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.
The past few years will forever be remembered as the years of a pandemic, the likes of which had not been seen for a century. And biopharmaceuticals took a starring role, with both COVID-19 vaccines and therapeutics dominating the news for the speed with which they were developed and their impact on global health. Nonetheless, regulatory agencies in both the United States and EU maintained the fast pace of prior years in moving products through their pipelines. This article is the latest survey of biopharmaceutical approvals, which we conduct every four years. The current survey period (January 2018–June 2022) witnessed the approval of 197 biopharmaceutical products (see Box 1 for definition) in the United States and/or EU, when counted by product trade name. Some products contain identical active ingredients or are sold under different trade names in the two regions; taking this into account, 180 distinct biopharmaceutical active ingredients entered the market.
These new approvals bring the cumulative number of individual biopharmaceutical products (by trade name) licensed in these regions to 541, containing 435 distinct active biopharmaceutical ingredients. However, over the years, 98 products have been withdrawn from the market subsequent to approval in one or both regions, almost always for commercial reasons. Taking withdrawals into account, the number of individual biopharmaceutical products with current active licenses is estimated to be 443 (Table 1).
Annual approval numbers over the current survey period ranged from a low of 19 in Europe in 2019 to a high of 42, also in Europe, in 2018 (Fig. 1a). Annual approval rates were sustained or exceeded in both regions in 2020 and 2021, reflecting strong regulatory response, despite the unexpected burden on the agencies caused by the pandemic. Products approved over the current period include 97 monoclonal antibodies, 19 hormones, 16 nucleic acid/gene-therapy-based products and 16 vaccines (the latter two categories overlap as five of the (COVID-19) vaccines are nucleic acid based). Additional notable approval categories include colony-stimulating factors (CSFs; 12 products, all biosimilars), cell-based products (9), enzymes (8), fusion products (7) and clotting factors (6).
Here we list all biopharmaceuticals approved from January 2018 to June 2022, examining what types of product reached the US and EU markets as well as the indication for which they were approved. As in previous articles1,2,3,4, we have not included tissue-engineering products, which the US Food and Drug Administration (FDA) classifies as medical devices.
In a snapshot
As in previous survey periods, new approvals followed predictable lines. Cancer was by far the most common indication (50 products). Other common indications included inflammation-related conditions (15 products), neutropenia (12 products), COVID-19 (11 products) and diabetes (10 products). Additional indications, less commonly targeted by biopharmaceuticals, included ebolavirus (the vaccines Mvabea, Zabdeno and Ervebo and the therapeutics Ebanga and Inmazeb), anthrax (the inhalation therapeutic Obiltoxaximab SFL), weight control and weight loss (Wegovy) and Alzheimer’s disease (Aduhelm).
Of the 197 biopharmaceutical products approved within the survey timeframe, 90 (46%) were genuinely new to the market, with the remainder representing biosimilars, me-too products and products previously approved elsewhere. Those 90 new products (by trade name) contained a total of 85 distinct active biopharmaceutical ingredients (Table 2). Looking at each region separately, 121 products were licensed in the United States, of which 70 (58%) were genuinely novel; 144 products gained marketing Authorization in the EU, of which 65 (45%) were genuinely novel.
In the same period, US regulators approved in total 244 non-biological pharmaceutical products containing novel molecular (chemical and biopharmaceutical) entities (NME); thus, 29% (70/244) of all genuinely novel drug approvals in the US were biopharmaceuticals. This compares to 40% for the previous survey period and 21–26% in survey periods before 2014. EU reporting formats for pharmaceuticals preclude calculation of an analogous figure for Europe.
Comparing approvals over the current survey period to those in earlier periods or to cumulative approvals confirms some interesting, if predictable, trends.
Since 2015, the rise in biopharmaceutical approval rates has been sustained. Between 2015 and 2019, 178 products gained approval, approximately three times the historical five-year approval average (Fig. 1b). Moreover, a further 117 products were approved in just the past year and a half, from January 2020 to June 2022. Contributing to this was a substantial increase in the numbers of both biosimilar and ‘me-too’-type products (Table 2) gaining approval in recent years. Although the absolute number of genuinely new biopharmaceutical entities also continued to increase (74 for the 2014–2018 survey, 85 for the current 2018–2022 period), as a proportion of total biopharmaceutical approvals the number of novel biopharmaceuticals has decreased over this period, to 45% (85/189) as compared to the previous period’s 56%.
Monoclonal antibodies stay strong
Monoclonal antibodies (mAbs) remain dominant in overall approvals, representing 53.5% of all approvals in the past four years (Fig. 2a) They also remain the most prominent category of genuinely new biopharmaceuticals coming on the market, constituting 51% of all genuinely new products approved in this survey period (Table 2) compared to 49% in the previous survey period (2014–2018).
The importance of mAbs to biopharmaceutical sales remains evident (Fig. 2b); the percentage of the total market value contributed by mAbs grew steadily during this survey, although COVID-19 vaccine sales affected this trend. However, with these vaccine revenues excluded, mAbs still represented 80% of total protein-based global biopharmaceutical sales last year. Also notable is an increase in approval rates for biosimilars, as well as for nucleic acid-based products and gene-engineered cells (Table 1).
Mammalian cell systems continue to be the most often used expression system during this time period. Of the 159 approved products made by recombinant means in cell-based systems, most (107, or 67%) are produced in mammalian cells. Nonetheless, this reverses a trend seen over many decades, as it is lower than the percentage of mammalian-cell-produced biopharmaceuticals approved during the last survey period (84%; Fig. 3). The expression systems used are invariably dictated by the post-translational modification (PTM) requirements of the products. A large proportion of, in particular, biosimilar and ‘me-too’-type products approved over the current survey period (Table 2) do not require glycosylation or other mammalian PTMs, enabling their production in nonmammalian and less expensive systems, most commonly Escherichia coli. Interestingly, when focusing solely on the genuinely novel active biopharmaceutical ingredients approved in this current period, a different story emerges, with 85% of these products made in mammalian systems.
As in previous surveys, the most often used mammalian cell culture system remains Chinese hamster ovary (CHO cells), which were used to produce 95 of those 107 individual products made in mammalian systems (89%). This reflects the well-known strengths of this production platform, including the ability to produce antibodies at titers of 3–8 g/liter at production scale5. Other mammalian systems used included NS0 mouse myeloma cells (7 products), as well as baby hamster kidney (BHK), human embryonic kidney (HEK), sp2/0 mouse myeloma cells and PER C6 immortalized primary human embryonic retinal cells (1 product each). Moreover, a single new product (Sevenfact) is produced via transgenic means, in the milk of transgenic rabbits—only the second recombinant protein produced in this transgenic system. (Two existing products are also made in transgenic systems: Atryn, approved in 2009, in transgenic goats' milk and Kanuma, approved in 2015, in transgenic chicken eggs.)
Of the nonmammalian production platforms, E. coli continues to dominate, used in the production of 36 products approved since 2018, with smaller numbers of products produced in Pichia pastoris (5) and Saccharomyces cerevisiae (4). Also notable is the bacterium Pseudomonas fluorescens, used to recombinantly produce the active ingredient (teriparatide) of the biosimilar Livogiva/Qutavina, as well as the active constituent of Rylaze (asparaginase) and one component of the multicomponent vaccine Vaxneuvance. Historically, P. fluorescens was used to produce a single biopharmaceutical, Bonsity, a recombinant parathyroid hormone (PTH) initially approved in 1987. The yeast Hansenula polymorpha is also used to produce one product approved in the current period (Heplisav B, a recombinant hepatitis B surface antigen). It was also used to produce the recombinant hepatitis B surface antigen active pharmaceutical ingredient (API) found in Hexacima/Hexyon, initially approved in 2013.
As with past surveys, most products approved during the current survey period are administered parenterally. A small number are administered directly to their intended site of action via nonparenteral means, such as the oral recombinant cholera vaccine Vaxchora (Table 1). Rybelsus (semaglutide), for type 2 diabetes, represents an interesting exception: this acylated, 39-amino-acid polypeptide is administered orally in tablet form, a first for the biopharma sector. The tablet also contains a novel excipient (salcaprozate sodium) as an absorption enhancer. This facilitates uptake of semaglutide across the epithelium of the gastrointestinal tract, and hence into the bloodstream. A bioavailability of 1% was recorded in humans during clinical studies.
Another interesting approval with challenging delivery is the Alzheimer’s product Aduhelm. This human IgG1, directed against aggregated soluble and insoluble forms of amyloid-β in the brain (a defining pathophysiological feature of Alzheimer’s), was approved in 2021 by the FDA under its accelerated approval process. Clinical studies confirmed that intravenous infusion of Aduhelm results in a reduction of amyloid-β plaques, although a clear and unambiguous link between this effect and appreciable clinical improvement remains to be established. This, along with some safety concerns, led the European Medicines Agency (EMA) to refuse to recommend approval in Europe. That an intravenous infusion of Aduhelm reduces amyloid-β plaques in the brain suggests that sufficient quantities of the antibody cross the blood–brain barrier to have a physiological effect. This finding may benefit other mAb-based therapies in development for diseases of the brain.
The impact of COVID-19
Clearly, COVID-19 represents the most significant and challenging new global threat to human health during the period of this survey. Since the first reported cases in November 2019, 636 million confirmed cases and 6.6 million deaths have been reported globally to the WHO (updated statistics available at https://COVID19.who.int).
Development and deployment of effective COVID-19 vaccines and therapeutics occurred with unprecedented speed, thanks to industry action and regulatory agility. Regulators shifted resources toward COVID-19-related activities and provided rapid scientific advice, compliance checks and accelerated assessment and evaluation procedures to product developers. Rolling reviews (regulatory assessment as data came in, rather than as part of a final marketing application) proved particularly effective. Such agility notwithstanding, FDA approvals of COVID-19 products were made through an existing framework for authorizing new drugs in emergency circumstances—the Emergency Use Authorization pathway (which is not strictly an approval)—whereas the EMA expedited approvals using their pre-existing Conditional Marketing Authorisation procedure. As a result, by September 2022, the FDA and EMA had, between them, approved or authorized 22 different COVID-19 medicines (6 vaccines and 16 therapeutics), of which 16 are biopharmaceuticals, mainly vaccines and mAbs. Updated product lists are available on the dedicated COVID-19 pages of both regulators’ websites.
Vaccination has had the greatest single impact on pandemic amelioration. As of November 2022, the World Health Organization estimates that a total of 13 billion vaccine doses have been administered globally. Data from the CDC show that, for those over 50 years of age, full vaccination decreases the risk of death by 12-fold). Approaches to vaccine API development and manufacture vary; approved vaccines include mRNA-based vaccines (Comirnaty and Spikevax), inactivated and adjuvanted SARS-CoV-2 virus (Valneva), engineered adenovirus encoding the SARS-CoV-2 spike protein (Vaxzevria and Jcovden) and recombinant spike protein (Nuvaxovid). From a technological perspective, mRNA-based vaccines have the greatest novelty and are likely to pave the way toward additional mRNA vaccines for COVID and non-COVID indications (Box 2).
In the current survey period, the market value of biopharmaceuticals has continued to rise. Consolidated data from various La Merie (http://www.lamerie.com) and Fierce Pharma (http://www.fiercepharma.com) financial reports indicate that total global sales for 2021 reached US $343 billion (Table 3). Indeed this figure is likely an under-representation, as revenues for biosimilars in some regions have not been publicly reported. Recombinant originator proteins, both mAb and non-mAb, collectively account for a lion’s share of this value ($271 billion), representing an increase of 44% over the $188 billion reported for this product category in our last survey, for 2017.
COVID-19 vaccines had the largest impact upon the biopharmaceutical landscape in commercial as well as technological and medicinal terms, with Comirnaty and Spikevax cumulatively generating revenues of $54.5 billion in 2021 (Table 3). Comirnaty ($36.8 billion) has displaced the long-time best-selling biopharmaceutical Humira ($21.2 billion) as the top-selling biopharmaceutical product, with Spikevax ($17.7 billion) ranking third in 2021. Indeed, Humira’s pre-eminence in the global biopharmaceutical market is likely over. In addition to the advent of COVID-19 vaccines, its ‘patent wall’ has all but ended, and a number of biosimilar rivals are likely to stream onto the US market in particular in the next year or two. Whereas Comirnaty is poised to retain the top spot globally this year, it is difficult to forecast the market for COVID-19 vaccines in future years. Much will depend on factors such as the course of the pandemic, the future need for booster programs, the severity of evolving viral strains and future approvals of additional COVID-19 medicines, both prophylactic and therapeutic. The unpredictability of the COVID-19 therapeutics markets is illustrated by Regeneron’s anti-spike-protein mAb-based product Regen-Cov (Ronapreve). After initially gaining an Emergency Use Authorization in November 2020, Regen-Cov generated $7.6 billion in global sales in 2021, but its lack of effectiveness against newer viral variants caused the FDA to effectively pause its use in January 2022.
From a commercial perspective, revenues generated by biosimilar, nucleic acid (excluding COVID-19 mRNA vaccines) and engineered cell-based products remain relative modest. Collectively they generated an estimated $17.9 billion in 2021, representing some 5% of the total biopharmaceutical market, and less than sales of Humira alone. Of the 73 biopharmaceuticals recording blockbuster status (sales above $1 billion) last year, two were biosimilars (Erelzi and Mvasi, recording sales of $1.5 and $1.1 billion, respectively) and two were (non-COVID) nucleic acid/gene-therapy-based products (Spinraza and Zolgensma, with sales of $1.9 and $1.3 billion, respectively). mAb-based products (including Fc fusion products) continue to represent the most lucrative single product class. Their total sales reached $217 billion last year, and they represented 15 of the top 20 products by sales generated (Table 4). In terms of target indications, the vast majority of such antibody-based products target inflammatory and autoimmune conditions (cumulative 2021 sales of $99.3 billion) and cancer (2021 cumulative sales of $68.4 billion).
Although most classes of originator biopharmaceuticals continue to show strong year-on-year growth, a notable exception is that of originator ‘established therapeutic proteins’ (erythropoietins, interferons, CSFs, human growth hormone (hGH) and follicle-stimulating hormone (FSH)). Data from La Merie publishing shows that this product class generated total global revenues of $11.7 billion in 2021, down 14% compared with 2020 ($13.6 billion). This mirrors a longer-term trend, in which the sales value of this class of product has more than halved in the past decade (down from $26.6 billion in 2012) The underlying reasons for this decline include competition from biosimilars and the approval of additional therapeutics targeting the same indications.
Biosimilars hit the big time
The survey period witnessed a continued surge in biosimilar approvals, as this class of product gains global acceptance. When considered by product trade name, 94 biosimilars have gained approval in the EU and/or the United States since 2006, although 10 have been subsequently withdrawn for commercial reasons and not all are actively marketed as yet.
By product category, the 94 biosimilar approvals thus far include 2 hGHs, 5 erythropoietins (EPOs), 20 granulocyte CSFs (G-CSFs; filgrastim and PEGylated filgrastim), 2 FSHs, 9 engineered insulins, 51 antibody- or antibody-fusion-based products and 5 PTHs. The 94 licensed products are based on 72 distinct active ingredients (Table 5).
By region, 83 biosimilar products have received marketing Authorization in the EU, with 44 of these (53%) having gained Authorization within the current survey period. In the United States, a total of 37 products have thus far been licensed, of which 27 (73%) were approved within this survey period. The acceleration in biosimilar approval rates seen in our last survey is thus maintained in this one. Notable approval trends since 2018 include the approval of a raft of polyethylene glycol (PEG)-filgrastims (biosimilars to Neulasta; 2021 global sales of $2 billion), a number of engineered insulins and mAbs with biosimilarity to adalimumab (Humira; 2021 sales of $21 billion), trastuzumab (Herceptin; 2021 sales of $2.9 billion and bevacizumab (Avastin; 2021 sales of $3.3 billion).
Despite the large number of recent biosimilar approvals, both the revenues generated and the overall savings accrued to patients and healthcare systems remain relatively modest in both the EU and United States. A recent report by IQVIA6 prepared for the European Commission, estimates the total European biosimilars market to have reached €8.8 billion in 2021, amounting to savings of €5.7 billion (savings calculated as actual spend versus the pre-biosimilar cost of the originator, reference product).
Moreover, the report finds that biosimilars recently launched in Europe achieved 50% penetration of the originator market in less than a year, whereas earlier biosimilars typically took over two years to reach an equivalent position. Biosimilars approved in the EU are considered automatically interchangeable from a medical viewpoint, although decisions regarding actual substitution (dispensing one medicine instead of another medicine without consulting the prescriber) are made at individual EU member state level.
According to FDA data, generic drugs account for 90% of all prescriptions in the United States and provided savings of more than $1 trillion to the US health care system over a decade. The statistics for biosimilars are, predictably, more modest. The Pharmaceutical Research and Manufacturers of America (PhRMA; www.phrma.org) reported that annualized savings from biosimilars reached $6.5 billion in 2020, with average biosimilar sales prices being as much as 45% less than the branded biologics price at the time of first biosimilar launch.
US biosimilar approval and market penetration is influenced by regulatory, legal and developmental cost considerations. For example, biosimilar status in the United States does not automatically equate to interchangeability (and hence substitution for the reference product without the involvement of the prescriber). Interchangeable biosimilar products must meet additional regulatory requirements, as outlined by the Biologics Price Competition and Innovation Act. The US patent litigation landscape in this space can also slow or stop putative biosimilar products reaching the market. Additionally, a recent study found that most comparative efficacy trials supporting FDA biosimilar approvals were larger (median 504 patients), longer (median of 52 weeks) and more costly (estimated median cost of $20.8 million) than pivotal trials for new molecular entities7. As witnessed in Europe, however, more recent US biosimilars are achieving faster market uptake, with bevacizumab, trastuzumab and rituximab biosimilars achieving 42%, 38% and 20% uptake within their first year on the market, trending toward 60% by the end of year two.
Monoclonal antibodies continue to dominate both in approval numbers (in the case of both originator and biosimilar categories) and commercial value. All newly approved antibodies were engineered in some way: they are either humanized or fully human, and most were additionally engineered to enhance or stabilize specific functional and/or structural characteristics. Jemperli and Evkeeza, both IgG4 mAbs, reportedly tend to form half-antibodies. To prevent this, each heavy chain contains a serine-to-proline substitution in the hinge region of the Fc domain, which stabilizes disulfide bonds between the two heavy chains.
Skyrizi, a humanized IgG1, represents another example of engineering. Used to treat plaque psoriasis and psoriatic arthritis, it acts by selectively binding the p19 subunit of IL-23, thereby inhibiting the latter from binding to its receptor. The framework of the antibody was engineered with two mutations in the Fc region, Leu234Ala and Leu235Ala, to reduce its potential effector function, which does not contribute to the product’s mode of action. The C-terminal lysine of the heavy chain was also deleted to reduce potential charge heterogeneity.
The period also witnessed the approval of five glycoengineered (afucosylated or low-fucose) products: Uplizna, Rybrevant, Blenrep, Fasenra and Poteligeo. Removal of the fucose residue in the antibody’s Fc glycocomponent can increase antibody-dependent cellular cytotoxicity (ADCC), potentially boosting the potency of mAbs whose mode of action depends on this antibody effector function.
Additional engineered formats that came on stream include three bispecific full-size mAbs: Vabysmo, the above-mentioned Rybrevant and the bispecific T cell engager (BiTE) product Lunsumio. Cabilivi, a bivalent nanobody, also gained approval, the first approval of a domain fragment. Three antigen-binding fragments also entered the market: Byooviz, Susvimo and Beovu. All three target macular degeneration and are administered by intravitreal injection. The smaller size of antibody fragments enables delivery of a high molar dose to the limited volume of the eye’s vitreous body, which may enhance tissue penetration at the retina and prolong the therapeutic effect.
Six new antibody–drug conjugates (ADCs) were approved during the survey period (Padcef, Enhertu, Tivdak, Trodelvy, Zynlonta and Blenrep), joining five previously approved ADC products. ADCs consist of an antibody chemically conjugated to a cytotoxic payload. Antibody-mediated binding to the target cell is followed by internalization, with subsequent intracellular cytotoxin release and action. Advances in cytotoxin discovery and chemical linker design have fueled increasing numbers of ADCs coming on stream. Cumulatively, ADCs generated $5.4 billion in 2021, with two such products achieving blockbuster status (Kadcyla and Adcetris).
The migraine therapy Vyepti, a humanized anti-calcitonin-gene-related peptide (CGRP) IgG1 antibody, is the first antibody to be produced in P. pastoris. Following intravenous administration, it binds CGRP, preventing its binding to its receptors, which influence the initiation, frequency and severity of migraine attacks. The mAb’s heavy chain N-glycosylation site has been removed via protein engineering, which eliminates any potential immunogenicity issues in humans due to a yeast-derived glycocomponent. Although the lack of a glycocomponent prevents ADCC and complement-dependent cytotoxicity (CDC) effector functions, the product’s mode of action does not rely on such functionality.
The current period also witnessed the conditional approval and emergency Authorization of several mAb-based products to treat COVID-19. The efficacy of mAb-based preparations aimed at SARS-CoV-2 may be compromised by mutations affecting the viral spike protein, as illustrated by products such as bamlanivimab and eteseviman (which are administered together) and REGEN-COV. This year, the FDA restricted the use of both products due to the emergence of the Omicron variant.
Nucleic acid-based approvals
Two of the most technically innovative, medically impactful and commercially successful products coming on stream in this survey period fall into this category—the COVID-19 mRNA vaccines Spikevax and Comirnaty. An additional 12 nucleic acid-based products were approved, adding substantially to the seven such products previously approved (Table 1). The new approvals include five small interfering RNA (siRNA)-based products (Amvuttra, Leqvio, Givlaari, Oxlumo and Onpattro), five antisense-based products (Amondys 45, Viltepso, Viondys 53, Waylivra and Tegsedi) and two gene therapy products (Zolgensma and Luxturna), which deliver therapeutic genes in adeno-associated viral vectors. Although 12 approvals signal progress in this field, almost all are orphan products and undergoing additional monitoring.
siRNA, antisense RNA and gene therapies therefore have as yet to make a broad impact on the mainstream biopharma market, particularly in regard to sales value. These modalities may benefit from lessons learned during the development of COVID-19 mRNA vaccines, but they face steeper technical challenges. mRNA vaccines capitalize on the massive amplification provided by the immune system—small doses administered intramuscularly and taken up by local antigen-presenting cells lead to a system-wide adaptive immune response (Box 2). In contrast, most non-vaccine nucleic acid products require substantially higher dosages, systemic administration, delivery to a specific tissue, prolonged therapeutic action and, in many cases, a non-immunogenic profile that allows chronic administration. These additional technical hurdles remain largely unresolved.
Engineered cell-based approvals
New cell-based therapies flooded into the market during this survey period, with nine such products gaining approval in the EU and/or United States. Previously there were but two. The majority of the new approvals (six products) are based on CAR-T cells, indicated for the treatment of blood-borne malignancies (multiple myeloma, leukemia and, in particular, lymphoma).
Many tumors manage to evade immune surveillance by downregulating the expression of major histocompatibility antigen class I (MHC-I) molecules. This prevents MHC-I-mediated presentation of tumor-specific peptides on the cancer cell surface and recognition of the MHC-I–peptide complex by cytolytic T lymphocytes via their T cell receptors (TCRs), which triggers cancer cell destruction by activated T cells.
CAR-T cells harness cancer-killing T cells independent of the MHC–TCR pathway. The CAR-T cell approach is now arguably the leading technology in this regard, surpassing alternatives such as T-cell-directed bispecific antibodies. CAR-T cells are genetically engineered to express on their surface a chimeric antigen receptor (CAR) that fuses an extracellular antibody fragment (usually a single-chain variable fragment, or scFv) specific for the target tumor surface antigen to intracellular T-cell-activating domains. CAR-T cell therapies are autologous, requiring isolation of a patient’s T lymphocytes via leukapheresis and ex vivo engineering of the cells to express the CAR. The engineered T cells are expanded in cell culture and cryopreserved until infused back into the patient.
CAR-T cell therapies have proven most effective against B cell cancers, whereas their extension to solid tumors remains challenging. Initial efficacy can be followed by cancer recurrence arising from tumor evolution. The approach can also present safety concerns, particularly cytokine release syndrome. The autologous nature of CAR-T cell therapy is inherently costly, with treatment list prices typically in the region of $400,000–$500,000.
Genetically engineered cell-based products have also been developed for non-cancer indications. One example is Zynteglo, a hematopoietic-stem-cell-based gene therapy approved in the EU in 2019 as an orphan product for the treatment of transfusion-dependent β-thalassemia. Zynteglo consists of autologous hematopoietic stem cells transduced with a functional β-globin gene. After infusion, the engineered cells repopulate the hematopoietic compartment, with clinical studies reporting ongoing expression of the β-globin gene 36 months after treatment. However, for commercial reasons, the sponsor company, Bluebird Bio, informed the EMA earlier this year of its intention to withdraw the product from the market. The treatment cost was in the region of €1.5 million per patient. In a further twist, the FDA approved Zynteglo in August of this year, reportedly with an associated price tag of $2.8 million per patient.
Traditional biotech product approvals
The current survey period also witnessed the approval of 37 traditional biotech products classified as new by regulatory authorities in terms of active substance—nine fewer than in our previous survey. Traditional products refer to those produced naturally or via nonrecombinant means in or by a biological source. The profile of approvals (Supplementary Table 1) largely mirrors product types approved in previous surveys, and include a range of blood-derived products and natural extracts, as well as traditional (nonrecombinant) vaccines and un-engineered cells.
Although estimates vary, data published by PhRMA indicate that there are more than 7,800 biopharmaceutical products in clinical development globally, of which over 1,000 have reached phase 3 trials. Cancer remains by far the single most common indication, with other common target indications including genetic disorders, cardiovascular disease, as well as neurological, eye and blood disorders—all leading causes of mortality or morbidity, particularly in the West. Almost a third of products in clinical development (2,533) are mAb based, maintaining these as the single largest experimental product class. Smaller but still notable numbers of gene-modified cell therapies (348) and nucleic acid- and gene-based therapies (546) are currently being assessed in the clinic. On the whole, therefore, the industry retains a strong experimental product pipeline. Data from Evaluate Pharma indicates that total global biotech products sales continue to steadily increase as a percentage of overall global pharmaceutical sales, growing from 18% in 2010 to over 30% currently.
There are more than 100 (non-COVID-19) mAb-based products currently in late-stage clinical development. Antibody approvals over the next several years will likely mirror the profile of this antibody cohort. Some 60 of these experimental mAbs target cancer. Although 18 target liquid malignancies, the majority target a range of solid tumor types including ovarian, prostate, melanoma, breast, small-cell lung cancer and renal cancer. Almost a third (18 products) are bispecific, and one-fifth (12 products) are antibody conjugates. The remaining 54 non-cancer mAbs target a wide range of conditions; almost all are human or humanized monospecific products. In addition to this cohort of experimental products, over a dozen anti-COVID-19 mAbs remain in clinical studies, although the impact of these products will ultimately depend upon their efficacy against current and future SARS-CoV-2 variants.
Earlier stages in the mAb developmental pipeline display a greater diversity of antibody formats (ADCs, bispecific and fragments) and a larger proportion of products targeting solid as opposed to hematological malignancies. For example, 80% of ADCs in oncology clinical trials target solid tumor types8. Solid tumors were the most common global causes of cancer death in 2020 according to the WHO, including lung (1.80 million deaths), colon and rectum (916,000 deaths), liver (830,000 deaths), stomach (769,000 deaths) and breast (685.000 deaths).
Nucleic acid and engineered cell-based therapies continue to represent a vibrant and growing sector of experimental as well as approved biopharmaceuticals. Recent validation by COVID-19 is providing particular impetus to the field of mRNA vaccines, and advances in CAR-T-cell-based therapeutic approaches will continue to drive the developmental pipeline in this field, particularly against solid tumors. Although only two gene therapy products based upon viral delivery were approved in the current survey period (Zolgensma and Luxturna), several such products are showing success in clinical trials. Indeed, one additional such product (BioMarin’s hemophilia A product Roctavian) has recently gained approval in Europe, and a biological license application (BLA) is currently being considered by the FDA. Roctavian’s active substance, valoctocogene roxaparvovec, comprises a nonreplicating recombinant adeno-associated viral vector housing a functional human factor VIII cDNA under the control of a liver-specific promoter. Clinical studies show that increased factor VIII expression was sustained for (so far) at least two years, with the need for additional factor VIII replacement treatment dropping by 97.5%. Reports from industry sources indicate that Biomarin anticipates Roctavian’s list price in Europe to be on the order of €1.5 million euros, net of all discounts.
Biosimilars will also continue to feature with increasing prominence on the biopharmaceutical landscape. Various US-facing reports indicate that almost 100 biosimilars targeting the American market are in clinical development and that cumulative sales of biosimilars over the next five years could total $80 billion. A recent report by Allied Market Research forecasts the global biosimilars market to reach as much as $143 billion by 2031, fuelled by sales of biosimilar mAbs, CSFs, EPO, insulins and hGH. Forecasts can vary, however. A report from Research & Markets predicts that global biosimilar sales will reach $88 billion by 2030, whereas Global Market Insights put the value at $100 billion.
COVID-19 is likely to feature on the biopharmaceutical landscape over the foreseeable future. mRNA and other vaccines are expected to require updating to match novel SARS-CoV-2 variants. Tracking data maintained by the WHO estimates there are currently 172 Covid vaccines in clinical development globally, of which 55 (32%) are protein subunit based, 40 (23%) are RNA based, and 23 (13%) are (nonreplicating) viral vector based.
The biopharmaceutical sector’s impressive response to the global COVID-19 pandemic is likely to inform and accelerate broader innovation in the sector, particularly within the vaccine space. Finally, regulatory experience accrued in the last survey period should accelerate the speed of the drug development and approval processes for future medicines.
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Walsh, G., Walsh, E. Biopharmaceutical benchmarks 2022. Nat Biotechnol 40, 1722–1760 (2022). https://doi.org/10.1038/s41587-022-01582-x
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