The Pharmaceutical Industry in 2023: An Analysis of FDA Drug Approvals from the Perspective of Molecules
Beatriz G. de la Torre, Fernando Alberício
Research Article — Peer-Reviewed Source
Original research published by Torre et al. in Molecules. Redistributed under Open Access — see publisher for license terms. MedTech Research Group provides these references for informational purposes. We do not conduct original research. All studies are the work of their respective authors and institutions.
With the COVID-19 pandemic behind us, the U.S. Food and Drug Administration (FDA) has approved 55 new drugs in 2023, a figure consistent with the number authorized in the last five years (53 per year on average). Thus, 2023 marks the second-best yearly FDA harvest after 2018 (59 approvals) in all the series. Monoclonal antibodies (mAbs) continue to be the class of drugs with the most approvals, with an exceptional 12, a number that makes it the most outstanding year for this class. As in 2022, five proteins/enzymes have been approved in 2023. However, no antibody-drug conjugates (ADCs) have been released onto the market. With respect to TIDES (peptides and oligonucleotides), 2023 has proved a spectacular year, with a total of nine approvals, corresponding to five peptides and four oligonucleotides. Natural products continue to be the best source of inspiration for drug development, with 10 new products on the market. Three drugs in this year's harvest are pegylated, which may indicate the return of pegylation as a method to increase the half-lives of drugs after the withdrawal of peginesatide from the market in 2013. Following the trends in recent years, two bispecific drugs have been authorized in 2023. As in the preceding years, fluorine and/or N-aromatic heterocycles are present in most of the drugs. Herein, the 55 new drugs approved by the FDA in 2023 are analyzed exclusively on the basis of their chemical structure. They are classified as the following: biologics (antibodies, proteins/enzymes); TIDES (peptide and oligonucleotides); combined drugs; pegylated drugs; natural products; nitrogen aromatic heterocycles; fluorine-containing molecules; and other small molecules.
Abstract
With the COVID-19 pandemic behind us, the U.S. Food and Drug Administration (FDA) has approved 55 new drugs in 2023, a figure consistent with the number authorized in the last five years (53 per year on average). Thus, 2023 marks the second-best yearly FDA harvest after 2018 (59 approvals) in all the series. Monoclonal antibodies (mAbs) continue to be the class of drugs with the most approvals, with an exceptional 12, a number that makes it the most outstanding year for this class. As in 2022, five proteins/enzymes have been approved in 2023. However, no antibody–drug conjugates (ADCs) have been released onto the market. With respect to TIDES (peptides and oligonucleotides), 2023 has proved a spectacular year, with a total of nine approvals, corresponding to five peptides and four oligonucleotides. Natural products continue to be the best source of inspiration for drug development, with 10 new products on the market. Three drugs in this year’s harvest are pegylated, which may indicate the return of pegylation as a method to increase the half-lives of drugs after the withdrawal of peginesatide from the market in 2013. Following the trends in recent years, two bispecific drugs have been authorized in 2023. As in the preceding years, fluorine and/or N-aromatic heterocycles are present in most of the drugs. Herein, the 55 new drugs approved by the FDA in 2023 are analyzed exclusively on the basis of their chemical structure. They are classified as the following: biologics (antibodies, proteins/enzymes); TIDES (peptide and oligonucleotides); combined drugs; pegylated drugs; natural products; nitrogen aromatic heterocycles; fluorine-containing molecules; and other small molecules.
1. Analysis
A year ago, we embarked on a new “normality” after the COVID-19 pandemic. Fortunately, this year (2023), we can confirm a scenario in which the disease is being treated in many countries like other diseases such as flu, which also causes a large number of deaths worldwide every year. An important outcome of the pandemic has been the establishment of mRNA technology for the development of vaccines for other diseases, such as cancer. This progress, accompanied by the incipient rise of oligonucleotides as new chemical entity (NCE) drugs, may indicate that the pharmaceutical industry is entering a new era with respect to nucleotides. In 2023, 55 new drugs have been approved by the U.S. Food and Drug Administration (FDA) [ 1 ]. This is the second-highest number, after 59 approvals in 2018. This year’s figure responds to one of the questions raised last year from when we analyzed the 37 drugs authorized by the FDA in 2022 [ 2 ]. This relatively low number in comparison with previous years [59 drugs accepted in 2018, 48 in 2019, 53 in 2020, and 50 in 2021] could be considered a temporary glitch rather than a consequence of the COVID-19 pandemic. Indeed, the pharmaceutical industry has been reinforced by the pandemic, as shown by the large number of drugs approved and those in the pipeline. The 55 drugs approved this year are divided between 17 biologics (17, 10, 13, 14, and 15 in 2018, 2019, 2020, 2021, and 2022, respectively), 9 TIDES (5 peptides and 4 oligonucleotides in 2023 against 1 and 3 in 2018; 3 and 2 in 2019 and 2020; 8 and 2 in 2021; and 4 and 1 in 2022), and 29 so-called small molecules, in total 38 NCEs (TIDES and small molecules) ( Figure 1 ) [ 1 , 2 , 3 ]. In the distribution between biologics and NCEs, 2023 can be considered a standard year, with 17 biologics vs. an average of 14 in the last five years and 38 NCEs vs. an average of 36 in the same period. In 2023, biologics accounted for 30% of all drugs, while in the last five years, this figure was approximately 28% (69 biologics out of a total of 247 drugs) [ 2 ]. In addition, the Center for Biologics Evaluation and Research (CBER) has added 22 new Biologics License Application approvals in 2023, almost double those registered in 2021 (13) and 2022 (12) [ 4 ], including several vaccines for the respiratory syncytial virus, the chikungunya virus, and meningococcal groups A, B, C, W, and Y, among others. Herein, the 55 new drugs approved by the FDA in 2023 are analyzed exclusively based on their chemical structure. To keep a good flow of the manuscript, we have kept the number of references at a minimum. Further information can be obtained in ref. [ 1 ].
2. Discussion
Table 1 shows the 17 biologics approved in 2023, of which 12 are monoclonal antibodies (mAbs), which represents the best year for this kind of drugs, and 5 are enzymes/proteins ( Table 1 ). Regarding biologics, and following the trend of recent years, 2023 has seen the approval of two bispecific mAbs. These drugs can simultaneously bind to two distinct epitopes on one antigen or to two different antigens. In this regard, authorization was given to glofitamab-gxbm (Columvi TM ), a bispecific CD20-directed CD3 T-cell engager, and elranatamab (Elrexfio TM ), which targets BCMA (a protein on myeloma cells) and CD3 (a protein on the immune system’s T-cells). In 2022, three of the biologics approved showed bispecificity [teclistamab-cqyv (Tecvayli TM ), faricimab-svoa (Vabysmo TM ), and tebentafusp-tebn (Kimmtrak TM )], while only one was approved in 2021 [amivantamab-vmjw (Rybrevant TM )], 2018 [emicizumab (Hemlibra TM )], and 2014 [blinatumomab (Blincyto TM )]. Last year, we highlighted the controversy around aducanumab-avwa (Aduhelm TM ), which was approved in 2021 for the treatment of Alzheimer’s disease and whose effectiveness was under discussion. In 2023, lecanemab (Leqembi TM ) has been approved for the same target. This drug was developed by Biogen—the same company that manufactured aducanumab-avwa—in association with Eisai. mAbs continue to be the most approved drug class, accounting for 22% (12 vs. 55) of all the drugs accepted by the FDA this year. In 2022, these drugs accounted for 24% (9 vs. 37). As in former years, cancer is the first target for mAbs. However, following the trend of previous years, mAbs have been approved for other targets such as Alzheimer’s disease, psoriasis, respiratory syncytial virus, ulcerative colitis, and myasthenia gravis, thus enlarging the application of these kinds of challenging drugs. The streak has been broken in 2023 regarding the approval of antibody–drug conjugates (ADCs) as none have been authorized, a situation that contrasts with previous years, in which up to 14 such drugs were accepted by the FDA. This year, three enzyme replacement therapies have received the green light. Velmanase (Lamzede TM ) is the first such therapy approved for the treatment of non-central nervous system manifestations of α-mannosidosis. Pegunigalsidase alfa (Elfabrio TM ), which is a pegylated, crosslinked, chemically modified recombinant human α-galactosidase A enzyme, is indicated for the treatment of Fabry disease. Finally, cipaglucosidase alfa-atga (Pombiliti TM ) provides an exogenous source of α-glucosidase for the treatment of Pompe disease. TIDES (oligonucleotides and peptides), although they belong to the class of chemical entities, often show structural complexity similar to that of biologics. TIDES are chemically synthesized, and their characterization and the profile of impurities allowed by regulatory agencies are similar to what is required for small molecules, thereby making their introduction into the market a real challenge. In 2023, nine TIDES (five peptides and four oligonucleotides) have been approved, which account for 16% (9 vs. 55) of all the drugs authorized this year—almost the same proportion as in 2022 (15%) (5 vs. 37)—thus reinforcing the importance of these kinds of drugs. As is our custom in these yearly reports, we consider peptidomimetics with a high presence of amino acids or peptide bonds to be peptides. The last few years have witnessed a double trend in the peptides approved by the FDA and other regulatory agencies. On the one hand, authorization has been given to large linear peptides with more than 30 amino acids, whose best exponent was the approval of tirzepatide (Mounjaro TM ) in 2022 for the treatment of type 2 diabetes and obesity. On the other hand, cyclic peptides of medium size often contain non-proteinogenic amino acids. In both cases, pending units of fatty acids or/and polyethyleneglycol (PEG) structures are present to increase the drugs’ half-lives. In 2023, three cyclic peptides with these characteristics have been approved. Zilucoplan (Zilbrysq TM ) ( Figure 2 ) is recommended for the treatment of myasthenia gravis in adults who are anti-acetylcholine-receptor-antibody-positive. Zilucoplan binds to protein complement component 5 (C5) and inhibits its cleavage into two fragments. It is a side-chain-to-side-chain homodetic cyclic peptide with a main backbone of 15 amino acids, all of them in the L-configuration. The cyclic structure is at the N-terminal part between the side chains of the Lys and Asp residues. A Lys residue situated at the C-terminal part bears a side chain containing a large PEG and a fatty structure (palmitic acid) linked by a γ-Glu residue. The combination of fatty acids linked by a γ-Glu residue to extend the half-life of the molecule in vivo is present in other peptides, including liraglutide, semaglutide, and tirzepatide, all of which were approved in recent years. The backbone of zilucoplan contains several non
3. Conclusions and Perspectives
COVID-19 has been the main cornerstone of the last three reports of this series. Since the declaration of the COVID-19 pandemic, this is the first report in which the acronym COVID-19 appears tangentially. In 2023, it appears only in regard to Paxlovid TM , which contains nirmatrelvir and ritonavir as APIs and was officially approved by the FDA for the treatment of individuals at high risk of progressing to a severe disease status. In 2022, Paxlovid TM received only emergency authorization. An optimistic conclusion regarding COVID-19 is that it will remain with us but like regular flu, without posing a significant high risk for most of the population, who recover from the infection better if vaccinated. Several drugs approved in previous years, namely the peptides tirzepatide (Mounjaro TM and Zepbound TM ) and semaglutide (Ozempic TM , Rybelsus TM , Wegovy TM ), have been “trending topics” in 2023. While Mounjaro TM , Ozempic TM , and Rybelsus TM are for the treatment of diabetes, Zepbound TM and Wegovy TM are indicated for fighting the silent pandemic of obesity. Semaglutide has been called the “Hollywood drug” due to its popularity among movie stars. Indeed, widespread popularity has led to a lack of semaglutide for patients with diabetes. Zepbound TM and Wegovy TM cost approximately $US 300 per week, and it is thought that three years of treatment is needed [ 6 ]. We are sure that readers will raise moral and ethical questions in relation to this, the answers to which are beyond the purpose of this report. Related to these two drugs, several new drugs with similar targets are completing clinical phases and are expected to be approved in the coming months. Among them, we can cite retatrutide, which is the first triple agonist of GLP-1, GIP, and GCGR receptors (tirzepatide is a double agonist (GLP-1 and GIP) and semaglutide only a GLP-1 agonist), and mazdutide, pemvidutide, cagrilintide, and survodutide, among others. These kinds of drugs will undoubtedly continue to feature in future reports. Figure 19 shows a breakdown of the FDA approvals this year based on the chemical structure of the drugs. Overall, 2023 has been an extraordinary year in terms of the approval of new drugs (55), surpassed only by 2018, which saw the authorization of 59. The years 2018 and 2023 share the top position in the number of biologics (17) accepted. mAbs, with 12 approvals in 2023, continue again to be the most numerous class of drugs to receive the green light. Two years ago, we gave the honorific title of “2021 Drug of the Year” to aducanumab-avwa (Aduhelm TM ), which was the first therapy approved by the FDA to directly tackle the biology associated with Alzheimer’s disease. It has not been consolidated on the market due to doubts about its effectiveness. However, this year, the same company, Biogen, in association with Eisai, has launched lecanemab (Leqembi TM ), which has the same target. No ADC has been added to the list this year, thus stabilizing the number of these drugs available at 14. Once again, TIDES, with nine new drugs (five peptides and four oligos), continues to be an important class of drug. It is important to highlight nedosiran (Rivfloza TM ), which contains 58 nucleotides with intrinsic synthetic difficulty. The high number of oligonucleotides approved opens the door for more members of this class of drugs to reach the market in the coming years. Considering biologics and TIDES together, the total number of 26 drugs accounts for almost 50% of all drugs approved, to the detriment of the so-called small molecules, which a few years ago accounted for more than 80% of all drugs that reached the market. This year, three pegylated drugs have been approved: the enzyme pegunigalsidase alfa (Elfabrio TM ); the peptide zilucoplan (Zilbrysq TM ); and the oligonucleotide avacincaptad pegol (Izervay TM ). In 2022, only the peptide tirzepatide (Mounjaro TM ), containing two mini PEGs in its side chain, received authorization. In 2021, five approved drugs were pegylated. This year’s approvals could signify consolidation of the return of pegylated drugs after the withdrawal of peginesatide from the market in 2013. In 2022, four drugs showed bispecificity, and in 2023, two mAbs [glofitamab-gxbm (Columvi TM ) and elranatamab (Elrexfio TM )] reflect the increasing importance of this kind of drug. Since 2014, nine drugs with bispecificity have been approved. A similar trend is observed for combination drugs, with three approvals in 2023, a similar number to that of the two previous years (three in 2022 and four in 2021). Natural products, with 10 FDA approvals, continue to be a crucial source of inspiration for drug development. Four of these products belong to the steroid class, which is one of the most frequent on the market. The presence of N-aromatic-heterocycle- and F-based drugs continues to be a constant, and in many cases, both motives are present in the same molecule. Overall, a comparison of the drug authorizations
| DOI | 10.3390/molecules29030585 |
| PubMed ID | 38338330 |
| PMC ID | PMC10856271 |
| Journal | Molecules |
| Year | 2024 |
| Authors | Beatriz G. de la Torre, Fernando Alberício |
| License | Open Access — see publisher for license terms |
| Citations | 105 |