase alfa), rh acid-α-glucosidase, produced Sanofi Genzyme Pompe disease (glycogen 2010 (US)
in CHO cells. storage disease type II)
VPRIV (velaglucerase alfa), rh glucocerebrosidase, produced in Shire (Dublin) Gaucher disease 2010 (EU & US)
a human fibroblast cell line. Shire (Cambridge, MA USA)
Elaprase (idursulfase), rh iduronate-2-sulfatase, produced in a Shire Mucopolysaccharidosis II 2007 (EU)
human cell line. (Hunter syndrome) 2006 (US
Naglazyme (galsulfase), rh N-acetylgalactosamine-4-sulfatase, BioMarin (Cork, Ireland & Long-term enzyme 2006 (EU)
produced in CHO cells. Novato, CA, USA) replacement therapy in 2005 (US)
mucopolysaccharidosis VI
Myozyme (algulcosidase alfa), rh acid glucosidase, produced Genzyme (Amsterdam) Pompe disease 2006 (EU & US)
in CHO cells. Discontinued 2014 (US)
Aldurazyme (laronidase), r α-l-iduronidase, produced in Genzyme (Amsterdam) Long-term replacement in 2003 (EU & US)
CHO cells. mucopolysaccharidosis I
Hylenex (hyaluronidase), rh hyaluronidase, produced in Halozyme Therapeutics Adjuvant to increase 2005 (US)
CHO cells. (San Diego) absorption and dispersion
of other drugs
Fabrazyme (agalsidase beta), rh α-galactosidase, produced in Genzyme Fabry disease 2003 (US)
CHO cells. (α-galactosidase A 2001 (EU)
deficiency)
Replagal (agalsidase alfa), rh α-galactosidase, produced in a Takeda (Dublin) Fabry disease 2001 (EU)
human cell line. (α-galactosidase A
deficiency)
Fasturtec (EU), Elitek (US) (rasburicase), r urate oxidase, Sanofi (Paris) Hyperuricemia 2002 (US)
produced in S. cerevisiae. 2001 (EU)
Cerezyme (imiglucerase), rh β-glucocerebrosidase, produced in Genzyme Gaucher disease 1997 (EU)
CHO cells. 1994 (US)
Pulmozyme (dornase alpha), r DNase, produced in CHO cells. Roche/Genentech Cystic fibrosis 1993 (US)
Fusion proteins
Kimmtrak (tebentafusp-tebn (US), tebentafusp (EU)); Immunocore (Dublin; EU) Uveal melanoma (type of 2022 (EU & US)
bispecific T cell engager fusion protein, produced in E. coli. Immunocore (Conshohocken, eye cancer)
PA, USA; US)
Ngenla (somatrogon), r chimeric fusion protein of hGH Pfizer Europe MA EEIG (Brussels) Growth disturbances 2022 (EU)
with one copy of the C-terminal peptide (CTP) from the due to growth hormone
β-chain of human chorionic gonadotropin at the N-terminus deficiency
and two copies of CTP at the C-terminus, produced in
CHO cells.
Elzonris (tagraxofusp-erzs (US), tagraxofusp (EU)), rh Stemline Therapeutics Blastic plasmacytoid 2021 (EU)
IL-3–truncated diphtheria toxin fusion protein, produced in (Amsterdam) dendritic cell neoplasm 2018 (US)
E. coli. Stemline Therapeutics
(New York)

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1757

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Lumoxiti (moxetumomab pasudotox (EU), moxetumomab AstraZeneca (Sodertalje, Hairy cell leukemia 2021 (EU)
pasudotox-tdfk (US)), r-immunotoxin fusion protein Sweden) 2018 (US)
consisting of an Ig light-chain variable domain (VL) and AstraZeneca Pharmaceuticals Withdrawn 2021 (EU)
heavy-chain variable domain (VH) genetically fused to a (Wilmington, DE, USA)
truncated form of Pseudomonas exotoxin, targeting CD22
cell surface receptors, produced in E. coli.
Nepexto (etanercept), r dimeric protein comprising 2 soluble Mylan (Dublin) Various inflammatory 2020 (EU)
p75 TNFR molecules fused to the human IgG1 Fc fragment, conditions
produced in a CHO cell line. Biosimilar to Enbrel.
Reblozyl (luspatercept (EU), luspatercept-aamt (US)), r-fusion Bristol Myers Squibb Pharma Certain (rare) forms of 2020 (EU)
protein consisting of two modified extracellular domains of EEIG (Dublin) anemia 2019 (US)
human activin receptor type IIB (ActRIIB) linked to the human Celgene (Summit, NJ, USA) &
IgG1 Fc domain. Binds selectively to transforming growth Acceleron Pharma, (Cambridge,
factor-beta (TGF-β) superfamily ligands; produced in CHO MA, USA))
cell line.
Benepali (etanercept, EU), Eticovo (etanercept-ykro, US)), rh Samsung Bioepis (Delft, the Arthritis, psoriasis, axial 2019 (US)
TNF receptor–IgG Fc fusion protein, produced in CHO cells. Netherlands) spondyloarthritis 2016 (EU)
Biosimilar to Enbrel. Samsung Bioepis
Erelzi (etanercept (EU), etanercept-szzs (US)), r dimeric fusion Sandoz (Kundl, Austria, & Rheumatoid arthritis, 2017 (EU)
protein consisting of TNF receptor extracellular domains linked Princeton, NJ, USA) selected other 2016 (US)
to an IgG1 Fc region, produced in CHO cells. Biosimilar to Enbrel. inflammatory diseases
Lifmior (etanercept), r dimeric fusion protein consisting of TNF Pfizer Europe MA EEIG (Brussels) Rheumatoid arthritis, 2017 (EU)
receptor extracellular domains linked to an IgG1 Fc region, selected other inflammatory Withdrawn 2020
produced in CHO cells. Same product as Enbrel (see below). diseases
Zaltrap (aflibercept), combination drug comprising binding Sanofi (Paris) Metastatic colorectal 2013 (EU)
domains of VEGF receptors 1 and 2 fused to an IgG Fc, produced Sanofi-Aventis US (Bridgewater, cancer 2012 (US)
in CHO cells. Same active substance as in Eylea (see below). NJ, USA)
Eylea (aflibercept), fusion protein comprising extracellular Regeneron Pharmaceuticals Neovascular (wet) 2012 (EU)
ligand-binding domains of VEGF receptor fused to IgG Fc, (Tarrytown, NY, USA) age-related macular 2011 (US)
produced in CHO cells. Same active substance as in Zaltrap Bayer (Berlin) degeneration
(see above).
Nulojix (belatacept), fusion protein comprising extracellular Bristol-Myers Squibb (Dublin) Prophylaxis of organ 2011 (EU & US)
domain of human CTLA4 fused to IgG Fc, which binds CD80 rejection following kidney
and CD86 on antigen-presenting cells, thereby inhibiting T cell transplant
activation; produced in CHO cells.
Arcalyst (US), Rilonacept Regeneron (EU) (rilonacept), Regeneron Pharmaceuticals Cryopyrin-associated 2009 (EU)
dimeric fusion protein with each monomer consisting of the periodic syndromes (CAPS) 2008 (US)
ligand-binding domains of the human IL-1 receptor and IL-1 Withdrawn 2012 (EU)
receptor accessory protein along with the Fc region of human
IgG-1, produced in CHO cells.
Nplate (romiplostim), dimeric fusion protein with each monomer Amgen Europe Thrombocytopenia 2009 (EU)
consisting of two thrombopoietin RBDs and the Fc region of 2008 (US)
human IgG-1, produced in E. coli.
Orencia (abatacept), fusion protein that links the extracellular Bristol-Myers Squibb Rheumatoid arthritis 2007 (EU)
domain of human cytotoxic-T-lymphocyte-associated antigen-4 2005 (US)
with modified Fc region of IgG1, produced in a mammalian
cell line.
Amevive (alefacept), dimeric fusion protein comprising the Astellas Pharma (Deerfield, IL, USA) Moderate to severe chronic 2003 (US)
extracellular CD2-binding portion of human LFA-3 linked to the plaque psoriasis in adults Withdrawn 2011
Fc region of human IgG1, produced in CHO cells.
Enbrel (etanercept), r TNF receptor–IgG fragment fusion protein, Amgen (Thousand Oaks, CA) Rheumatoid arthritis 2000 (EU)
produced in CHO cells. Same product as Lifmior (see above). Pfizer (Brussels) 1998 (US)
Ontak (denileukin diftitox), r IL-2–diphtheria toxin fusion protein Eisai (Tokyo) Cutaneous T cell lymphoma 1999 (US)
that targets cells displaying a surface IL-2 receptor, produced Ligand Pharmaceuticals Discontinued 2014
in E. coli. (San Diego)
Gene-therapy and nucleic acid-based products (nucleic acid-based vaccines are included in the ‘Vaccine’ section)
Amvuttra (vutrisiran), a transthyretin-directed siRNA. Alnylam (Cambridge, MA, USA) Polyneuropathy 2022 (US)
of hereditary
transthyretin-mediated
amyloidosis

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1758

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Amondys 45 (casimersen), chemically synthesized PMO Sarepta Therapeutics Duchenne muscular 2021 (US)
antisense oligonucleotide. (Cambridge, MA, USA) dystrophy
Leqvio (inclisiran), chemically synthesized ds siRNA covalently Novartis (Dublin) Hypercholesterolemia, 2021 (US)
linked to a triantennary GalNAc, facilitating hepatocyte update. Novartis (East Hanover, NJ, USA) mixed dyslipidemia 2020 (EU)
Givlaari (givosiran), chemically synthesized, chemically Alnylam Netherlands Acute hepatic porphyria 2020 (EU)
modified ds siRNA conjugated to a triantennary GalNAc (Amsterdam) 2019 (US)
ligand to facilitate hepatic delivery. Silences aminolevulinate Alnylam (Cambridge, MA, USA)
hepatic synthase 1 (ALAS1) mRNA.
Oxlumo (Lumasiran), chemically synthesized ds siRNA Alnylam (Amsterdam) Primary hyperoxaluria 2020 (EU & US)
covalently linked to a triantennary GalNAc, facilitating Alnylam (Cambridge, MA, USA) type 1
hepatocyte update.
Viltepso (viltolarsen), chemically synthesized PMO antisense NS Pharma (Paramus, NJ, USA) Duchenne muscular 2020 (US)
oligonucleotide. dystrophy
Zolgensma (onasemnogene abeparvovec), nonreplicating Novartis Europharm (Dublin) Spinal muscular atrophy 2020 (EU)
adeno-associated vector housing the human survival motor Novartis Gene Therapies 2019 (US)
neuron gene (SMN1). (Bannockburn, IL, USA)
Viondys 53 (golodirsen), chemically synthesized PMO Sarepta Therapeutics Duchenne muscular 2019 (US)
antisense oligonucleotide. (Cambridge, MA, USA) dystrophy
Waylivra (volanesorsen), synthetic antisense PTO Akcea Therapeutics (Dublin) Familial chylomicronemia 2019 (EU)
oligonucleotide. syndrome
Luxturna (voretigene neparvovec-rzyl (US), voretigene Novartis (Dublin) Retinal dystrophy 2018 (EU)
neparvovec (EU)), a live, nonreplicating adeno-associated Spark Therapeutics 2017 (US)
virus genetically modified to express the human RPE65 gene. (Philadelphia)
Onpattro (patisiran), chemically synthesized, 21-nucleotide Alnylam (Amsterdam) Hereditary transthyretin 2018 (EU & US)
ds siRNA oligonucleotide, formulated as lipid nanoparticles. Alnylam Pharmaceuticals amyloidosis
(San Diego)
Tegsedi (inotersen), a 20-nucleotide ss oligonucleotide Akcea (Dublin) Hereditary transthyretin 2018 (EU & US)
manufactured by direct chemical synthesis. Ionis Pharmaceuticals (Carlsbad, amyloidosis
CA, USA)
Spinraza (nusinersen sodium), an 18-nucleotide antisense Biogen (Badhoevedorp, the Spinal muscular atrophy 2017 (EU)
oligonucleotide manufactured by direct chemical synthesis. Netherlands) 2016 (US)
Biogen (Cambridge, MA, USA)
Exondys 51 (eteplirsen), a chemically synthesized antisense Sarepta Therapeutics (Cambridge, Duchenne muscular 2016 (US)
oligonucleotide. MA, USA) dystrophy
Imlygic (talimogene laherparepvec), an engineered herpes Amgen Melanoma 2015 (EU & US)
simplex virus type 1 capable of producing GM-CSF.
Kynamro (mipomersen sodium), a chemically synthesized Kastle Therapeutics (Chicago) Familial 2013 (US)
antisense oligonucleotide. hypercholesterolemia Discontinued 2022
Glybera (alipogene tiparvovec), a human LPL gene housed in an uniQure (Amsterdam) Lipoprotein lipase 2012 (EU)
engineered adeno-associated virus 1 vector. deficiency Withdrawn 2017
Macugen (pegaptanib sodium injection), a synthetic PEGylated Eyetech (Palm Beach Gardens, Neovascular, age-related 2006 (EU)
oligonucleotide that specifically binds VEGF. FL, USA) macular degeneration 2004 (US)
PharmaSwiss (Prague) Withdrawn 2019
Vitravene (fomivirsen), an antisense oligonucleotide. Isis Pharmaceuticals (Carlsbad, Cytomegalovirus retinitis in 1999 (EU)
CA, USA) AIDS patients 1998 (US)
Novartis Ophthalmics Europe Withdrawn 2002 (EU),
(Farnborough, UK) 2005 (US)
Engineered cell-based
Breyanzi (lisocabtagene maraleucel), autologous, purified Bristol-Myers Squibb (Dublin) B cell lymphoma 2022 (EU)
CD8+ and CD4+ T cells, both engineered to encode an Bristol-Myers Squibb (Bothell, 2021 (US)
anti-CD19 CAR. WA, USA)
Carvykti (ciltacabtagene autoleucel), BCMA-directed Janssen Biotech (Raritan, Multiple myeloma 2022 (US)
genetically modified autologous T cell immunotherapy. NJ, USA)
Abecma (idecabtagene vicleucel), genetically modified Bristol-Myers Squibb (Dublin) Multiple myeloma 2021 (EU & US)
autologous T cells transduced with an anti-BCMA CAR Celgene (Summit, NJ, USA)
lentiviral vector. Bluebird Bio (Cambridge,
MA, USA)

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1759

Feature

Table 1 (continued) | Biopharmaceuticals approved in the United States and European Union through end of June 2022

Product Company (location) Therapeutic indication Date approved

Skysona (elivaldogene autotemcel), autologous CD34 -cell- +

Bluebird Bio (Utrecht, Early cerebral 2021 (EU)
enriched population containing hematopoietic stem cells the Netherlands) adrenoleukodystrophy Withdrawn 2021
transduced with a lentiviral vector (LVV) encoding ABCD1
cDNA for human adrenoleukodystrophy protein (ALDP).
Libmeldy (atidarsagene autotemcel), autologous CD34+ Orchard Therapeutic Metachromatic 2020 (EU)
hematopoietic stem and progenitor cells (HSPCs), transduced (Amsterdam) leukodystrophy
with a lentiviral vector housing the arylsulfatase A gene.
Tecartus (brexucabtagene autoleucel), autologous peripheral Kite Pharma (Amsterdam) Mantle cell lymphoma 2020 (EU & US)
blood T cells, CD4 and CD8 selected and CD3 and CD28 Kite Pharma (Santa Monica,
activated and transduced with retroviral vector expressing CA, USA)
anti-CD19 CD28/CD3ζ chimeric antigen receptor.
Zynteglo (betibeglogene autotemcel), autologous Bluebird Bio (Utrecht, the β-thalassemia 2019 (EU)
CD34+-cell-enriched population containing hematopoietic Netherlands) Withdrawn 2022
stem cells transduced with a lentiglobin lentiviral vector
encoding the β-A-T87Q-globin allele.
Kymriah (tisagenlecleucel), autologous T cells genetically Novartis (Dublin) Acute lymphoblastic 2018 (EU)
modified to encode an anti-CD19 CAR comprising a murine Novartis (East Hanover, NJ, USA) leukemia, large B cell 2017 (US)
single-chain antibody fragment (scFv) specific for CD19, lymphoma
followed by a CD8 hinge and transmembrane region fused
to the intracellular signaling domains for 4-1BB (CD137)
and CD3ζ.
Yescarta (axicabtagene ciloleucel), autologous T cells Kite Pharma (Amsterdam) Large B cell lymphoma 2018 (EU)
genetically modified to express a CAR comprising a murine Kite Pharma (Santa Monica, 2017 (US)
anti-CD19 single-chain variable fragment (scFv) linked to CA, USA)
CD28 and CD3ζ co-stimulatory domains.
Strimvelis, autologous CD34+ cells transduced with an Orchard Therapeutics (Amsterdam) Severe combined 2016 (EU)
engineered retroviral vector encoding the human adenosine immunodeficiency
deaminase sequence.
Zalmoxis, allogeneic T cells genetically modified to express MolMed (Milan) Hematopoietic stem 2016 (EU)
the herpes simplex thymidine kinase suicide gene and cell transplantation, Withdrawn 2019
a truncated form of the human low-affinity nerve growth graft-versus-host disease
factor receptor gene.
Data were collected from several sources (http://www.fda.gov/, https://www.ema.europa.eu/en). Products are listed consecutively from most recent approval in each class, with registrations
since 2018 in boldface and withdrawals and discontinuations in italics. r, recombinant; rh, recombinant human. ADC, antibody–drug conjugate; BHK, baby hamster kidney cell line; BMP,
bone morphogenetic protein; CAR, chimeric antigen receptor; CGRP, calcitonin gene-related peptide; CHO, Chinese hamster ovary cell line; CLL, chronic lymphocytic leukemia; ds,
double-stranded; EGF, epidermal growth factor; EPO, erythropoietin; FSH, follicle stimulating hormone; G-CSF, granulocyte colony-stimulating factor; GalNAc, N-acetylgalactosamine; GLP,
glucagon-like peptide; GM-CSF, granulocyte-macrophage colony stimulating factor; HBsAg, hepatitis B surface antigen; HEK, human embryo kidney cell line; HER2, human epidermal growth
factor receptor 2; hGH, human growth hormone; HPV, human papillomavirus; IFN, interferon; Ig, immunoglobulin; IGF, insulin-like growth factor; IL, interleukin; mAb, monoclonal antibody;
PEG, polyethylene glycol; PTH, parathyroid hormone; RBD, receptor-binding domain; siRNA, small interfering RNA; ss, single-stranded; TNF, tumor necrosis factor; tPA, tissue plasminogen
activator; VEGF, vascular endothelial growth factor.

nature biotechnology Volume 40 | December 2022 | 1722–1760 | 1760