Global first-in-class drugs approved in 2023-2024: Breakthroughs and insights.

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Introduction

A key focus of drug discovery research is first-in-class (FIC) drug approvals. FIC drugs are defined by the US Food and Drug Administration (FDA) as newly approved drugs with a new mechanism of action different from existing therapies with novel targets and mechanisms or drugs providing the first treatment option for an unmet medical need. 1 Successful FIC drugs are often revolutionary, not only providing substantial financial rewards but also revealing new areas for drug discovery research. 2 , 3 In 2024, the FIC drug zolbetuximab-clzb (Vyloy), a monoclonal antibody that targets the claudin 18 isoform 2, was approved. 4 , 5 The approval of the drug also validated the feasibility of claudin 18.2-targeted therapy and facilitated the development of drugs that act on this target, such as bispecific antibodies and antibody-drug conjugates (ADCs). 6 Research and development (R&D) of FIC drugs is challenging, time consuming, resource intensive, and high risk. 7 , 8 Generally, FIC drugs must act on novel target candidates, and then drug molecules must be rationally designed to achieve therapeutic effects on a specific disease, making the discovery and validation of new targets extremely important. 9 Clinical data or biological studies typically drive this R&D process. 10 In this respect, the discovery of new targets is the rate-limiting step in FIC drug discovery. 11 Moreover, the target validation process of FIC drugs is carried out throughout the drug development process, from the preliminary laboratory research stage to postmarketing applications, to continually assess the safety and efficacy of the drugs and the connection of the new targets with diseases. 12 Another challenge is the design of drug candidates for these new targets, which at least involves discovery, optimization, and validation processes that typically take years. 13 Understanding the relationships among molecules, targets, and diseases is key to developing FIC drugs. Therefore, previously reported FIC drugs represent a valuable resource for guiding future drug design.

In 2023 and 2024, tremendous progress was made in terms of the number of marketed drugs, reflecting an increasing understanding of biological mechanisms and disease pathogenesis. We collected new drug approvals from four official drug administrations worldwide, including China’s National Medical Products Administration (NMPA), the FDA, Japan’s Pharmaceuticals and Medical Devices Agency (PMDA), and the European Medicines Agency (EMA) of the European Union (EU). We subsequently screened novel drugs (drugs approved for the first time in a subject area) among the approved drugs on the basis of the definition from the FDA. 14 According to our statistics, 1,035 drugs entered the market from January 2023 to October 2024, and 337 novel drugs out of those 1,035 drugs received approval from the four official drug authorities. Eighty-one FIC drugs stood out from the 337 novel drugs because of their new mechanisms of action or new targets. In this review, we focus on the analysis of FIC drugs, including FIC small-molecule drugs, FIC macromolecular drugs, and their indications and disease targets. We list FIC drugs representing outstanding innovations and clinical significance and explain their mechanisms and indications. In addition, we discuss the trend of FIC drug R&D and provide suggestions for future FIC drug design.

FIC drug discovery drives new drug approvals

Considering that FIC drugs have new mechanisms or targets, their functional role is crucial for their pioneering status and leading position in their class. 15 Therefore, novel drugs with enhanced efficacy have the potential to be developed with further medical R&D on FIC targets and mechanisms. 7 Unmet clinical needs and the expectation of personalized medications have driven research on FIC drugs with better efficacy and safety in recent years. 1 In terms of drug approvals in 2023 and 2024, the distribution of novel drugs differed worldwide, as shown in Figure 1 . According to our statistics, 1,035 new drugs were approved from January 2023 to October 2024. A total of 426 drugs were novel drugs. As some novel drugs were approved in more than one place, the actual number of novel drugs was 337, including 81 FIC drugs (24.0%) ( Figure 1 A; Table 1 ). 3 , 16 , 17 Figure 1 The number and percentage of novel drugs, FIC drugs, and other drugs approved globally (A) Overview of novel drugs, FIC drugs, and modified/hybrid/generic/biosimilar drugs. As some novel drugs were approved in more than one place, the actual number of novel drugs was 337, not 426. (B) The numbers and percentages of novel drugs and modified/hybrid/generic/biosimilar drugs and the number of FIC drugs. In China, approved drugs are classified as novel drugs, modified drugs, or first generic drugs. In the US, approved drugs are classified as novel drugs, first generic drugs, biosimilar drugs, and modified drugs. In Japan, approved drugs are mainly classified as novel drugs, biosimilar drugs, and modified drugs. In the EU, approved drugs are classified as novel drugs, new indication drugs, generic drugs, biosimilar drugs, hybrid drugs, and other drugs. The green, blue, cyan, and orange colors correspond to drugs approved by China, the US, Japan, and the EU, respectively. Table 1 Global first-in-class drugs approved in January 2023–October 2024 Number Drug Category Disease Target/mechanism 1 daprodustat small molecule anemia caused by chronic kidney disease (CKD) for adults on dialysis hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor 2 nitisinone small molecule hepatorenal tyrosinemia (HT-1) 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor 3 sparsentan small molecule proteinuria in primary IgA nephropathy endothelin type A receptor (ETAR) and angiotensin II (Ang II) type 1 receptor (AT1R) antagonist 4 omaveloxolone small molecule Friedrich’s ataxia mechanism unknown, nuclear factor erythroid 2-related factor 2 (NRF2) activator, Kelch-like ECH-associated protein 1 (KEAP1) inhibitor 5 glumetinib small molecule non-small cell lung cancer (NSCLC) c-mesenchymal-to-epithelial transition (c-MET) inhibitor 6 trofinetide small molecule Rett syndrome mechanism unknown 7 leritrelvir small molecule COVID-19 SARS-CoV-2 3CLpro inhibitor 8 leniolisib small molecule activated PI3Kδ syndrome phosphoinositide 3-kinase δ (PI3Kδ) inhibitor 9 deucravacitinib small molecule psoriasis tyrosine kinase 2 (TYK2) inhibitor 10 fezolinetant small molecule hot flashes caused by menopause neurokinin 3 receptor (NK3R) antagonist 11 perfluorohexyloctane small molecule dry eye disease interact with the air-liquid interface of the tear film 12 nirmatrelvir, ritonavir small molecule mild to moderate COVID-19 SARS-CoV-2 main protease inhibitor 13 anaprazole small molecule duodenal ulcer H + /K + ATPase inhibitor 14 futibatinib small molecule unresectable FGFR2 fusion gene-positive biliary tract cancer fibroblast growth factor receptor (FGFR) inhibitor 15 mavacamten small molecule obstructive hypertrophic cardiomyopathy myosin inhibitor 16 carglumic acid small molecule hyperammonemia N-acetylglutamate synthase (NAGS) allosteric modulator 17 lotilaner small molecule demodex blepharitis γ-aminobutyric acid (GABA)-gated chloride channels (GABACl) putative antagonist 18 ganaxolone small molecule epileptic seizures GABA receptor-positive allosteric modulator 19 belumosudil small molecule chronic graft versus host disease (cGVHD) rho kinase type 1/2 (ROCK1/2) inhibitor 20 palovarotene small molecule fibrodysplasia ossificans progressiva retinoic acid receptor-γ (RAR-γ) agonist 21 ritlecitinib small molecule alopecia areata Janus kinase 3 (JAK3) inhibitor; Tyrosine kinase expressed in hepatocellular carcinoma (TEC) inhibitor 22 taurolidine, heparin small molecule incidence of catheter-related bloodstream infections thiadiazinane antimicrobial plus an anticoagulant 23 capivasertib small molecule breast cancer AKT kinase inhibitor 24 nirogacestat small molecule desmoid tumors γ-secretase inhibitor 25 iptacopan small molecule paroxysmal nocturnal hemoglobinuria complement factor B inhibitor 26 birch triterpenes small molecule epidermolysis bullosa mechanism unknown 27 maribavir small molecule post-transplant cytomegalovirus (CMV) infection human CMV pUL97 viral protein kinase inhibitor 28 berdazimer small molecule molluscum contagiosum mechanism of action unknown 29 lonafarnib small molecule Hutchinson-Gilford progeria syndrome and processing-deficient progeroid laminopathies farnesyl transferase (FTase) inhibitor 30 rimegepant small molecule acute and preventive migraine calcitonin gene-related peptide receptor (CGRPR) antagonist 31 aprocitentan small molecule hypertension endothelin A (ET A ) and endothelin B (ET B ) receptors antagonists 32 danicopan small molecule extravascular hemolysis with paroxysmal nocturnal hemoglobinuria complement factor D inhibitor 33 imetelstat small molecule low- to intermediate-1 risk myelodysplastic syndromes oligonucleotide human telomerase inhibitor 34 elafibranor small molecule primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid peroxisome proliferator-activated receptor (PPAR) agonist 35 golidocitinib small molecule relapsed or refractory peripheral T cell lymphoma JAK1 inhibitor 36 tapinarof small molecule atopic dermatitis and psoriasis aryl hydrocarbon receptor-modulating agent 37 ensifentrine small molecule chronic obstructive pulmonary disease (COPD) phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) inhibitors 38 vorasidenib small molecule grade 2 astrocytoma or oligodendroglioma isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) inhibitors 39 flortaucipir (18F) small molecule diagnostic radiopharmaceutical for the central nervous system aggregated tau protein modulator 40 delgocitinib small molecule moderate to severe chronic hand eczema Janus kinase inhibitor 41 arimoclomol small molecule Niemann-Pick disease type C HSP70 co-inducer 42 xanomeline and trospium chloride small molecule schizophrenia M1/M4 muscarinic acetylcholine receptor modulator 43 velmanase alfa macromolecule non-CNS manifestations of α-mannosidosis replace natural α-mannosidase 44 Fc-vwf-xten fusion protein macromolecule hemophilia A recombinant antihemophilic factor 45 tofersen macromolecule amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 ( SOD1 ALS) SOD1 antisense oligonucleotide 46 respiratory syncytial virus vaccine, adjuvanted macromolecule lower respiratory tract disease caused by respiratory syncytial virus stabilized prefusion F subunit vaccine 47 zuberitamab macromolecule diffuse large B cell lymphoma CD20 inhibitor 48 beremagene geperpavec-svdt macromolecule wounds in patients 6 months of age and older with dystrophic epidermolysis bullosa with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene HSV-based gene therapy with COL7A1 transgene 49 delandistrogene moxeparvovec-rokl macromolecule Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene AAV-based gene therapy with a micro-dystrophin transgene 50 donislecel macromolecule type 1 diabetes allogeneic pancreatic islets 51 valoctocogene roxaparvovec-rvox macromolecule severe hemophilia A AAV-based gene therapy with modified factor VIII transgene 52 pegmolesatide macromolecule anemia caused by chronic kidney disease (dialysis patient) erythropoietin receptor (EpoR) agonist 53 talquetamab macromolecule multiple myeloma GPRC5DxCD3 T cell engager 54 pozelimab macromolecule CHAPLE disease C5 antibody 55 respiratory syncytial virus vaccine, adjuvanted macromolecule lower respiratory tract disease caused by respiratory syncytial virus bivalent stabilized prefusion F subunit vaccine 56 erenumab macromolecule migraine CGRP antagonist 57 nedosiran macromolecule primary hyperoxaluria type 1 LDHA antisense oligonucleotide 58 anakinra macromolecule familial Mediterranean fever interleukin-1 receptor 1 (IL1R1) antagonist 59 aponermin macromolecule multiple myeloma DR4 and DR5 activator 60 chikungunya vaccine, live macromolecule disease caused by chikungunya virus live, attenuated chikungunya virus vaccine 61 ADAMTS13, recombinant-krhn macromolecule congenital thrombotic thrombocytopenic purpura (cTTP) recombinant ADAMTS13 62 exagamglogene autotemcel macromolecule sickle cell disease (SCD) CRISPR-Cas9-based BCL11a-gene editing therapy 63 lovotibeglogene autotemcel macromolecule SCD and a history of vaso-occlusive events (VOEs) lentivirus-based gene therapy with HbAT87Q transgene 64 faricimab macromolecule diabetic macular edema angiopoietin-2 (ANGP2) and vascular endothelial growth factor A (VEGFA) antagonist 65 luspatercept macromolecule anemia associated with myelodysplastic syndrome transforming growth factor-β (TGF-β) superfamily inhibitor 66 evinacumab macromolecule homozygous familial hypercholesterolemia angiopoietin-like protein 3 (ANGPTL3) inhibitor 67 lifileucel macromolecule unresectable or metastatic melanoma autologous tumor-infiltrating lymphocytes (TILSs) 68 atidarsagene autotemcel macromolecule pre-symptomatic late infantile (PSLI), pre-symptomatic early juvenile (PSEJ), or early symptomatic early juvenile (ESEJ) metachromatic leukodystrophy (MLD) human arylsulfatase A mRNA gene replacement 69 sotatercept-csrk macromolecule pulmonary arterial hypertension activin signaling inhibitor that binds to activin A and other TGF-β superfamily ligands 70 nogapendekin alfa inbakicept macromolecule bladder cancer IL-15 receptor agonist 71 mavorixafor macromolecule WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis) CXC chemokine receptor 4 (CXCR4) antagonist 72 tarlatamab-dlle macromolecule extensive stage small cell lung cancer bispecific delta-like ligand 3 (DLL3)-directed CD2 T cell engager 73 ivonescimab macromolecule EGFR mutation-positive locally advanced or metastatic non-squamous NSCLC VEGF-A and PD-1 antibody 74 cetuximab macromolecule RAS/BRAF wild-type metastatic colorectal cancer (mCRC) EGFR antibody 75 afamitresgene autoleucel macromolecule unresectable or metastatic synovial sarcoma genetically modified autologous T cell immunotherapy 76 axatilimab-csfr macromolecule cGVHD colony-stimulating factor 1 receptor (CSF-1R) inhibitor 77 seladelpar macromolecule PBC PPAR-delta agonist 78 amivantamab macromolecule incurable relapsed NSCLC EGFR and MET receptor antibody 79 sacituzumab govitecan macromolecule hormone receptor-negative and HER2-negative surgically incurable or relapsed breast cancer anti-trophoblast cell surface antigen 2 (TROP2) monoclonal antibody, DNA topoisomerase 1 inhibitor 80 marstacimab-hncq macromolecule bleeding episodes related to hemophilia A or B anti-tissue factor pathway inhibitor 81 zolbetuximab-clzb macromolecule gastric or gastroesophageal junction (GEJ) adenocarcinoma claudin 18.2 antibody

In the US, on the basis of the New Drug Therapy Approvals 2023 (Novel Drug Approvals for 2023 | FDA), New Drug Therapy Approvals 2024 (Novel Drug Approvals for 2024), and 2023 First Generic Drug Approvals (2023 First Generic Drug Approvals | FDA) reports, the total number of FDA-approved drugs was 315, including 117 novel drugs (37.1%) and 198 modified/generic/biosimilar drugs (62.9%). Among the 117 novel drugs, 18 93 received approval from the Center for Drug Evaluation and Research (CDER) of the FDA. The FDA’s Center for Biologic Evaluation and Research (CBER) also approved 24 novel therapeutic products. Among the 117 novel drugs, 51 FIC drugs were approved by the FDA ( Figure 1 B). The approval of 117 novel drugs and 51 FIC drugs demonstrated great achievements in the US medical industry in 2023 and 2024. The NMPA in China approved 352 drugs, including 151 (42.9%) novel drugs, 53 (15.1%) 2024 first generic drugs, and 148 (42.0%) modified drugs. 16 A total of 22 FIC drugs were approved by the NMPA ( Figure 1 B). On the basis of the high quantity and improved quality of drug approvals, advancements in the pharmaceutical industry in China were remarkable in 2023 and 2024. In Japan, the PMDA approved 223 drugs, including 78 novel drugs (35.0%) with 16 FIC drugs, 142 modified drugs (63.7%), and three biosimilar drugs (1.3%) ( Figure 1 B). Most approvals were for drugs administered at new doses (49.8%). In the EU, the EMA approved more novel drugs (80 drugs with 19 FIC drugs, 55.2%; Figure 1 B) than generic/hybrid/other drugs (65 drugs, 44.8%).

Original innovation research drives the advancement of small-molecule FIC drugs

Small-molecule drugs with low molecular weights have particular advantages 19 in terms of target affinity and selectivity, 20 pharmacokinetic (PK) properties, 21 patient compliance, 21 etc. According to their sources, small-molecule drugs can be categorized into synthetic small-molecule drugs, natural products/derivatives, endogenous substances/derivatives, nucleoside/amino acid/glucose derivatives, etc. In 2023 and 2024, 173 novel small-molecule drugs were approved, and 42 FIC drugs were FIC small-molecule drugs. The chemical structures of 42 FIC small-molecule drugs are shown in Figure 3 . The largest proportion of novel small-molecule drugs and FIC drugs is synthetic small-molecule drugs (76.4%), which are artificially designed and synthesized. Natural products (6.3%) or endogenous substances (8.6%) are also significant sources for FIC drug R&D. Small monomers of some biological macromolecules (8.6%) contribute to the development of two FIC small-molecule drugs, including derivatives such as glucose, amino acids, and nucleosides ( Figure 2 ). On the basis of statistics, most drugs are discovered via rational drug design and molecular screening. Figure 2 The percentages and classifications of novel small-molecule drugs and FIC small-molecule drugs The doughnut plot shows the percentages and classifications of novel small-molecule drugs. Pie charts with different radii show the percentages and classifications of FIC small-molecule drugs. Small-molecule drugs include mainly synthetic small-molecule drugs, endogenous substances/derivatives, nucleoside/amino acid/glucose derivatives, and natural products/derivatives.

Among 42 FIC small-molecule drugs ( Figure 3 ), iptacopan (Fabhalta) in the indole drug class is an FIC complement factor B inhibitor 22 and the first oral monotherapy 23 approved for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH). In the treatment of PNH, C5 inhibitors, such as eculizumab and ravulizumab, represent an advanced treatment strategy that is limited by the incomplete response of patients to eculizumab due to an insufficient bone marrow erythropoietic response, residual intravascular hemolysis, and recurrent extravascular hemolysis (EVH). 24 Iptacopan, a proximal complement pathway inhibitor, has demonstrated significant efficacy in both intravascular hemolysis mediated by C3b and EVH mediated by the terminal complement pathway. 25 Compared with previous treatments, such as eculizumab or ravulizumab (intravenous injection) and pegcetacoplan (subcutaneous injection), this drug overcomes the challenge of persistent hemolytic anemia in patients with PNH and provides an oral treatment option. 22 It is also more affordable than some anti-C5 treatment regimens, 25 which relieves the economic burden on patients. The FIC factor D inhibitor danicopan (Voydeya) was approved in 2024 and is indicated for the same disease as iptacopan. Notably, factor D is upstream of iptacopan’s target, factor B. 26 Unlike iptacopan, danicopan is an aminopyridine derivative 27 that is used as an add-on therapy to C5-targeted antibodies for EVH in adults with PNH and is approved by the FDA. Compared with monotherapy with C5-targeted antibodies, the combination of danicopan and C5-targeted antibodies can effectively control EVH and broaden the scope of therapeutic targets in the complement pathway. 28 , 29 Figure 3 The chemical structure of 42 FIC small-molecule drugs

The heterocyclic compound futibatinib (Lytgobi) is an FIC covalent fibroblast growth factor receptor (FGFR) kinase inhibitor 30 , 31 that was approved by the PMDA for unresectable FGFR2 fusion gene-positive biliary tract cancer that has progressed after cancer chemotherapy. FGFR signaling is related to the proliferation, apoptosis, migration, and differentiation of cells, and the inhibition of FGFR signaling is an effective strategy for treating cancer. 32 This drug was the first FGFR covalent inhibitor 32 found to irreversibly bind to FGFR1–4 and has entered clinical development for multiple cancer types. 33 Notably, many reversible FGFR inhibitors are under investigation, but acquired drug resistance has been observed. 33 , 34 , 35 Owing to the covalent irreversible inhibition mechanism of futibatinib and its low susceptibility to acquired resistance, it stands out among these drugs and was approved in 2023. 33 In addition to its effects on biliary tract cancer, it also has effects on seven other tumor types with ten different types of FGFR1–4 aberrations. 33 Thus, this drug is expected to be applied to more diseases.

Among FIC small-molecule drugs from natural products, endogenous substances, or small monomers of some biological macromolecules, birch triterpenes (Filsuvez), 36 whose active ingredient is a natural product, 37 has been approved by the FDA for the treatment of wounds associated with dystrophic and junctional epidermolysis bullosa (EB) in adults and pediatric patients aged 6 months and older. The FDA also approved a first-line therapy, palovarotene (Sohonos), 38 which is a stilbenoid 39 for adults and pediatric patients (females 8 years and older and males 10 years and older) with fibrodysplasia ossificans progressiva (FOP) to reduce the volume of new heterotopic ossification. The pathogenesis of FOP involves gain-of-function mutations in the gene encoding activin A receptor type I (ACVR1)/activin-like kinase 2 (ALK2). 40 Activin A binds to the mutant ACVR1 and activates the downstream SMAD family member 1/5/8 (SMAD1/5/8) signaling pathway, leading to chondrogenesis. 41 , 42 The drug effectively acts on the retinoic acid receptor gamma and blocks chondrogenesis to suppress heterotopic ossification. 42 However, it is a known teratogen for the developing fetus and may affect growth in children. 42 The first treatment for Rett syndrome approved by the FDA, 43 trofinetide (Daybue), 44 is an endogenous tripeptide analog (glypromate) in the brain. The FIC drugs taurolidine and heparin (Defencath) 45 also received approval from the FDA. The active ingredient of the drug, taurolidine, is a derivative of the amino acid taurine and can be used to treat catheter-related bloodstream infections as a broad-spectrum antibacterial agent that prevents the integrity of microbial cell walls 46 and adhesion to mammalian cells. 47 , 48 Imetelstat (Rytelo), the first and only oligonucleotide telomerase inhibitor approved by the FDA, 49 has a 13-mer nucleotide sequence that is complementary to the RNA component of human telomerase and competitively binds to it, causing the progressive shortening of telomeres and cell death. 50 It was indicated for low- to intermediate-1-risk myelodysplastic syndrome (MDS) and demonstrated durable red blood cell (RBC) transfusion independence (RBC-TI) in a phase 3 clinical trial, which identified its superiority in terms of drug mechanism. 51

Overall, 42 (51.9%) of the 81 FIC drugs approved in 2023 and 2024 were small-molecule FIC drugs. Small-molecule drugs with a long development history and mature drug use are still important drivers of FIC drug R&D. In addition to in-depth research and observation of pathogenesis, the sources of small-molecule drug development are becoming more diverse to contribute to FIC drug R&D.

Antibody drugs have emerged as a new force of FIC drug

According to the definition by the FDA, biological products are generally large, complex molecules used to diagnose, prevent, treat, and cure diseases and medical conditions. 52 In recent years, various types of macromolecular drugs with few side effects 53 have developed rapidly. These include antibodies, enzyme replacement therapies, hormone therapies, nucleic acid-based therapies, and vaccines, which play key roles in many serious diseases; for example, vaccines are used for infectious diseases, and enzyme replacement therapies or hormone therapies are used for treating enzyme or hormone deficiency-related diseases, and their mechanisms are different from those of small-molecule drugs. The category with the highest number of novel macromolecular drugs is the antibody/ADC category (40.0%), and of the 39 FIC macromolecular drugs, 16 FIC drugs are antibodies or ADCs ( Figure 4 ). Antibodies can be applied as monoclonal antibodies, bispecific antibodies, and ADCs. 54 In addition, 23 FIC drugs fall into other categories of macromolecular drugs, such as peptide-, enzyme-, vaccine-, and nucleic acid-based therapies ( Figure 4 ). Figure 4 The percentages and classifications of novel and FIC macromolecular drugs The percentages and classifications of novel macromolecular drugs and the numbers and categories of FIC macromolecular drugs. The novel macromolecular drugs are mainly classified as antibody/ADC drugs, vaccines, nucleic acid-based therapies, enzymes, cell therapies, peptides, factors, hormones, cytokines, interferons, and others.

Among the 16 FIC antibody drugs, talquetamab (Talvey), approved by the EMA and the FDA, is an FIC 55 bispecific antibody that engages with G-protein-coupled receptor family C group 5 member D (GPRC5D) and the immunoregulatory membrane protein CD3 on the surface of T cells for the treatment of multiple myeloma (MM) that has returned (relapsed) and not responded to treatment (refractory). 56 , 57 The drug shows a similar efficacy profile and durability of response to the first bispecific antibody, teclistamab, 58 and expands the validated target list for T cell-recruiting bispecific antibodies. 59 The human monoclonal immunoglobulin (Ig) IgG4 antibody pozelimab is an FIC drug approved by the FDA for the treatment of CHAPLE disease. 60 This disease is caused by the genetic loss of the complement regulatory protein CD55. Before this approval, the off-label use of eculizumab could improve the features of this disease. However, intravenous infusion of this drug every 2 weeks is a challenge for patients in regions with low-level medical infrastructure and limited resources. 61 Pozelimab, which targets complement protein C5, is the only approved subcutaneously administered drug for patients with this disease. 61 , 62

The first claudin 18.2 monoclonal antibody, zolbetuximab-clzb (Vyloy), also received approval from the FDA in 2024. The drug combined with fluoropyrimidine- and platinum-containing chemotherapy is used for the first-line treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN18.2 positive. Claudin 18.2 is the second of two isoforms of CLDN18. Different from the most targeted therapy agents that act on cell-membrane-expressed targets, claudin 18.2 is a tight junction protein that is expressed in the paracellular spaces of nonmalignant gastric epithelia. 6 , 63 The approval of this drug has expanded the scope of therapeutic approaches and encouraged researchers to exploit more potential targets. 6

Among the other 23 macromolecular FIC drugs, pegmolesatide (Saint Luolai), 17 a synthetic peptide from Jiangsu Hansoh Pharmaceutical Group, is indicated for anemia in adults with chronic kidney disease (CKD) who have not received erythropoiesis-stimulating agents (ESAs) and are not on dialysis and for those who are receiving short-acting erythropoietin (EPO) treatment and are on dialysis. 64 , 65 Since the withdrawal of the EPO-mimetic peptide (EMP) peginesatide 66 due to fatal anaphylactic reactions, 67 the specific ESA pegmolesatide has achieved advances. Its advantages include the use of preservative-free single-dose vials and its subcutaneous administration route. 68 It is also a long-acting product that is dosed monthly and has noninferior efficacy and safety 68 , 69 compared with epoetin alfa, an existing EPO receptor agonist. 70 Overall, the drug provides a new treatment regimen for patients. Velmanase alfa-tycv (Lamzede) was the first long-term enzyme replacement therapy for non-central nervous system (CNS) manifestations of α-mannosidosis (AM) to secure approval. 71 AM is a rare genetic endocrine and metabolic disease caused by mutations in the mannosidase alpha class 2B member 1 (MAN2B1) gene. 72 Hematopoietic stem cell transplantation was the previous treatment for this disease, but it lacks stable efficacy for some patients. However, treatment can lead to expressive speech and hearing deficiencies. 73 The enzyme replacement therapy velmanase alfa-tycv (Lamzede) can decrease the serum levels of oligosaccharides and improve patients’ hearing and quality of life and is regarded as a standard treatment for patients. 73 Arexvy was the first respiratory syncytial virus (RSV) vaccine to treat patients with RSV infection aged over 60 years and was approved by the EMA in June 2023. 74 Adults 60 years of age and older with lower respiratory tract disease (LRTD) caused by RSV infection may benefit from the vaccine. Another RSV vaccine, Abrysvo, 75 received approval from the EMA in August 2023. Unlike Arexvy, it was the first vaccine for pregnant individuals to prevent RSV infection in infants. 76 Notably, the two RSV vaccines were also approved in the US and Japan to benefit more patients. Biogen’s and Ionis’s FIC gene therapy, tofersen (Qalsody), secured accelerated approval from the FDA in 2023 for amyotrophic lateral sclerosis (ALS) associated with a mutation in the superoxide dismutase 1 (SOD1) gene (SOD1-ALS). 77 In 2024, it also received approval from the NMPA and EMA for the same disease. Approximately 2% of adult patients have rare diseases caused by SOD1 gene mutations. 78 Tofersen, an antisense oligonucleotide (ASO), can bind to mutated SOD1 mRNA to form complexes, and these complexes can be recognized and cleaved by the enzyme RNase H, 78 which suppresses the progression of this rare disease. It is the first gene therapy for SOD1-ALS 79 and offers an effective therapeutic approach for this disease. 80

With the progress of biotechnology, methods for research on macromolecular drugs are gradually being perfected, and new types of macromolecular drugs are being accepted by more patients. Macromolecular drugs have their own advantages in FIC drug R&D, such as better efficacy, fewer adverse effects, and special mechanisms. Among 39 FIC macromolecular drugs, antibody drugs are dominant, accounting for 16 approved FIC drugs. A total of 23 FIC macromolecular drugs belong to other types, which also demonstrates that FIC macromolecular drugs continue to become more diverse. 81 , 82 Moreover, on the basis of previous data from the FDA, the numbers of FIC antibody/ADC drugs approved from 2011 to 2014, 2015 to 2018, and 2019 to 2022 were 7, 20, and 17, respectively. 1 From January 2023 to October 2024, 8 were approved, which is half the number approved in 2019–2022 and greater than the number approved in 2011–2014. These findings demonstrate that antibody/ADC drugs have emerged as a new force of FIC drugs. We believe that macromolecular drugs will provide more effective and safe treatment modalities for patients in the future.

Cancer is the main indication for FIC drugs

We subsequently analyzed the disease distribution of new drugs approved in 2023 and 2024. Notably, the drug indications were widely distributed among 17 disease areas, and the top two disease fields in 2023 and 2024 were cancer/tumors (272 drugs, 25.8%) and neurological diseases (152 drugs, 14.7%) ( Figure 5 A). The situation for FIC drug approval is similar to that for new drugs. Cancer/tumors was the most common target disease for FIC drugs (18 drugs). Blood disease was the second most common disease area (12 drugs), and infectious disease ranked third (9 drugs) ( Figure 5 B). Figure 5 Distribution of drug indications (disease targets) (A) The number of new drugs and FIC drugs approved in 2023 and 2024 for different disease areas. (B) The percentages of approved drugs indicated for cancer/tumors. If the indications of the approved drugs include FIC drug indications, then the drugs are labeled in brown. (C) The percentages of approved drugs indicated for various neurological diseases. If the indications of approved drugs include FIC drug indications, then the drugs are labeled in brown.

As a major public health problem worldwide, 83 , 84 , 85 , 86 cancer/tumors represent the largest proportion of all disease areas. 87 , 88 , 89 Among all drugs used in cancer/tumors, most drugs are therapies for lung cancer (17.7%), lymphoma (11.0%), and breast cancer (10.6%). The FIC drugs distribute in breast cancer, lymphoma, MM, lung cancer, etc. ( Figure 5 B). Although some cancer/tumor types contain less drug approvals than lung cancer, lymphoma, or breast cancer, there are FIC drug approvals in these diseases, such as glioma, melanoma, and colorectal cancer. These findings may indicate that these diseases have received increasing attention. Among drugs in the cancer/tumor area, nirogacestat (Ogsiveo) is an FIC γ-secretase inhibitor that has received approval from the FDA 90 for the treatment of desmoid tumors. The disease is a kind of rare disease with a high recurrence rate that has long been treated via surgery before nirogacestat was approved. 91 Nirogacestat shows high efficacy and mild adverse reactions, making it an effective treatment option for patients. 92

The death receptor 4/5 (DR4/5) agonist aponermin in combination with thalidomide and dexamethasone was granted marketing authorization by China’s NMPA for the first time worldwide. 93 In various cancers, DR4/5 are activated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to induce the apoptosis of cells. 94 In fact, the drug is a recombinant, circularly permuted form of human TRAIL 93 with greater stability and more potent antitumor activity than native TRAIL. 93 Currently, although several drugs have been approved, MM is still incurable for most patients. 95 The approval of aponermin suggested a new approach for the treatment of this disease and demonstrated the feasibility of targeting the TRAIL pathway. 96

There were also new breakthroughs in the treatment of non-small cell lung cancer (NSCLC) in 2024. An FIC bispecific monoclonal antibody targeting programmed cell death protein 1 (PD-1) and vascular endothelial growth factor (VEGF)-A, ivonescimab, was approved by the NMPA for the treatment of patients with EGFR-mutated locally advanced or metastatic non-squamous NSCLC. 97 As a new treatment approach, in phase 3 clinical trials, the drug combined with chemotherapy significantly improved progression-free survival, and its superiority over the PD-1 blocker pembrolizumab was also identified. 98 , 99 It can also be applied to avoid some side effects associated with VEGF inhibitors and checkpoint inhibitors. 99

The second disease area of approved drugs is neurological disease, whose main diseases are attention-deficit hyperactivity disorder (ADHD) (13.8%), epilepsy (11.2%), and Alzheimer’s disease (AD) (9.9%). FIC drugs also distribute in Alzheimer's disease (AD), migraine, epilepsy, sclerosis, etc. ( Figure 5 C). Eight FIC drugs were granted marketing authorization in these areas ( Figure 5 A). There are also some neurological diseases, such as migraine (4.6%) and Duchenne muscular dystrophy (2.6%), for which fewer drugs were approved. Therefore, it is noteworthy that these FIC drugs may facilitate new developments related to these diseases. Among the eight related FIC drugs, omaveloxolone (Skyclary) was granted marketing authorization by the FDA, which was regarded as a major milestone in Friedreich ataxia (FA) therapy and has made a difference in the rare neurological disease area. 100 , 101 , 102 Furthermore, this drug was the first approved by the FDA to treat the rare severe neurodegenerative disorder FA. This disorder is caused by an intronic GAA repeat expansion in the frataxin (FXN) gene, resulting in a reduction in frataxin levels and the production of reactive oxygen species (ROSs), 100 which can damage the nervous system. 103 The drug acts on the nuclear factor erythroid 2-related factor 2 (NRF2) pathway 100 and prevents the activation of Kelch-like ECH-associated protein 1 (KEAP1), a ubiquitin E3 ligase that controls the degradation of NRF2, resulting in the accumulation of newly produced NRF2, which ameliorates oxidative and inflammatory stress and slows disease progression. 104

Epilepsy is a disease of the brain that causes recurrent epilepsy seizures in patients because of abnormal neuronal activity 105 and affects more than 70 million people worldwide. 106 The EMA granted approval for Ztalmy, whose active ingredient is ganaxolone, 107 as an orphan medicine for epileptic seizures in children from 2 to 17 years of age who were facing cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD). 108 It is an FIC steroid hormone analog that produces a neuroactive type A gamma-aminobutyric acid (GABA A ) receptor allosteric modulator 109 , 110 that lacks steroid hormone activity and binds to both synaptic and extrasynaptic GABA A receptors, 109 highlighting its mechanistic superiority over other modulators, 111 such as benzodiazepines, which only bind to synaptic GABA A receptors. 112 Ganaxolone-responsive extrasynaptic GABA A receptors can maintain functional activity during prolonged seizures. 112 The burden of neurological diseases is still substantial, 113 and new marketed drugs will offer more therapeutic strategies to improve neurological health.

In the blood and infectious disease areas, 21 FIC drugs were approved ( Figure 5 A). Among them, luspatercept (Reblozyl), an FIC erythroid maturation agent, was approved by the PMDA for anemia associated with MDS. This drug was also the first therapeutic option for this indication granted marketing authorization by the FDA. 114 , 115 It has shown sustained efficacy with an acceptable safety profile during a phase 3 clinical trial. 116 Notably, this approval will benefit Japanese patients by reducing RBC transfusion requirements and increasing hemoglobin levels. 116 , 117 The live chikungunya vaccine (Ixchiq) is the first vaccine for chikungunya. 118 Chikungunya is a mosquito-transmitted viral infection that has caused approximately 5 million reported disease cases over the past 15 years and has been reported in more than 100 countries worldwide, especially in Africa, Southeast Asia, and South America. 119 The drug addresses the lack of a vaccine for the disease and meets an urgent clinical need. 120 , 121

The classification of drug indications can help us understand key areas of drug research and facilitate updates on the treatment situation for some diseases. On the basis of our statistics, cancer is the main indication for FIC drugs. Although the number of FIC drugs that are used to treat neurological diseases is not in the dominant position, the number of approved drugs in this area ranks second, which demonstrates that there are some unmet clinical needs for some diseases in this area, for which breakthroughs are needed. We anticipate that new approved FIC drugs will cover more indications, especially some diseases with few treatment options, 122 such as Rett syndrome, desmoid tumors, and FA.

Kinases remain key targets for FIC drugs

Ideal therapeutic targets in one disease often reflect the pathogenesis of this disease. The classification of drug targets is a ongoing analysis of the mechanisms of approved drugs, which will facilitate disease treatment. The drugs approved in 2023 and 2024 span a range of target categories, including immune-related proteins, receptors and their ligands, enzymes, ion channels, factors, and transporters. This highlights the persistent efforts to explore novel therapies for diverse diseases by acting on diverse and pivotal targets. Among all the targets, the top types are enzymes (with 330 medications, accounting for 36.5% of the approved targeted drugs) and kinases (148 drugs) ( Figures 6 A and 6B). The target distribution of FIC drugs is similar to that of approved drugs. Enzymes are the most common target of FIC drugs (26 drugs), and among enzymes, kinases rank first in terms of the number of approved FIC drugs (11 drugs) ( Figure 6 C). Kinases, as modulators of protein phosphorylation, are involved in many aspects of biological function and disease mechanisms. 123 The first protein kinase B (AKT) kinase inhibitor, 124 AstraZeneca’s capivasertib (Truqap), was approved by the FDA 125 in combination with fulvestrant for adults with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer 126 with one or more phosphoinositide 3-kinase alpha/protein kinase B alpha/phosphatase and tensin homolog (PIK3CA/AKT1/PTEN) alteration. AKT, a serine/threonine-protein kinase with three isoforms, AKT1, AKT2, and AKT3, was recorded primarily in 1977 and identified in 1991. 127 , 128 As a competitive inhibitor against all AKT isoforms that occupy the binding position of ATP in AKT, capivasertib attenuates the phosphorylation of AKT substrates and affects cell growth and proliferation. 129 Figure 6 Therapeutic targets of drugs approved in 2023 and 2024 (A) The percentages of drugs approved in 2023 and 2024 that act on various targets and the number and distribution of FIC drugs in these target categories. (B) Number of drugs targeting different categories of enzymes. If the target is a target of FIC drugs, then it is labeled in purple. (C) Number of FIC drugs that act on different enzymes.

In a new class of highly selective dual inhibitors of Janus kinase 3 (JAK3) and tyrosine kinase expressed in hepatocellular carcinoma (TEC), 16 , 130 ritlecitinib (Litfulo) received approval for alopecia areata (AA) from the NMPA of China, the FDA, the PMDA of Japan, and the EU’s EMA. 131 JAK3 and the TEC kinase family of tyrosine kinases are nonreceptor tyrosine kinases. The inhibition of JAK3 and TEC may modulate several signaling pathways involved in the pathogenesis of AA. 132 , 133 The precise mechanism of action has not been fully elucidated. 134 In a randomized, double-blind, multicenter, phase 2b–3 trial, ritlecitinib was effective and well tolerated in patients aged 12 years and older with AA. 135 Different JAK subtype inhibitors can also be indicated for different diseases. In 2024, the FIC JAK1-specific inhibitor golidocitinib was approved by the NMPA for the treatment of relapsed or refractory peripheral T cell lymphoma (r/r PTCL) that had progressed on or was refractory to at least one prior systemic therapy. 136 , 137 JAK1 plays an important role in STAT3 phosphorylation and activation. Activation of the JAK-STAT pathway is involved in T cell malignancies. Because of the increased side effects of molecules that act on other JAK family members, a selective JAK1 inhibitor is inferred to be an ideal therapeutic agent. 138 In clinical trials, golidocitinib also demonstrated a favorable benefit-risk profile to facilitate its final approval. 138

In addition to enzymes, there were several other common targets of drugs that were approved in 2023 and 2024. For example, 17.4% of approved drugs act on GPCRs and nine FIC drugs targeting GPCRs received approval ( Figure 6 A). Among the nine FIC drugs, the FIC dual antagonist of the endothelin type A receptor (ET A R) and the angiotensin II (Ang II) type 1 receptor (AT 1 R) (DEARA), sparsentan (Filspari), was indicated for the treatment of proteinuria in adults with primary IgA nephropathy who were at risk of rapid disease progression and secured accelerated approval. 139 IgA nephropathy is a rare autoimmune disease, 140 and AT 1 R and ET A R are activated in its pathogenesis, 141 which is associated with proteinuria. 142 This drug is the first and only nonimmunosuppressive therapy approved by the FDA for IgA nephropathy. Without compromising efficacy, it improves medication adherence in patients with IgA nephropathy. 143 Moreover, its antagonism of two targets leads to better effects than antagonism of either molecule alone. 141 This drug has a potential role in the treatment of proteinuria via angiotensin-converting enzyme inhibition or angiotensin receptor blockade as a first-line therapy. 143 With new mechanisms of action, xanomeline and trospium chloride (Cobenfy) were also approved by the FDA for the treatment of schizophrenia. 144 Xanomeline is a selective agonist of the M₁ and M₄ muscarinic receptors, and trospium is a pan-muscarinic receptor antagonist. 145 Monotherapy with xanomeline can lead to some adverse events because of the activation of peripheral muscarinic receptors. 145 Trospium cannot cross the blood-brain barrier because of its physicochemical properties. 145 Therefore, the combination of these two drugs ameliorates side effects and has favorable efficacy. 146 Moreover, this combination also represents the first antipsychotic medication without D2 dopamine receptor-blocking activity, which was previously used as the typical therapeutic approach. 144

The discovery of new therapeutic targets represents the first step in FIC drug R&D. 147 Analyzing the target types of approved drugs can help us understand the research trends related to new therapeutic targets. Although many drugs that act on kinases have entered the market, among known kinases, only one in ten kinases are validated as therapeutic targets for the treatment of cancer, 148 and at least 70% of kinases have not been explored as drug targets. 149 In the future, more research on kinases is needed. Other than kinases, GPCRs, immune-related proteins, and nuclear HRs are targets with considerable research potential.

Prospects

In 2023 and 2024, many new FIC drugs were approved worldwide. The FDA approved the most FIC drugs. China’s NMPA, the EU’s EMA, and Japan’s PMDA also made important contributions to FIC drug approval. On the basis of the data from the FDA from 2011 to 2024, the number of FIC drugs approved from January 2023 to October 2024 was high. 1 The numbers of FIC small-molecule drugs and FIC macromolecular drugs were also similar. Moreover, FIC small-molecule drugs and FIC macromolecular drugs are widely distributed across more drug types, which demonstrates the progression and integration of traditional drug design and new biotechnology to facilitate the development of FIC drugs. Several FIC drugs play pivotal roles in some difficult miscellaneous diseases, such as cancer, and rare diseases, such as Rett syndrome, MM, and FA, and represent first treatment or breakthrough therapies for these diseases. However, more efforts are still needed to identify new treatments for some diseases, such as CHAPLE disease, desmoid tumors, and AD, to address unsolved problems and the lack of effective treatments. Kinases are important therapeutic targets for FIC drug R&D. Further in-depth research is needed on the biological functions of kinases and drug design based on kinases. Although many drugs were approved in 2023 and 2024, there is still considerable potential for breakthroughs in drug R&D. For example, breakthrough therapies or FIC drugs are still needed for many difficult neurological diseases. Moreover, transporters are relatively rare targets of newly approved drugs, so further research on these potential targets may be valuable. 150

On the basis of the analysis of some candidate drugs, further breakthroughs may be made in the neurological disease field in 2025. The potential FIC drugs seltorexant, 151 which is indicated for major depressive disorder (MDD), and suzetrigine, 152 which is used to treat moderate to severe acute pain, have shown positive results in phase 3 clinical trials. In terms of the therapeutic targets, gepotidacin, an FIC DNA topoisomerase 2 inhibitor, 153 and elinzanetant, the first dual antagonist targeting both neurokinin 1 (NK-1) and neurokinin 3 (NK-3) receptors, 154 are awaiting approval, which indicates that enzymes and GPCRs may continue to occupy a dominant position in 2025 drug approval. We also expect that the investigation of new target types will lead to the emergence of FIC drugs and the development of new therapeutic approaches for disease treatment.

FIC drugs continue to play a pioneering role in drug R&D. They have facilitated great achievements in treating diseases more effectively and extending the new mechanism of drugs, which not only provides a deeper understanding of disease pathology but also highlights improvements in global public health and quality of life. We also anticipate that drug R&D will guide further development of drugs that cover more diseases and treat more patients.

Data and code availability

Data are available from the corresponding author upon reasonable request.

Acknowledgments

This study was supported by the 10.13039/501100001809 National Natural Science Foundation of China ( 82173741 and 81930100 ), the Youth Fund of the 10.13039/100014717 National Natural Science Foundation of China ( 82304309 ), the 10.13039/501100004608 Natural Science Foundation of Jiangsu Province ( BK20230103 and BK20231014 ), and the China Young Elite Scientists Sponsorship Program by CAST ( 2021QNRC001 ). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author contributions

D.Z., Q.Z., X.L., Q.Y., and L.W. organized and wrote the manuscript. D.Z. participated in the data collection, illustration design, and manuscript writing. Q.Z. designed the illustrations and helped polished the manuscript. X.L., Q.Y., and L.W. revised the manuscript. All authors contributed to the manuscript and approved the final version.

Declaration of interests

The authors declare no competing interests.

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