Polypharmacology: new drugs in 2023-2024.

Introduction

Polypharmacology is an innovative paradigm in drug discovery and therapeutic development that aims to develop drug candidates that modulate multiple molecular targets within a biological system. Unlike ‘traditional’ drug development, often focused on designing molecules that interact with a single specific target (a ‘one drug, one target’ approach) [ 1 ], polypharmacology aims to rationally use multi-target-directed ligands (MTDLs) to embrace the inherent complexity of biological systems, intrinsic feedback mechanisms, crosstalk, and molecular pathways [ 2 ]. This is of particular importance in the case of chronic and multifactorial conditions, such as cancer, metabolic disorders, neurodegenerative and cardiovascular diseases, driven by the dysregulation of multiple interconnected pathways [ 3 – 4 ].

Therapeutic strategies that address a single molecular target only might fail to achieve lasting efficacy, may be vulnerable to the emergence of resistance mechanisms or adherence might not be adequate [ 1 , 5 ]. By contrast, simultaneous modulation of multiple targets and disease pathways by MTDLs appears to be a solution to overcome these challenges [ 6 ]. MTDLs offer the chance to reduce the number of medications taken simultaneously and to simplify dosing schedules (multiple single-target drugs may require more frequent administration than e.g. once daily) which makes it easier for patients to follow their prescribed therapeutic regimen. This is particularly important in the context of chronic diseases or in elderly patients with multimorbidity. The convenience of using a single formulation instead of multiple ones is likely to improve treatment outcomes by increasing patient adherence [ 5 ]. Moreover, addressing multiple aspects of a disease simultaneously can result in better outcomes, which can further motivate patients to maintain their treatment [ 1 , 5 – 6 ].

Small-molecule multi-targeting compounds are also likely to offer a more predictable pharmacokinetic profile. Moreover, due to complementary synergistic effects, a lower dose of a given multi-targeting drug may be required to achieve the desired outcome, which might diminish the risk of adverse drug effects. In some cases, due to the reduction of the need for simultaneous administration of multiple separate drugs, the risk of drug-drug interactions is reduced [ 5 – 6 ]. Furthermore, if one of the MTDL’s domains is a specified antibody (as in the case of antibody-drug conjugates, i.e., dual-target-directed ligands, which belong to the most successful MTDLs), the chance for effective targeted therapy arises [ 2 , 7 ].

On the other hand, MTDLs are promiscuous agents, i.e. their nature encompasses both therapeutic effects through interaction with the intended targets and potential adverse events and increased toxicity resulting from off-target interactions [ 8 – 10 ]. Thalidomide (originally developed in the 1950s as a sedative and anti-nausea medication which later appeared to cause teratogenic effects) is often used as a striking example of risks associated with drug promiscuity [ 5 ]. The complexity of the molecular design process of MTDLs and their de novo synthesis also deserves particular attention [ 2 ]. Firstly, choosing a proper target requires an intricate, comprehensive understanding of the interactions between multiple biological pathways at the molecular and cellular levels. Secondly, designing a molecule capable of interacting with all chosen targets and achieving the right balance between targeting multiple sites and concomitantly avoiding off-target effects can be very challenging. What is more, either due to the requirement of complicated resource-intensive technological processes or due to issues with the stability of molecules, synthesis of the designed molecule may be highly unprofitable or impossible [ 2 ].

Polypharmacology has always played a role in the drug development process and therapy, albeit unintentionally [ 1 ]. In the past, the multi-targeting properties of therapeutic compounds were discovered in most cases serendipitously [ 5 , 10 – 11 ]. Nowadays, rapid advances in computational modeling, machine learning (ML) and deep learning (DL) techniques enable more efficient modeling of target protein structures and consequently a more predictable process of rational design of new compounds with planned multi-target activity [ 10 – 11 ]. The increasing use of artificial intelligence (AI) for identifying synergistic co-targets of a given MTDL and distinguishing them from anti-targets, which are responsible for causing harmful side effects, might give a chance to overcome many of the limitations of polypharmacology discussed earlier [ 11 – 12 ]. AI-supported docking simulations and compound interaction predictions are promising tools for anticipating the pharmacodynamics of compounds [ 11 ]. Moreover, AI-driven generative chemistry enables quick de novo creation of a plenitude of multi-targeted structures using a wide range of DL frameworks. However, those generative models often lack experimental verification, and the compounds they create are rarely novel and feasible for synthesis [ 11 – 12 ]. Nevertheless, the use of high-quality benchmark datasets and a human-in-the-loop framework with input from experts in the field of medicinal chemistry might help with refinement and enhancement of the practical application of such models. As the understanding of disease biology and drug-target interactions continues to evolve, the rational design of MTDLs as a core of polypharmacology will play an increasingly important role in the treatment of complex, multifactorial diseases and the future of personalized and precision medicine.

In our previous work, Ryszkiewicz et al. (2023) [ 5 ], we thoroughly discussed the concept of polypharmacology and compared the promises of clinical use of MTDLs to the benefits of traditional polytherapy, which is primarily based on the use of multiple selective compounds (for other reviews, see Manen-Freixa and Antolin (2024) [ 9 ]; Kabir and Muth (2022) [ 6 ] or Feldmann and Bajorath (2022) [ 10 ]). Moreover, we gave some remarkable examples of MTDLs already successfully used in pharmacotherapy of patients. Furthermore, we presented the full list of multi-target drugs marketed in Germany in 2022, highlighting their contribution to contemporary pharmacology. Noteworthy, those drugs underwent the central registration procedure by the European Medicines Agency (EMA) earlier. The present review updates the multi-target drugs marketed in the European Union (EU) for the years 2023 and 2024, with a specific focus on the German pharmaceutical market and local post-approval drug status.

New multi-target drugs in 2023–2024– arrangement of pharmacophores

In 2023 and 2024, 30 and 43 new drugs were authorized by the EMA, respectively, and consequently marketed in Germany (and also other EU countries) [ 13 – 14 ]. A closer look at the profile of the 73 newly introduced agents [ 15 – 16 ] showed that 18 of them can be categorized as having multi-targeting properties (seven in 2023, and eleven in 2024, Table 1 ). The drugs encompass small molecules, peptides, macromolecules (immunoglobulins, antibodies), and one conjugate of an antibody plus a small molecule. Before the 18 entities are described in terms of their pharmacological properties and indications (see next section), structural details of how the two pharmacophores are arranged in the molecule will be given for three examples, which represent three basic modes of spatial arrangement, previously reviewed in Ryszkiewicz et al. (2023) [ 5 ] and Kabir and Muth (2022) [ 6 ]. The pharmacophores can either be linked (i.e. combined using a spacer (linker), which can be enzyme-degradable in vivo), fused (i.e. directly attached to each other via covalent bonding with the omission of linker groups) or merged (integrated to form a single, unified entity, when two or more pharmacophores share a common structural core).

In the case of loncastuximab tesirine (#1 in Table 1 ), the antibody binding to CD19 (loncastuximab) is linked with the cytotoxic part of the molecule (tesirine) via a spacer (Fig. 1 ). In tirzepatide (#17 in Table 1 ), some amino acid residues specific for glucagon-like peptide 1 (GLP1) or for glucose-dependent insulinotropic peptide (GIP) are fused ; on the other hand, other amino acid residues are shared by both peptides, i.e. pharmacophores are merged (Fig. 2 and further discussed in its legend). Sparsentan (#15 in Table 1 ) represents a pure example of merged pharmacophores, i.e., the parts of the molecule leading to blockade of ET A and AT 1 receptors are overlapping (Fig. 3 ).

New multi-target drugs in 2023–2024– description

Ten of the 18 multi-target drugs are indicated for the treatment of cancer and cancer-related symptoms (#1-#10), another five for the treatment of autoimmune and/or inflammatory disorders (#11-#15), and one each for the treatment of eczema (#16), type II diabetes mellitus (and obesity) (#17), and Duchenne muscular dystrophy (#18).

The drugs used for managing malignant cancers can be divided into three groups. Drug #1 is an antibody-drug conjugate. The antibody domain provides selective delivery of an attached cytostatic molecule to cells expressing a given protein on their surface, thereby improving therapeutic effect, diminishing the risk of adverse drug reactions, and giving a chance to overcome the resistance of tumor cells to chemotherapy. Drugs #2-#6 are bispecific antibodies. Via simultaneous binding to cancer cells and T lymphocytes, they engage cytotoxic T-cells in a response against the tumor. Drugs #7-#10 are small organic compounds that inhibit protein kinases with different potency and selectivity. Due to the alteration of the dysregulated function of the affected target proteins, uncontrolled cell growth, survival, and division is blocked.

B-cell lymphomas represent a broad group of hematologic cancers with varying degrees of aggressiveness. Diffuse large B-cell lymphoma (DLBCL), a type of non-Hodgkin lymphoma, is one of the most common (and also the most aggressive) forms of this kind of neoplasm [ 17 ]. Despite the initial treatment, consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone, with the addition of rituximab (anti-CD20 monoclonal antibody) being effective in about 60–65% of patients, therapeutic options for the relapsed/refractory stage are very limited [ 7 , 18 ]. Fortunately, three novel agents indicated for the treatment of this condition have reached the market in 2023 (Table 1 ). Loncastuximab tesirine (Zynlonta ® ; #1, Table 1 ; Fig. 1 ) is an antibody-drug conjugate, consisting of a CD19-directed humanised IgG1 kappa monoclonal antibody, attached through a protease-cleavable linker to SG3199, a pyrrolobenzodiazepine (PBD) dimer, which acts as an alkylating agent. SG3199 connected to its linker is also known as SG3249 or tesirine (Fig. 1 ) [ 19 – 20 ]. CD19 is expressed on B-type lymphocytes only. After the loncastuximab domain has bound to CD19, the whole antibody-cytotoxic drug conjugate is internalized, and then PBD dimers are released via proteolysis. Eventually, due to the binding of SG3199 to DNA, inter-strand crosslinks are formed, which results in the disruption of DNA replication, blocks cell division, and results in cell death [ 7 , 18 ]. Interestingly, even if the expression of CD19 on malignant B lymphocytes is low or undetectable, the cytotoxic effect of loncastuximab tesirine is still manifested [ 21 ]. Zynlonta ® was approved by the Food and Drug Administration (FDA) in the USA in 2021 [ 19 ]; in Europe, it was marketed two years later [ 18 ]. Loncastuximab tesirine has substantial antitumor activity in heavily pretreated Caucasian [ 22 ] and Chinese [ 23 ] patients with relapsed or refractory DLBCL, but both clinical trials have a single-arm design only (no placebo or active control). The most common adverse reactions are neutropenia, anemia, fatigue and increases in γ-glutamyltransferase activity [ 20 ].

Another two agents indicated for third-line DLBCL treatment, i.e. epcoritamab (Tepkinly ® ; #2, Table 1 ) and glofitamab (Columvi ® ; #3, Table 1 ), are IgG1 bispecific antibodies and share a similar mechanism of action [ 24 ]. Both epcoritamab and glofitamab are considered conditional agonists, which means that their activity is strictly dependent on simultaneous bonding to CD20 expressed on malignant B-cells, and CD3 expressed on T-cells. If the above condition is met, the formation of an immunological synapse , engaging both arms of a given bispecific antibody, will occur, resulting in T-cell activation, proliferation, secretion of cytokines, and subsequent depletion of CD20-expressing B-cells [ 25 – 26 ]. There are some characteristic differences between both antibodies [ 27 – 29 ]. Unlike epcoritamab, glofitamab binds bivalently to CD20. Moreover, the Fc region of epcoritamab is silenced to prevent target-independent immune response mechanisms. Therefore, the risk of undesirable antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cellular cytotoxicity (CDCC), and antibody-dependent cellular phagocytosis (ADCP) is vastly diminished [ 29 ].

Both medications have been studied in single-arm clinical trials and showed significant effectiveness with acceptable safety profiles [ 27 ]. There are now several new approaches for third-line DLBCL treatment but head-to-head comparisons have so far not been performed. An indirect comparison (inverse probability of treatment weighting) suggests that epcoritamab is equally effective as chimeric antigen receptor T-cell (CAR T) therapy but superior to chemoimmunotherapy, and polatuzumab- and tafasitamab-based regimens [ 30 ]. Note that the most common adverse effect associated with epcoritamab and glofitamab is cytokine release syndrome (CRS). It typically presents with symptoms such as fever (pyrexia), hypotension, tachycardia, and hypoxia [ 28 – 29 ].

Multiple myeloma (MM) is a bone marrow malignant neoplasm characterized by the clonal proliferation of plasma cells, which develop from activated B-lineage cells. This leads to the excessive production of monoclonal immunoglobulins or their light chains, which can accumulate and cause systemic damage [ 31 – 32 ]. The response to initial MM treatment (including the proteasome inhibitor bortezomib, the immunomodulator lenalidomide, and the glucocorticoid dexamethasone) is often inadequate. Relapses frequently occur at different stages of disease progression. Therefore, MM is still considered incurable [ 33 – 34 ]. Talquetamab (Talvey ® ; #4, Table 1 ), Teclistamab (Tecvayli ® ; #5, Table 1 ), and Elranatamab (Elrexfio ® ; #6, Table 1 ) are three novel fourth-line treatment options in patients with relapsed or refractory MM [ 35 ]. All three agents are considered bispecific antibodies; the first two (#4, and #5) are G4 proline, alanine, alanine immunoglobulins (IgG4 PAA) [ 36 – 38 ]. Such a modification enhances the stability of the antibody in the serum [ 39 ]. All three drugs promote T-cell-mediated cytotoxicity via recruitment of CD3-expressing T-cells, as discussed earlier for epcoritamab and glofitamab. Talquetamab is directed against G protein-coupled receptor, family C, group 5, member D (GPRC5D), an orphan receptor expressed on malignant plasma cells [ 40 – 41 ]. Simultaneous binding of GPRC5D on MM cells and CD3 on cytotoxic T-cells results in T-cell activation, release of perforins and granzymes from secretory vesicles, and subsequent lysis of GPRC5D-expressing MM cells [ 42 ]. Noteworthy, the expression of GPRC5D in other tissues seems marginal, which limits the compound’s toxicity [ 43 ]. Both teclistamab and elranatamab, besides targeting CD3+ T-cells, are directed against B cell maturation antigen (BCMA), which is expressed on MM cells, but also on late-stage B-cells and plasma cells. Through drawing CD3-expressing T-cells in close proximity to BCMA+ cells, activated cytotoxic T-cells evoke the lysis and death of BCMA-expressing cells. Noteworthy, this effect occurs regardless of native T-cell receptor specificity and does not involve major histocompatibility complex (MHC) class 1 molecules [ 44 – 45 ].

Each agent shows a relatively high response rate in monotherapy in patients with heavily pretreated MM [ 46 ]. However, there are no direct comparative clinical trials to date. In order to partially overcome this problem, indirect comparisons have been carried out. Using the inverse probability of treatment weighting (see above), both talquetamab [ 47 ] and teclistamab [ 48 ] are suggested to be superior to fourth-line treatment of MM, according to physicians’ choice. Moreover, matching-adjusted indirect treatment comparisons of the respective single-arm clinical trials of teclistamab and elranatamab revealed that elranatamab is superior to teclistamab [ 49 ]. For each of the three antibodies, CRS is considered the most common adverse reaction [ 36 – 38 ].

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths globally. Although the armamentarium of available therapies is gradually expanding, there are not many late-line treatment options, especially for heavily pretreated, metastatic CRC [ 50 – 51 ]. The vascular endothelial growth factor receptor (VEGFR) inhibitor fruquintinib (Fruzaqla ® ; #7, Table 1 ; Fig. 4 a), a potent anti-angiogenic agent, fills this gap [ 50 – 52 ]. Unlike the representatives of earlier VEGFR inhibitor generations (such as regorafenib), fruquintinib is also suitable for combination therapy, as its pharmacokinetics seem more favourable and its off-target effects are vastly reduced [ 50 ]. In a double-blind, randomized clinical trial patients treated with placebo plus best supportive care showed a lower overall survival than patients treated with fruquintinib plus best supportive care [ 53 ]. Hypertension, anorexia, and proteinuria are the most frequent adverse reactions of fruquintinib [ 52 ].

Intrahepatic cholangiocarcinoma (iCCA) is a type of cancer that arises in the bile ducts, and accounts for 3% of gastrointestinal tract cancers. The prognosis is very poor (5-year survival <20%) and treatment options for the late-stage disease are limited [ 54 ]. As fibroblast growth factor receptor 2 (FGFR-2) fusion or rearrangement occurs in 13-20% of iCCA patients, it has emerged as a promising drug target [ 55 – 56 ]. Futibatinib (Lytgobi ® ; #8, Table 1 ; Fig. 4 b), unlike other representatives of FGFR inhibitors, covalently binds to all four FGFR isoforms, and therefore irreversibly inhibits constitutive FGFR signaling [ 57 ]. Thus, its efficacy is less likely to be limited by acquired drug resistance [ 55 , 58 ]. A clinical benefit for iCCA patients was measurable; note that the drug had been studied in a single-arm clinical trial only [ 55 ]. Hyperphosphatemia is considered the most frequent side effect [ 57 ].

The serine/threonine kinase AKT is the key node in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR molecular pathway, which regulates a variety of cellular processes, including metabolism, gene transcription, migration, proliferation, cell cycle, and cellular survival. Activation of AKT in estrogen receptor-positive (ER+) breast cancer is associated with poor prognosis and resistance to endocrine therapy [ 59 – 60 ]. Mutations in the catalytic subunit of PI3K (PIK3CA), mutations in AKT1, upstream activation from other signaling pathways, and loss of phosphatase and tensin homolog (PTEN) function are the main causes of AKT activation in tumors [ 60 – 61 ]. Capivasertib (Truqap ® ; #9, Table 1 ; Fig. 4 c) is a potent first-in-class inhibitor of the 3 isoforms of AKT (AKT1, AKT2, and AKT3). It inhibits the growth of cell lines from both hematological diseases and solid tumors, including breast cancer cells, regardless of the presence of PIK3CA or AKT1 mutations, or PTEN alterations [ 61 – 62 ]. In a randomized double-blind clinical trial, co-therapy of capivasertib and the estrogen receptor antagonist fulvestrant resulted in a longer progression-free survival than the administration of fulvestrant alone; this held true for patients with hormone receptor-positive advanced breast cancer when the disease had progressed during or after prior therapy with an aromatase inhibitor (e.g., letrozole), with or without a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor (e.g., palbociclib) [ 60 , 63 ]. The most frequent adverse reaction is diarrhoea [ 61 ].

Anemia is a common manifestation of myelofibrosis (MF), a rare myeloproliferative cancer entity with a median survival of ~ 6 years after diagnosis [ 64 – 65 ]. Momelotinib (Omjjara ® ; #10, Table 1 ; Fig. 4 d) is the first (and only) drug approved in Europe dedicated to patients with MF-related splenomegaly and anemia [ 66 ]. Momelotinib and its major metabolite (M21) are inhibitors of Janus kinases JAK1 and JAK2, and of the mutant variant JAK2 V617F , which contribute to the signaling of a number of cytokines and growth factors that are important for immune function and haematopoiesis. Moreover, due to antagonism at the activin A receptor type 1 (ACVR1), liver hepcidin expression is decreased, which results in improvement of iron availability and erythrocyte production [ 67 ]. Momelotinib and M21 also inhibit other kinases, including other JAK family members, the inhibitor of κB kinase (IKK) and the interleukin-1 receptor-associated kinase 1 (IRAK1) [ 66 , 68 ]. Momelotinib is a useful treatment option across all levels of anemia severity, including cases with concurrent thrombocytopenia [ 64 ], which, in two head-to-head clinical trials was superior to danazol (parameter: total symptom score [ 69 ]) and noninferior to ruxolitinib (spleen volume [ 70 ]). The predominant drug-related side effect is diarrhoea [ 68 ].

The prevalence of autoimmune diseases and immune-mediated inflammatory disorders is worldwide and constantly increasing [ 71 ]. This has an impact on patients’ quality of life, but also adds an additional economic burden to the healthcare system. Alopecia areata is an autoimmune disorder that causes hair loss, typically in small, round patches on the scalp or other body areas [ 72 – 73 ]. It affects 2% of the world population, and is linked to reduced life quality, and significant psychosocial challenges, often resulting in anxiety and depression. The progression of the condition is unpredictable, with periods of spontaneous improvement followed by relapses [ 73 ]. Ritlecitinib (Litfulo™; #11, Table 1 ; Fig. 4 e) is an irreversible dual kinase inhibitor [ 74 ]. By blocking Janus kinase 3 (JAK3), it inhibits interleukin-derived (IL-2, IL-4, IL-7, IL-15, and IL-21) signaling in cellular settings. Additionally, simultaneous blockade of the tyrosine kinase expressed in the hepatocellular carcinoma (TEC) kinases family results in reduced cytolytic activity of CD8 + T-cells and NK cells [ 74 – 75 ]. Although the involvement of JAK3 and TEC-mediated signaling pathways in the pathogenesis of alopecia areata seems evident, its complete pathophysiology is still not fully understood. Ritlecitinib treatment resulted in dose-dependent early decreases in absolute lymphocyte levels, subpopulations of CD3+, CD4+, and CD8 + T-lymphocytes, and CD16/56+ NK cells, with no changes in the CD19+ B lymphocyte count, and immunoglobulin (IgG, IgA, IgM) levels [ 74 ]. Ritlecitinib ≥ 30 mg per day for 24 weeks (with or without 200-mg loading dose during the initial 4 weeks) reduced scalp hair loss more markedly than placebo in a randomized, double-blind study [ 74 ]. Its main drug-related side effect is diarrhoea (~ 9% of patients) [ 75 ]. Ritlecitinib should not be used together with other JAK inhibitors, biologic immunomodulators, ciclosporin, or other strong immunosuppressants [ 74 ].

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that causes long-lasting inflammation and ulcers in the inner lining of the colon and rectum. With an estimated prevalence of 5 million cases worldwide, UC is considered a significant global health concern [ 76 ]. Etrasimod (Velsipity ® ; #12, Table 1 ; Fig. 4 f) is a sphingosine-1-phosphate (S1P) receptor modulator [ 77 ]. It selectively modulates three S1P receptor subtypes (S1P1, S1P4, and S1P5) with minimal affinity to S1P3, and no activity on S1P2, and is considered a balanced beta-arrestin and G-protein agonist at the S1P1 receptor [ 78 – 80 ]. Etrasimod reduces the lymphocyte count in peripheral blood, thereby reducing the quantity of activated lymphocytes in the tissue. The exact mechanism is unknown. Interestingly, the effect shows some degree of selectivity, as a greater reduction was observed in the case of cells associated with the adaptive immune response, which are known to play a role in driving UC pathology, compared to a minimal effect on cells involved in the innate immune response, important for immunosurveillance [ 80 ]. Etrasimod is recommended as a second-line treatment option, when previous conventional or biological therapies were inadequately tolerable, ineffective, or drug tolerance has developed [ 78 – 79 ]. Its efficacy was greater in patients naïve to biologics [ 79 ]. In a randomized double-blind clinical trial, etrasimod led to clinical remission more frequently than in placebo-treated controls, both when induction (after 12 weeks) and maintenance therapy (after 52 weeks) was considered [ 81 ]. Etrasimod has a shorter half-life in comparison to the S1P receptor modulator ozanimod and does not require dose titration. It also showed fewer interactions with other drugs and food. The most frequent side effects include lymphopenia and headache [ 80 ].

Immunosuppressants are also an important part of the treatment for myasthenia gravis (MG), an autoimmune disorder that leads to severe muscle weakness as a result of disrupted communication between nerves and muscles. Because autoantibodies against the nicotinic acetylcholine receptor are detected in about 80–90% of MG patients, acetylcholinesterase inhibitors (e.g., pyridostigmine) are frequently administered [ 82 ]. The synthetic macrocyclic peptide zilucoplan (Zilbrysq ® ; #13, Table 1 ) serves as a valuable add-on to such symptomatic treatment [ 83 ]. Zilucoplan appears to inhibit the activation of the terminal complement pathway via two distinct mechanisms: (i) By binding to C5 and blocking its conversion to C5a and C5b, the cytolytic activity of the membrane attack complex (MAC) is suppressed. (ii) It creates a steric hindrance that prevents C5b binding to C6, which blocks the MAC if any C5b is formed [ 83 – 84 ]. In a randomized double-blind clinical trial, zilucoplan improved motor skills like chewing, swallowing and breathing more markedly than placebo [ 85 ]. The most widespread side effects of zilucoplan consist of injection site reactions and pain, and upper respiratory tract infections [ 84 ].

Primary biliary cholangitis (PBC), the most common autoimmune liver disease, is marked by damage to interlobular bile ducts, resulting in cholestasis and the progression of liver fibrosis [ 86 – 87 ]. Treatment approaches are mainly focused on cholestatic consequences [ 88 ]. Unfortunately, nearly 40% of patients present an incomplete response to ursodeoxycholic acid (UDCA), the first-line drug in PBC [ 89 ]. Thus, other medications are needed as an adjuvant or replacement for UDCA. Activation of peroxisome proliferator-activated receptor (PPAR) α and δ by elafibranor (Iqirvo ® ; #14, Table 1 ; Fig. 4 g), the first-in-class dual PPAR agonist, and its main active metabolite GFT1007, improves cholestasis, and decreases toxicity by modulating bile acid transporters, as well as the synthesis and detoxification of bile. The activation of PPARα and PPARδ also exerts anti-inflammatory effects [ 90 – 91 ]. In a randomized double-blind clinical trial in patients with PBC in whom UDCA was associated with inadequate response or unacceptable side effects, elafibranor improved biochemical indicators of cholestasis more markedly than placebo [ 87 ]. According to an expert opinion, the clinical efficacy of elafibranor is generally comparable to that of other second-line treatment options for PBC (such as the semi-synthetic bile acid analogue obeticholic acid, the lipid-lowering agent bezafibrate, and the PPARδ agonist seladelpar) [ 88 ]. Frequent drug-related side effects (more than 10% of patients) include non-serious, mild to moderate reactions, such as abdominal pain, diarrhoea, nausea, and vomiting [ 91 ].

Primary immunoglobulin A nephropathy (IgAN; sometimes also termed Berger´s disease), one of the most common forms of glomerulonephritis worldwide, is characterized by the deposition of circulating IgA-containing immune complexes in glomerular mesangial cells, which triggers subsequent glomerular and tubulointerstitial inflammation and fibrosis [ 92 ]. Endothelin 1 and angiotensin II contribute to IgAN progression by promoting hemodynamic changes, mesangial cell proliferation, enhanced expression and activity of proinflammatory and profibrotic factors, oxidative stress, and podocyte damage [ 93 – 94 ]. Persistent proteinuria and kidney failure are among the most common IgAN consequences. Sparsentan (Filspari ® ; #15, Table 1 ; Fig. 3 ) does not act via the immune system [ 95 ] but rather via antagonism against the two vasoconstrictive agents described above. In detail, it is the first-in-class dual endothelin ET A R and angiotensin AT 1 R receptor antagonist [ 94 ] and reduces proteinuria more effectively than angiotensin II receptor blockade alone [ 96 – 97 ]. The most frequent side effect of sparsentan is hypotonia [ 93 ].

Overactivation of the JAK-STAT pathway plays a role also in inflammatory conditions, including chronic hand eczema, a skin condition characterized by fluctuating symptoms, such as intense itching of hands and wrists, erythema, and swelling, often accompanied by pain. This can have a negative impact on the patients' quality of life, causing considerable discomfort and emotional distress [ 98 ]. Topical corticosteroids are the first-line medications for alleviating these symptoms. However, their prolonged use can cause skin thinning, irritation, or the development of stretch marks [ 99 – 100 ]. Topical formulations with delgocitinib (Anzupgo ® ; #16, Table 1 ; Fig. 4 h), a pan-JAK inhibitor, can therefore serve as a valuable alternative. Delgocitinib inhibits the activity of all JAK family members, i.e. JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). By doing so, it attenuates the signaling of pro-inflammatory cytokines, such as interleukin (IL)-2, IL-4, IL-6, IL-13, IL-21, IL-23, interferon (IFN)-α, and granulocyte-macrophagecolony-stimulating factor (GM-CSF) [ 101 – 102 ]. In a randomized double-blind clinical trial, delgocitinib cream demonstrated greater effectiveness compared to the cream vehicle [ 98 ]. The most frequent side effects are adverse reactions at the site of application [ 101 ].

Another first-in-class dual-targeting agent, tirzepatide (Mounjaro ® ; #17, Fig. 2 ; Table 1 ), is a long-acting glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP1) analogue, with high selectivity for human GIP and GLP1 receptors [ 103 ]. Both receptors are expressed on the α and β pancreatic endocrine cells, as well as in various other tissues including the heart, blood vessels, gastrointestinal system, immune cells (leukocytes), kidneys, and brain regions crucial for regulating appetite [ 104 ]. Long-term glycemic control in adults with type 2 diabetes mellitus is often difficult to achieve [ 105 ]. GLP1 agonists such as exenatide, liraglutide, and semaglutide currently serve as second-line therapy, following metformin [ 1 ]. However, adverse effects limit the ability to increase the dosage, thereby reducing the potential for higher therapeutic efficacy, particularly in terms of weight loss. To address this, combining GLP1 and GIP receptor agonism in a single drug was considered a potential solution, aided by the high molecular structure similarity between GLP1 and GIP (see Fig. 2 ) [ 1 ]. Tirzepatide reduces fasting and postprandial glucose levels. It also regulates appetite by increasing feelings of satiety and fullness while reducing hunger, leading to a decrease in food intake, body weight, and body fat percentage [ 106 ]. Consequently, tirzepatide was first approved by the EMA for diabetes treatment and half a year later for treatment of overweight (Table 1 ).

Tirzepatide resembles semaglutide (which is a GLP1 receptor agonist only) in its therapeutic profile. In terms of molecular structure, tirzepatide offers three key advancements over the first-generation GLP1 agonists: firstly, several residues in the peptide chain are modified to enhance GIP receptor-activating activity; secondly, the C-terminal is extended with a sequence from exenatide; thirdly, a fatty acid side chain is attached, similarly to semaglutide, to extend its half-life (see Fig. 2 ). In quantitative terms, tirzepatide was superior to semaglutide both in the treatment of diabetes (reduction of glycated hemoglobin) [ 107 ] and overweight [ 108 ]. The most common adverse reactions of tirzepatide include mild to moderate gastrointestinal disorders, e.g., nausea, diarrhea, and vomiting, which were more frequent during the dose escalation phase and decreased over time [ 104 ].

Duchenne muscular dystrophy (DMD) is a serious, progressive genetic disorder that leads to the gradual weakening of muscles, causing a rapid decline in mobility. DMD typically manifests between the ages of 2 and 5 years, and predominantly affects boys [ 109 ]. Glucocorticoids like prednisone and deflazacort are commonly used to treat DMD due to their strong anti-inflammatory effects. However, long-term use of these drugs can lead to serious side effects, such as growth suppression, weight gain, bone malformation, and an increased risk of infections [ 110 ]. To address this, vamorolone (Agamree ® ; #18, Table 1 ; Fig. 4 i) was developed (i) as a novel dissociative corticosteroid, aiming to maintain effectiveness while reducing these harmful side effects [ 111 ]. Vamorolone binds to the glucocorticoid receptor, thereby triggering anti-inflammatory effects via inhibition of NF-κB mediated gene transcripts. (ii) Additionally, it prevents aldosterone from activating the mineralocorticoid receptor. (iii) Furthermore, due to its unique structure, vamorolone likely does not interact with 11ß-hydroxysteroid dehydrogenases, which reduces the potential for side effects that might arise from local increases in glucocorticoid activity [ 111 – 112 ]. The exact mechanism by which vamorolone provides therapeutic benefits for patients with DMD is not yet fully understood [ 112 ].

Two doses of vamorolone were tested against placebo and the standard glucocorticoid prednisone in double-blind, randomized clinical trials; the efficacy of vamorolone was higher than that of placebo and the efficacy of the higher dose of vamorolone was comparable to that of prednisone [ 113 – 115 ]. Typical adverse effects of vamorolone are cushingoid features, weight gain, insulin resistance, suppression of adrenal function, and irritability [ 112 – 114 ]. However, vamorolone, which was studied in boys aged from 4 to younger than 7 years, unlike prednisone did not affect growth nor did it affect bone turnover markers (which declined with prednisone) [ 114 ]. When boys treated with prednisone for 24 weeks were switched to vamorolone for another 24 weeks, growth significantly increased and bone turnover biomarkers showed a rapid reversal of their prednisone-induced decline [ 115 ].

New multi-target drugs in 2023–2024– evaluation

Newly introduced drugs are subject to at least two systems of evaluation after their introduction in Germany. The first evaluation system is described in the Pharmazeutische Zeitung , a weekly appearing journal for pharmacists, in which the degree of innovation is given in terms of me-too preparation, step innovation, and disruptive innovation (e.g., for epcoritamab (#2) and ritlecitinib (#11) in Gensthaler et al. (2023) [ 116 ]). The rating is listed for each of the 18 compounds in Table 1 . Drugs were rated as step or disruptive innovations with two exceptions only.

The second type of evaluation is provided by the Joint Federal Committee ( Gemeinsamer Bundesausschuss ) consisting of representatives of physicians, dentists, hospitals, and health insurance providers. In accordance with the German Social Code, Book Five (SGB V), section 35a , they check after six months whether a newly introduced drug has an advantage over the standard therapy (this explains why the assessment for the very recently introduced drugs capivasertib, elafibranor, and delgocitinib is not yet available). When an additional benefit cannot be demonstrated, the annual treatment costs of the new drug must not exceed those of the appropriate comparator [ 117 ]. This procedure is stricter than that of the EMA, who postulates the therapeutic effect and safety of the new drug only. Table 1 shows that a minor or not quantifiable additional benefit could be shown for epcoritamab, glofitamab, talquetamab, fruquintinib, momelotinib, sparsentan, tirzepatide (for one group of diabetes patients only), and vamorolone.

The deeper sense of the activities of the Gemeinsamer Bundesausschuss is to dampen the steadily increasing costs of drugs. The assessment of the additional benefit of newly introduced drugs has already been discussed in the previous paragraph. To keep costs low, also SGB V, Sect. 34 , is of interest, which contains a list of drugs that predominantly increase the quality of life, e.g. by reduction of body weight or stimulation of hair growth. Costs of such life-style drugs will not be covered by statutory health insurances with their 74 million policyholders. Recently, tirzepatide (treatment of overweight only) and ritlecitinib have been added to this list (Table 1 ) [ 118 ].

Conclusions

Polypharmacology, i.e. the design, synthesis, and clinical implementation of multi-targeting molecules, might offer favorable synergistic effects and could be a promising way, e.g., for overcoming drug resistance in malignant cancers or to provide a better alternative to poorly tolerated medications. Among the 73 substances introduced in Germany in 2023–2024, 18 were identified as multi-target-directed ligands (MTDLs), including small molecules, peptides, immunoglobulins (antibodies), and one antibody-drug conjugate. The number of polypharmacological drugs introduced remains relatively consistent year-to-year (11 substances approved in 2024, 7 in 2023, and 10 in 2022) [ 5 ]. Most of them are dedicated to cancer therapy. The chemical structures of three new MTDLs in which the pharmacophores are linked, fused or merged are described in more detail, respectively. The 18 new MTDLs comprise ten antitumor agents, including drugs indicated for B-cell lymphomas, multiple myeloma, colorectal cancer, cholangiocarcinoma, breast cancer, and myeloproliferative cancer-related splenomegaly. Another five drugs act against autoimmune disorders, like alopecia areata, ulcerative colitis, myasthenia gravis, primary biliary cholangitis, and IgA nephropathy. Another three drugs are indicated for the treatment of hand eczema, type II diabetes mellitus (and overweight) and Duchenne muscular dystrophy. All but two drugs were rated as step or disruptive innovations according to Pharmazeutische Zeitun g, a German journal for pharmacists. Another rating in Germany, provided by a committee of physicians, dentists, hospitals, and health insurances ( Gemeinsamer Bundesauschuss ), revealed that eight of the 14 MTDLs evaluated so far show an additional benefit beyond that of the currently available standard therapy.

Abbreviations

Activin A receptor, type 1

Antibody-dependent cellular cytotoxicity

Antibody-dependent cellular phagocytosis

Artificial intelligence

RAC(Rho family)-alpha serine/threonine protein kinase

Angiotensin 1 receptor

B-cell maturation antigen

Body mass index

Complement protein C5(b), C6

Chimeric antigen receptor T-cell

Cluster of differentiation 3, 4, 8, 16, 19, 20, 38, 56

Complement-dependent cellular cytotoxicity

Cyclin-dependent kinase 4/6

Colorectal cancer

Cytokine release syndrome

Deep learning

Diffuse large B-cell lymphoma

Duchenne muscular dystrophy

Endothelial growth factor receptor

European Medicines Agency

Endothelin A receptor

European Union

Food and Drug Administration

Fibroblast growth factor receptor (1, 2, 3, 4)

Glucocorticoid receptor

Glucose-dependent insulinotropic peptide

Glucagon-like peptide 1

Granulocyte-macrophage-colony-stimulating factor

G protein-coupled receptor, class C, group 5, member D

Receptor tyrosine kinase within the erb-b2 family

Inflammatory bowel disease

Intrahepatic cholangiocarcinoma

Interferon alpha

Immunoglobulin A nephropathy

Immunoglobulin G, A, M

Inhibitor of kappa-B kinase

Interleukin-1, 2, 4, 6,7, 13, 15, 21, 23

Interleukin-1 receptor-associated kinase 1

Janus kinase 1/2/3, receptor tyrosine kinase

JAK2 receptor tyrosine kinase V617F mutant variant

Membrane attack complex

Mineralocorticoid receptor

Myelofibrosis

Myasthenia gravis

Major histocompatibility complex

Machine learning

Multiple myeloma

Multi-target-directed ligand(s)

Mammalian target of rapamycin serine/threonine protein kinase

Nuclear factor kappa-light-chain-enhancer of activated B cells

Primary biliary cholangitis

Pyrrolobenzodiazepine

Programmed cell death protein 1

Phosphatidylinositol-3-kinase

Phosphatidylinositol-4,5-bisphosphate-3-kinase catalytic subunit alpha

Peroxisome proliferator-activated receptor alpha, delta

Phosphatase and tensin homolog deleted on chromosome ten

Sphingosine-1-phosphate

Sphingosine-1-phosphate receptor 1, 2, 3, 4, 5

German Social Code, Book Five

Signal transducer and activator of transcription

Tyrosine kinase expressed in hepatocellular carcinoma

Non-receptor tyrosine kinase 2

Ulcerative colitis

Ursodeoxycholic acid

Vascular endothelial growth factor (receptor)

Author contributions

P.R.: Conceptualization, Data curation, Funding Acquisition, Methodology, Project administration, Resources, Software, Visualization, Writing – original draft, Writing – review&editing. B.M.: Writing – review&editing. E.S.: Supervision, Writing – review&editing.

Funding

The study was supported by the Medical University of Białystok, Poland, grant No. B.SUB.24.236.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Piotr Ryszkiewicz, Email: piotr.ryszkiewicz@umb.edu.pl.

Eberhard Schlicker, Email: e.schlicker@uni-bonn.de.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.