Multi-target-directed drugs: new additions in 2025 and post-marketing safety surveillance of drugs marketed in 2022–2024

Abstract

Polypharmacology is dedicated to the development of compounds acting on at least two targets (multi-target-directed ligands, MTDLs). In 2025, the European Medicines Agency (EMA) approved 38 drugs, and 11 out of them were MTDLs. Most of them are antibody-drug conjugates, bispecific antibodies, or kinase inhibitors, all of which are indicated for tumor treatment, including datopotamab deruxtecan (hormone receptor-positive, HER2-negative breast cancer), tisotumab vedotin (advanced cervical carcinoma), linvoseltamab (fourth-line treatment of multiple myeloma), and erdafitinib (advanced urothelial carcinoma). The small molecule tiratricol is an orphan drug, which is indicated for the treatment of the very rare Allan-Herndon-Dudley syndrome. The second part of the present review is dedicated to the post-marketing safety surveillance of MTDLs approved by the EMA in 2022–2024. For 19 out of the 27 MTDLs, which are still available on the European market, comprehensive pharmacovigilance studies, mainly based on the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), were found. New safety signals have been identified, including Stevens-Johnson syndrome and progressive multifocal leukoencephalopathy. The analysis also revealed a more favorable safety profile of the MTDL tirzepatide (a dual glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide analogue) compared to the single-targeted drug semaglutide (glucagon-like peptide-1 analogue), including lower reporting rates of acute kidney injury and no significant suicidality signal.

Introduction

Polypharmacology is an emerging strategy of design, development, and clinical implementation of multi-target-directed ligands (MTDLs) i.e., agents capable of modulating two or more molecular targets simultaneously [1, 2]. This approach, which emerged beyond the classical ‘one drug-one target’ paradigm, is particularly relevant in the context of complex diseases, such as cancer, neurodegenerative disorders, inflammatory and cardiovascular diseases, where the involvement of multifaceted etiological components limits the effectiveness of single-target-based therapies [2, 3]. The demand for such innovative medications is increasing also due to limits in clinical efficacy, the occurrence of adverse drug reactions (ADRs), and multidrug resistance, especially seen in the context of infectious diseases [4] and cancer [3, 5, 6].

In guiding multi-target drug design, the integration of omics data, clustered regularly interspaced short palindromic repeats (CRISPR) functional screens, and pathway simulations plays a pivotal role in target selection and multi-target ligand prediction [7]. Assumptions of network pharmacology enable the construction of drug-target networks [8]. Artificial intelligence (AI) algorithms offer deep generative models along with scalable and versatile platforms able to identify potential drug targets, predict the efficacy, and optimize lead compounds [9, 10]. Along with the approach of machine learning, they facilitate the generation of molecules with the most optimal balance between potency, selectivity, and safety [10]. For example, at the early stage of the development of kinase inhibitor candidates, selectivity profiles are typically obtained, and non-kinase off-target inhibitory activity is predicted [11]. However, the dynamic, self-learning nature of AI systems needs full regulatory guidance, continuous validation, and ethical oversight to enable trustworthy AI deployment in the design of next-generation multi-target compounds [10].

On the one hand, polypharmacology offers the chance to reduce ADRs and improve patient compliance in comparison to ‘classic’ combination therapies, based on highly selective ligands [7, 12]. This can be achieved not only due to a generally more predictable pharmacokinetic profile of MTDLs than of drug combinations, but also due to the advantage of using a single formulation and simplification of dosing regimens [13, 14]. Additionally, complementary synergistic effects may permit the desired therapeutic outcome to be achieved at lower doses of multi-target agents, potentially minimizing the risk of ADRs. On the other hand, engagement of MTDLs raises safety concerns. Off-target effects, an inherent consequence of the promiscuous nature of those molecules, might contribute to adverse reactions that are not fully predictable from preclinical in vitro and in vivo models or early-phase clinical trials [14]. Such effects may arise from the convergence of pharmacodynamic interactions or tissue-specific target expression, particularly in (highly) heterogeneous patient populations. These challenges emphasize the critical importance of post-marketing drug safety surveillance, as even comprehensive pre-approval evaluations may fail to identify rare, delayed, or population-specific ADRs [15]. Moreover, fast-track approvals, especially in the case of drugs with orphan designation (see glossary in Table 1), are associated with more unreported ADRs, along with more frequent post-marketing safety updates [16]. Real-world pharmacovigilance systems – incorporating spontaneous reporting databases, electronic health records, and large-scale observational studies – are therefore essential to detect safety signals that emerge only after widespread clinical exposure [17].

Table 1.

Glossary of selected terms of the present article

Item	Explanation	References
Breast cancer tumor markers	The occurrence of HR and the HER2/neu marker in breast cancer has prognostic and therapeutic relevance. HR-positive breast cancer accounts for 70% of the cases and can be treated specifically by many procedures including inavolisib (Table 2). HER2-positive breast cancer accounts for 15–20% of the cases and has a poorer prognosis than HR-positive breast cancer but can be specifically treated with drugs like datopotamab deruxtecan (Table 2) and trastuzumab deruxtecan (Table 3). Triple-negative breast cancer accounts for 10–15% and on the rule has a poor prognosis.	[18]
CRS	… is a systemic hyperinflammatory response that is characterized by fever, hypotension, and hypoxia and can lead to organ dysfunction. CRS occurs due to the activation and proliferation of multiple immune cell types, including T-cells … and the subsequent release of pro-inflammatory cytokines. IL-6 signaling plays a central role in the pathophysiology of CRS by activating vascular endothelial cells.	[19]
ICANS	… is characterized by confusion, reduced consciousness level, aphasia, raised intracranial pressure, and seizures. It is thought to be caused by cytokine-mediated endothelial activation and disruption of the blood-brain barrier. It therefore typically occurs alongside CRS but can occur after CRS has resolved.	[19]
Myasthenia gravis	… is a rare autoimmune disease that causes debilitating muscle weakness due to impaired neuromuscular transmission. The standard medical therapy consists of symptomatic treatment with acetylcholinesterase inhibitors (e.g., pyridostigmine) and immunomodulating agents (e.g., corticosteroids). New strategies include complement blockade (i.e., eculizumab, ravulizumab, and zilucoplan) and neonatal Fc receptor antagonism (i.e., efgartigimod and rozanolixizumab).	[20]
Orphan drug	Orphan drugs undergo an expedited approval procedure by the regulatory authority in charge (e.g., FDA or EMA). In the case of EMA, orphan drug designation is possible if the corresponding disease is less frequent than 5 per 10,000 inhabitants. Phase 3 studies may be based on non-randomized open-label single-arm trials, studying only half of the patient population enrolled in non-orphan trials. There is a user fee reduction, scientific advice by the EMA and an extended market exclusivity for a period of 10 years.	[16]
PML	… is a rare but often fatal demyelinating disease of the central nervous system caused by JCV. Natalizumab, a drug used for advanced stages of multiple sclerosis, is a prototypical drug leading to this disease.	[21]
Severity of adverse events (side effects)	According to the National Cancer Institute, adverse events (side effects) are classified as: grade 1 – mild; grade 2 – moderate; grade 3 – severe; grade 4 – life-threatening, and grade 5 – death related to adverse event.	[22]

CRS, cytokine release syndrome; EMA, European Medicines Agency; Fc, fragment crystallizable region of an antibody; FDA, Food and Drug Administration; HER2/neu, receptor tyrosine kinase within the erb-b2 family; HR, hormone receptors (estrogen and progesterone receptors); ICANS, immune effector cell-associated neurotoxicity syndrome; IL-6, interleukin 6; JCV, human polyomavirus 2; PML, progressive multifocal leukoencephalopathy

In the context of polypharmacology, post-marketing safety surveillance represents an especially strategic role. The broader target profile of such agents may lead to complex adverse event patterns that may require advanced AI-driven methodologies and network-based safety analyses [23, 24]. Moreover, due to expedited approvals, many novel anti-cancer drugs (which account for the majority of newly marketed MTDLs) are considered clinically immature [17]. Continuous benefit-risk reassessment, supported by real-world evidence, enables the early identification of their unpredicted interactions with unexpected targets and gives the chance to implement risk minimization strategies, labeling updates, and potential dose adjustments [15, 24].

This paper is the third one in a series of communications dedicated to multi-target drugs approved by the European Medicines Agency (EMA) in the years 2022 to 2025. In the first paper (Ryszkiewicz et al., 2023 [12]), we thoroughly described the principles of polypharmacology and compared the anticipated clinical benefits of MTDLs with those of ‘classical’ combination therapy employing selective drugs (for other recent reviews see Abdelsayed, 2025 [7]; Manen-Freixa and Antolin, 2024 [25]). We also provided a list of multi-target drugs authorized by the EMA and marketed in Germany in 2022. In the subsequent paper (Ryszkiewicz et al., 2025 [13]), this list was extended to the years 2023 and 2024. The current review provides an update for 2025 and, in addition, a summary of post-marketing drug safety surveillance studies regarding the MTDLs marketed in the years of 2022, 2023, and 2024.

New multi-target drugs in 2025

In 2025, 38 new drugs were authorized by the EMA and marketed in Germany and other European Union (EU) countries [26, 27]. A more detailed analysis revealed that 11 can be classified as multi-target compounds (Table 2). Nine out of them are indicated for tumor treatment (#1-#9), one for the prophylaxis of migraine (#10), and one for the treatment of peripheral thyrotoxicosis (#11). Antitumor drugs can be divided into three main categories, according to the classification listed in Ryszkiewicz et al. (2025) [13]. Drugs #1 and #2 are antibody-drug conjugates (ADCs). The antibody domain enables targeted delivery of a linked cytostatic agent to cells that express a specific surface protein, thereby enhancing therapeutic efficacy, reducing adverse effects, and potentially overcoming tumor resistance to chemotherapy. Drugs #3 and #4 are bispecific antibodies. By concurrently targeting cancer cells and T lymphocytes, they activate cytotoxic T-cells to respond against the tumor (T-cell engagers). Drugs #5-#9 are low-molecular-weight organic compounds that inhibit enzymes like protein kinases. By inhibiting dysregulated target proteins, these molecules block aberrant signaling pathways responsible for uncontrolled tumor cell proliferation and survival.

Table 2.

New multi-target drugs introduced in Germany in 2025¹

No.	INN (brand name)	ATC code	Short description	Molecular mechanisms	Indication(s)	References	Degree of innovation2	Additional benefit3
1.	Datopotamab deruxtecan (Datroway®)	L01FX35	antibody-drug conjugate	antibody (b) TROP2	unresectable or metastatic HR-positive, HER2-negative breast cancer in adult patients who have received endocrine therapy and at least one line of chemotherapy in the advanced setting	[28, 29]	1	Ø
				DXd (-) topoisomerase I
2.	Tisotumab vedotin (Tivdak®)	L01FX23	antibody-drug conjugate	antibody (b) TF on the surface of tumor cells	recurrent or metastatic cervical cancer in adult patients with disease progression on or after systemic therapy	[30, 31]	3	Ø
				vedotin (-) polymerization of microtubules
3.	Linvoseltamab (Lynozyfic®)	not yet assigned	bispecific antibody	(b) BCMA on malignant MM B-lineage cells	relapsed and refractory MM in adult patients who have received at least 3 prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, and have demonstrated disease progression on the last therapy	[32, 33]	1	Ø
				(b) CD3 on cytotoxic T cells
4.	Odronextamab (Ordspono®)	L01FX34	bispecific antibody	(b) CD20 on malignant B cells	relapsed or refractory follicular lymphoma and DLBCL in adult patients after two or more lines of systemic therapy	[34, 35]	1	Ø
				(b) CD3 on cytotoxic T cells
5.	Repotrectinib (Augtyro®)	L01EX28	kinase inhibitor	(-) ROS1 (-) TRKA (-) TRKB (-) TRKC (-) ALK	(i) ROS1-positive advanced NSCLC in adult patients (ii) Advanced solid tumors expressing an NTRK gene fusion in adult and pediatric patients ≥ 12 years of age, who: have received a prior NTRK inhibitor, or have not received a prior NTRK inhibitor, and treatment options not targeting NTRK provide limited clinical benefit, or have been exhausted	[36, 37]	2	Ø Ø
6.	Erdafitinib (Balversa®)	L01EN01	kinase inhibitor	(-) FGFR (all isoforms, including FGFR2 and FGFR3)	unresectable or metastatic urothelial carcinoma in adult patients with susceptible FGFR3 genetic alterations who have been previously treated with at least one line of therapy containing a PD-1 or PD-L1 inhibitor	[38]	2	Ø
7.	Mirdametinib (Ezmekly®)	L01EE05	kinase inhibitor	(-) MEK1 (-) MEK2	symptomatic, inoperable plexiform neurofibromas in patients with neurofibromatosis type 1, aged ≥ 2 years	[39, 40]	2	+ nq
8.	Inavolisib (Itovebi®)	L01EM06	enzyme inhibitor	(-) p110α (+) degradation of mutated p110α	PIK3CA-mutated, estrogen receptor-positive, HER2-negative, locally advanced or metastatic breast cancer, in combination with palbociclib and fulvestrant, following recurrence on or within 12 months of completing adjuvant endocrine treatment who had been (i) treated (ii) not treated with a CDK4/6 inhibitor (e.g., palbociclib)	[41, 42]	2	Ø ++
9.	Vorasidenib (Voranigo®)	L01XM04	enzyme inhibitor	(-) IDH1 (-) IDH2	predominantly non-enhancing grade 2 astrocytoma or oligodendroglioma with an IDH1 R132 or IDH2 R172 mutation in adult and adolescent patients aged ≥ 12 years and weighing ≥ 40 kg who only had surgical intervention and are not in immediate need of radiotherapy or chemotherapy	[43, 44]	2	+ nq
10.	Atogepant (Aquipta®)	N02CD07	antagonist of G protein-coupled receptors	(-) several receptors of calcitonin/CGRP-receptor family	prophylaxis of migraine in adults who have ≥ 4 migraine days per month	[45, 46]	2	Ø
11.	Tiratricol (Emcitate®)	H03AA04	thyroid hormone metabolite	(+) TRα (+) TRβ	peripheral thyrotoxicosis in patients with MCT8 deficiency (Allan-Herndon-Dudley syndrome), from birth	[47, 48]	3	+ nq

¹in countries in which other regulatory authorities are in charge (e.g., Food and Drug Administration (FDA) for the USA), drugs might have reached approval earlier or an additional indication might have been assigned

²degree of innovation according to Pharmazeutische Zeitung: 1 – me-too preparation; 2 – step innovation; 3 – disruptive innovation

³evaluation by the Joint Federal Committee (Gemeinsamer Bundesausschuss): additional benefit was considerable (++), could not be quantified in terms of minor, considerable or major (+ nq) or was absent (Ø)

ALK, anaplastic lymphoma kinase; ATC, anatomical therapeutic chemical classification; BCMA, B-cell maturation antigen; CD3, 20, 38, cluster of differentiation 3, 20, 38; CDK4/6, cyclin-dependent kinase 4/6; CGRP, calcitonin gene-related peptide; DLBCL, diffuse large B-cell lymphoma; DXd, deruxtecan; FGFR(2, 3), fibroblast growth factor receptor (2, 3); HER2, human epidermal growth factor receptor 2; HR, hormone receptors (estrogen and progesterone receptors); IDH1, 2, isocitrate dehydrogenase 1, 2; INN, international nonproprietary name; MCT8, monocarboxylate transporter 8; MEK1, 2, mitogen‑activated protein kinase 1, 2; MM, multiple myeloma; NSCLC, non-small cell lung cancer; NTRK, neurotrophic receptor tyrosine kinase; PIK3CA, p110α, phosphatidylinositol-4,5-bisphosphate-3-kinase catalytic subunit alpha gene/protein; PD-1, programmed death receptor 1; PD-L1, programmed death receptor 1 ligand 1; ROS1, ROS proto-oncogene 1 receptor tyrosine kinase; TF, tissue factor; TRα, β, thyroid hormone receptors α, β; TRKA, B, C, tropomyosin receptor tyrosine kinase A, B, C; TROP2, trophoblast cell surface antigen 2; (+), activates; (-), blocks; (b) binds to

Breast cancer, characterized by significant heterogeneity, is one of the main causes of malignancy-related deaths in women [49]. A better understanding of its mechanisms of tumorigenesis and progression contributed to advancements in treatment strategies and the development of novel treatment approaches, which support the idea of precision oncology and personalized medicine [49, 50]. ADCs perfectly meet this concept, giving a chance to targeted delivery of a given cytostatic molecule directly to cancer cells expressing a certain marker on their surface and minimizing the risk of systemic side effects [51, 52]. Trophoblast cell surface antigen 2 (TROP2), a type I transmembrane glycoprotein, is overexpressed in numerous types of tumors, including all forms of breast cancer [53]. The first-in-class anti-TROP2 ADC, sacituzumab govitecan, a third-line treatment option for unresectable or metastatic triple-negative or hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer (see glossary in Table 1) in adult patients, was authorized by the EMA in 2021 [54]. Another TROP2-directed ADC, datopotamab deruxtecan (Datroway^®; #1, Table 2; Fig. 1), also shows notable efficacy and a tolerable safety profile [28, 29, 55]. Datopotamab, a humanized anti-TROP2 IgG1 antibody, is attached to the topoisomerase I inhibitor deruxtecan (DXd) via a tetrapeptide-based protease-cleavable linker (Fig. 1). Such a conjugate is stable in human plasma. After binding to TROP2 expressed on the surface of tumor cells, datopotamab deruxtecan is internalized, and subsequently DXd is released, which results in DNA damage and cellular apoptosis [55]. Like many other ADCs, datopotamab deruxtecan may exhibit cytotoxic effects indirectly, via antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), and the bystander cytotoxic effect of DXd on TROP2-positive tumor cells and adjacent surrounding cells. The most prevalent side effects of datopotamab deruxtecan (affecting more than 1 in 10 people) include stomatitis, nausea, and fatigue [29].

Fig. 1.

Chemical structure of datopotamab deruxtecan, an antibody-drug conjugate with linked pharmacophores indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Datopotamab (a humanized IgG1 monoclonal antibody) is covalently bound to deruxtecan (DXd, an exatecan derivative), a topoisomerase I inhibitor (blue rectangle, broken line) via a tetrapeptide-based (gly-gly-phe-gly) cleavable linker (green parentheses). Approximately 4 DXd molecules are attached to each antibody molecule [28]

Cervical cancer, similarly to breast cancer, remains a significant contributor to cancer incidence and mortality among women worldwide, with an estimated 660,000–670,000 new diagnoses and 300,000–350,000 deaths per year in the early 2020s [56]. Human papillomavirus (HPV) infection is a leading yet preventable cause of this condition, in addition to alterations in cell proliferation signaling, and tumor immune microenvironment modulation [57]. In the setting of metastatic and/or recurrent disease, immune-checkpoint inhibitors (e.g., pembrolizumab), anti-angiogenic agents (e.g., bevacizumab), and ADCs are considered as treatment options [58]. Tisotumab vedotin (Tivdak^®; #2, Table 2, Fig. 2), a representative of the latter agents, consists of an anti-tissue factor (TF) IgG1 antibody attached to monomethyl auristatin E (MMAE), a microtubule-disrupting agent (Fig. 2). After binding of the tisotumab domain to TF, expressed at elevated levels on a plenitude of solid tumors, including cervical cancer, the whole ADC-TF complex is internalized. Then, MMAE is released via proteolytic cleavage. Disruption of the microtubule network of actively dividing cells leads to the arrest of the cell cycle and apoptotic cell death [30, 31]. Besides its direct cytotoxic effect in TF-expressing tumor cells, tisotumab vedotin also causes ADCC, ADCP, bystander cytotoxicity, and immunogenic cell death. The most frequently reported ADRs of tisotumab vedotin comprise peripheral neuropathy, nausea, nosebleed, conjunctivitis, hair loss, anemia, and diarrhoea [31].

Fig. 2.

Chemical structure of tisotumab vedotin, an antibody-drug conjugate with linked pharmacophores indicated for the treatment of recurrent or metastatic cervical cancer. Tisotumab (a humanized IgG1 kappa anti-tissue factor (TF) monoclonal antibody) is covalently bound to vedotin (brown rectangle, broken line), i.e., the microtubule-disrupting agent monomethyl auristatin E (MMAE) (blue rectangle, broken line), attached via a p-aminobenzoic acid (PABA) moiety (grey rectangle, broken line) and a dipeptide-based (val-cit, green parentheses) cleavable linker to IgG1 antibody [30]

Bispecific antibodies are an emerging immunotherapy approach in the treatment of multiple myeloma (MM), a hematologic malignancy marked by the uncontrolled proliferation of plasma cells within the bone marrow along with the overproduction of monoclonal antibodies [59–61]. MM rapidly acquires resistance to currently available chemotherapy options, making additional or substitute therapies essential. In recent years, three IgG4-based bispecific antibodies, i.e. talquetamab, teclistamab, and elranatamab, have reached the market authorization by the EMA [13, 60]. Linvoseltamab (Lynozyfic^®; #3, Table 2) is another IgG4-based fourth-line treatment option for patients with refractory or relapsed MM [32]. By simultaneous binding (i) to the B-cell maturation antigen (BCMA) on the surface of malignant MM B-lineage cells, late-stage B-cells, and plasma cells, and (ii) to the cluster of differentiation 3 (CD3) protein on cytotoxic T cells, an immunological synapse is created. This results in T-cell activation and lysis of targeted cells, regardless of the major histocompatibility complex (MHC) class I molecules on antigen-presenting cells or T-cell receptor specificity [33]. Although teclistamab and elranatamab share an analogous mechanism of action, linvoseltamab offers comparable to slightly better efficacy with a favorable safety profile, according to cross-trial comparisons [62, 63]. One of the most commonly reported side effects of linvoseltamab is cytokine release syndrome (CRS; typically associated with symptoms such as fever, tachycardia, hypoxia, and hypotension), which is related to the T cell-induced lysis of the targeted B cells (for glossary, see Table 1); other common side effects are musculoskeletal pain, neutropenia, and cough [33].

The development of bispecific antibodies marks a significant advancement also in the treatment of relapsed/refractory B-cell lymphomas, fulfilling critical therapeutic gaps for patients with limited conventional options [64]. Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma characterized by substantial molecular heterogeneity. Although available therapeutic regimens significantly improved outcomes in the last few years, relapses still occur in nearly 40% of patients [65]. Odronextamab (Ordspono^®; #4, Table 2), a third-line treatment option for DLBCL, is a human IgG4-based bispecific antibody. Moreover, it is also indicated for the treatment of follicular lymphoma, an indolent yet incurable non-Hodgkin lymphoma [34, 66]. Odronextamab binds to CD20 present on malignant B cells and CD3 on cytotoxic T cells, i.e., a CRS is also typical for this drug (Table 2); other main side effects of odronextamab encompass neutropenia, fever, and anemia [35].

Rearrangements in the proto-oncogene receptor tyrosine kinase ROS1 gene characterize a specific, therapeutically addressable group of non-small cell lung cancer (NSCLC), accounting for approximately 2% of cases, associated with non-smoker status, younger age, and frequently presenting with brain metastases [67, 68]. Fusion proteins containing ROS1 or tropomyosin receptor tyrosine kinase (TRK) domains can promote tumor development by excessively activating downstream signaling pathways, resulting in uncontrolled cell growth [36]. The use of ROS1 tyrosine kinase inhibitors (TKIs) has markedly improved patient outcomes. Although first-generation drugs, such as crizotinib and entrectinib, demonstrate high response rates (over 60%-70%), their long-term effectiveness is restricted by resistance mutations and limited blood-brain barrier permeability [69]. Repotrectinib (Augtyro^®; #5, Table 2; Fig. 3) potently inhibits ROS1, anaplastic lymphoma kinase (ALK), and TRK kinases (TRKA, TRKB, TRKC) and is indicated for the treatment of locally advanced and metastatic solid tumors, including NSCLC [37]. By binding inside the adenosine triphosphate (ATP)-binding pocket, it avoids steric interference from both gatekeeper and solvent-front mutations [36, 37]. Repotrectinib shows activity in TKI-naïve and TKI-resistant tumors, expressing fusion oncogenes ROS1, TRKA, TRKB, TRKC, and their corresponding mutations (ROS1^G2032R, ROS1^D2033N, TRKA^G595R, TRKB^G639R, and TRKC^G623R) [36, 69]. Moreover, its penetration to the central nervous system is vastly enhanced [68, 69]. The most common side effects include dizziness, dysgeusia, constipation, paresthesia, anemia, and dyspnea [36].

Fig. 3.

Chemical structures of the recently marketed multi-target-directed ligands (MTDLs): repotrectinib, erdafitinib, mirdametinib, inavolisib, vorasidenib, and atogepant

Urothelial carcinoma, the most prevalent cancer of the urinary tract, remains a major clinical challenge. Especially in its metastatic stage, prognosis still remains poor, despite ongoing advancements in treatment, with ADCs like sacituzumab govitecan and immune checkpoint inhibitors like pembrolizumab introduced as alternatives to the ‘traditional’ first-line platinum-based chemotherapy [70]. As many as 70% of low-grade non-muscle-invasive bladder cancers and 20‑40% of patients with advanced urothelial cancer exhibit somatic fibroblast growth factor receptor 3 (FGFR3) alterations [71, 72]. This leads to the activation of downstream signaling pathways and subsequent cellular proliferation [71]. Erdafitinib (Balversa^®; #6, Table 2; Fig. 3) is the first small-molecule pan-FGFR TKI approved in advanced bladder cancer [38, 73] and represents an example of targeted therapy. By targeting the FGFR2 and FGFR3 receptors, along with their mutated forms, it inhibits FGF signaling, which results in cell death [73]. The most common side effects are hyperphosphatemia, diarrhea, stomatitis, and xerostomia (dry mouth) [38].

The NF1 gene encodes neurofibromin 1, a GTPase-activating protein that negatively regulates rat sarcoma virus GTPase (RAS) signaling [74]. Neurofibromatosis type 1, caused by mutations in the NF1 gene, is an autosomal-dominant condition and results in the formation of plexiform neurofibromas. These benign tumors of peripheral nerves, frequently associated with pain, disfigurement, and functional impairment, may progress into malignant peripheral nerve sheath tumors and cause substantial morbidity [74–76]. Mitogen‑activated protein kinase (MEK) inhibition remains the only approved treatment approach [74], with mirdametinib (Ezmekly^®; #7, Table 2; Fig. 3), an oral small-molecule inhibitor of MEK1 and MEK2, being the first agent indicated both for adult and pediatric patient populations [39, 40]. Loss of NF1 function results in sustained RAS activation and drives tumor growth [74]. Mirdametinib, an orphan drug (see glossary in Table 1), inhibits MEK activity within the RAS‑rapidly accelerated fibrosarcoma (RAF)‑MEK pathway, thereby suppressing growth and survival of tumor cells in which the RAF‑MEK‑extracellular signal-regulated kinase (ERK) pathway is activated [39]. Mirdametinib offers a significant advancement in the treatment of neurofibromatosis type 1-associated plexiform neurofibromas, offering durable reduction of tumor volume, relief of pain, improved quality of life, and a tolerable safety profile [76]. The most commonly reported side effects are acneiform dermatitis, diarrhea, nausea, an increase in blood creatine phosphokinase, and musculoskeletal pain [39].

Mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit alpha (PIK3CA) gene are common in breast cancer and lead to abnormal activation of the PI3K/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway, strongly implicated in tumorigenesis and drug resistance [77, 78]. In estrogen-receptor positive, HER2-negative advanced breast cancer (see glossary in Table 1), dysregulation of this pathway is considered a key mechanism underlying resistance to endocrine therapy and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, the first-line therapeutic options [78]. Inavolisib (Itovebi^®; #8, Table 2; Fig. 3) is an inhibitor of the protein p110α, encoded by the PIK3CA gene. Additionally, it acts as a mutant degrader by promoting the degradation of mutated p110α [41]. Because of its dual mechanism of action, inavolisib suppresses the activation of downstream PI3K pathway mediators, including AKT, which results in a reduction of cellular proliferation and induction of apoptosis in breast cancer cells with PIK3CA mutations [41, 42]. Among the side effects of inavolisib, the most common ones are hyperglycemia, stomatitis, diarrhea, and thrombocytopenia [42].

Mutations in genes encoding isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) enzymes lead to the overproduction of 2-hydroxyglutarate (2-HG), an oncogenic metabolite, which impairs cellular differentiation [43, 79]. Within the spectrum of diffuse gliomas, IDH-mutant grade 2 tumors mainly affect young patients [80]. Despite their indolent growth pattern, they demonstrate persistent progression, and recurrence is almost inevitable [81, 82]. Surgical resection remains the first-line intervention, followed by magnetic resonance imaging (MRI) surveillance in low-risk patients and radiochemotherapy in those at high risk [81]. Although these procedures improve overall survival, they may negatively impact cognitive function, quality of life, financial stability, employment, and overall independence [80]. The orphan drug vorasidenib (Voranigo^®; #9, Table 2; Fig. 3), a highly brain-penetrant first-in-class inhibitor of mutant IDH1/2 enzymes, addresses the need for a novel approach that postpones disease progression and defers the use of radio- and chemotherapy [44, 80, 83]. By targeting the mutants of IDH1 and IDH2, vorasidenib reduces the excessive production of 2-HG, thereby leading to differentiation of malignant cells and reduction of their proliferation. The most common side effects observed after vorasidenib treatment are fatigue, diarrhea, and laboratory abnormalities (i.e., increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT)) [43, 44].

Migraine is associated with increased plasma levels of calcitonin gene-related peptide (CGRP), a neuropeptide that functions as a strong vasodilator and contributes to the modulation of pain [45, 84]. Several monoclonal antibodies directed against CGRP (galcanezumab, fremanezumab, and eptinezumab) or its receptor (erenumab) and small-molecule CGRP receptor antagonists (rimegepant) indicated for migraine prophylaxis and/or acute treatment have reached the market recently [84, 85]. The latter drugs are highly selective ligands, whereas in the case of atogepant (Aquipta^®; #10, Table 2; Fig. 3), modulation of more than one calcitonin/CGRP-receptor family member could be involved in its pharmacological effects. Yet, the exact biological mechanism responsible for atogepant’s role in migraine prevention has not been definitively identified [46]. Its most common adverse reactions are nausea, constipation, and fatigue/somnolence [46, 86].

Monocarboxylate transporter 8 (MCT8) deficiency is a rare X-linked genetic condition stemming from mutations in the SLC16A2 gene [87]. Under physiological conditions, MCT8 is responsible for the transport of thyroid hormones, particularly triiodothyronine (T3), across the cell membrane into cells, thereby enabling their proper metabolic and developmental functions [88]. Mutations in the MCT8 gene lead to Allan-Herndon-Dudley syndrome, a condition marked by severe neurodevelopmental impairment and motor dysfunction caused by insufficient thyroid hormone levels in the brain, along with accompanying endocrine abnormalities resulting from chronic thyrotoxicosis due to elevated thyroid hormone levels outside the central nervous system [89]. The orphan drug tiratricol (Emcitate^®; #11, Table 2; Fig. 4), an agonist of the thyroid hormone receptors TRα and TRβ, is a novel treatment option. As a metabolite of active thyroid hormone T3, it shares a high degree of structural similarity. Although its degradation (via deiodination and conjugation) and elimination (via bile and urine) follow the same pathway as T3, tiratricol is characterized by its different tissue specificity. Moreover, unlike T3 and L-thyroxine (T4), tiratricol is able to enter MCT8-dependent cells without a functioning MCT8. Therefore, tiratricol is able to replace T3 in MCT8-dependent tissues and restore normal thyroid hormone activity [47, 48]. Commonly reported adverse effects of tiratricol involve hyperhidrosis, diarrhea, irritability, anxiety, and nightmares [47].

Fig. 4.

Comparison of the structures of tiratricol, a dual thyroid hormone receptor TRα and TRβ agonist, and the human thyroid hormones 3,3’,5-triiodothyronine (T3; INN liothyronine) and L-thyroxine (T4; INN levothyroxine). T3 is a 5’-deiodinized form of T4 (3,3‘,5,5’-tetraiodo-L-thyronine). Tiratricol (3,3’,5-triiodothyroacetic acid) is a derivative (and metabolite) of T3 [48]. INN, international nonproprietary name

New multi-target drugs in 2025 – evaluation

In Germany, newly introduced drugs are subjected to at least two systems of evaluation. 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 (taken from Gensthaler et al., 2026 [90]). Table 2 provides rating for each of the 11 compounds. Drugs were rated as step or disruptive innovations with three 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, after six months they check whether a newly introduced drug has an advantage over the standard therapy. When an additional benefit cannot be demonstrated, the annual treatment costs of the new drug must not exceed those of the appropriate comparator [91]. This procedure is more rigorous than that of the EMA, which postulates the therapeutic effect and safety of the new drug only. A considerable additional benefit exists for (one indication of) inavolisib (Table 2). For mirdametinib, vorasidenib, and tiratricol, an additional benefit was also demonstrated, although its magnitude could not be quantified (Table 2). Notably, for orphan drugs the additional medical benefit is considered to be proven through the grant of the marketing authorization.

Post-marketing surveillance of multi-target drugs authorized by EMA in 2022 to 2024: safety verification

Our search in the PubMed database revealed that post-registration safety evaluation studies were available for 19 out of the 27 compounds marketed in Germany in 2022–2024 [12, 13] and still available on the EU market (Table 3). Duvelisib (indicated for chronic lymphatic leukemia or follicular lymphoma [12]) was withdrawn in EU in February 2026 upon the request of the authorization holder due to commercial reasons [92]. The majority of real-world safety data in those studies was derived from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), which, although primarily reflecting the United States population, provides valuable early pharmacovigilance insights also for the use of these drugs in Europe.

Table 3.

Summary of post-marketing pharmacovigilance studies regarding multi-target-directed ligands introduced in Germany in years 2022–2024

INN (brand name) Short description	Indications1	Post-marketing data	Comparison to safety profile of other drugs	Sex/Age analysis	Main ADRs; new signals	Advantage of polypharmacology in terms of drug safety	Clinical recommendations	References
Trastuzumab deruxtecan (Enhertu®) antibody-drug conjugate	unresectable or metastatic HER2-positive (or HR-positive, HER2-low or HER2-ultralow) breast cancer; advanced NSCLC with activating HER2 mutation; advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma	5 studies (including 3 based on FAERS2 and 1 on JADER3)	yes	partial4	interstitial lung disease, pulmonary embolism, musculoskeletal, infection-related, and GI ADRs, left ventricular dysfunction	n/e	dose adjustment, interstitial lung disease monitoring	[93–98]
Enfortumab vedotin (Padcev®) antibody-drug conjugate	unresectable or metastatic urothelial cancer (as monotherapy or in combination with pembrolizumab)	3 studies (FAERS)	yes (other ADCs)	yes (higher cardiovascular risk in males)	focus on peripheral neuropathy, skin reactions [99, 100], and cardiovascular symptoms [93]; new: SJS/TEN-like reactions (fatal skin toxicity); retroperitoneal fibrosis	n/e	early dermatologic and cardiovascular monitoring	[93, 99–101]
Amivantamab (Rybrevant®) bispecific antibody	advanced NSCLC with EGFR mutations (in combinations or as monotherapy)	4 studies (FAERS)	no	partial; mortality ↑ in older males with pneumonitis or pneumonia	infusion-related reaction, rash, acneiform dermatitis, paronychia, venous thrombosis, abnormal blood pressure, hypokalemia	n/e	strict monitoring, including dermatologic and cardiovascular ADRs (high mortality!), dose adjustment	[102–106]
Teclistamab (Tecvayli®), Talquetamab (Talvey®), Elranatamab (Elrexfio®) bispecific antibodies	relapsed and refractory MM (after at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody in patients who have demonstrated disease progression on the last therapy)	2 studies (FAERS)	yes (other T-cell engagers, including glofitamab, epcoritamab, mosunetuzumab, tebentafusp)	no	CRS and ICANS (e.g. consciousness level↓); elranatamab: eye disorders new: teclistamab: spinal cord compression, unresponsiveness to stimuli, elranatamab: hydronephrosis, syncope	n/e	monitoring for delayed toxicities, high vigilance	[107–111]
Glofitamab (Columvi®) bispecific antibody	relapsed or refractory DLBCL (after at least two lines of systemic therapy)	2 studies (FAERS)	yes (see teclistamab)	partial (worse outcomes in older males)	CRS; mantle cell lymphoma; new: hypogammaglobulinemia	n/e	CRS prevention, pre-treatment protocols, monitoring for early toxicities	[107, 112, 113]
Epcoritamab (Tepkinly®) bispecific antibody	relapsed or refractory DLBCL and follicular lymphoma (after at least two lines of systemic therapy)	2 studies (FAERS)	yes (see teclistamab)	no	CRS, ICANS, renal and urinary disorders, infections; new: hydronephrosis, PML	n/e	early monitoring of renal and urinary function; vigilance for CRS	[21, 107, 114]
Mosunetuzumab (Lunsumio®) bispecific antibody	relapsed or refractory follicular lymphoma (after at least two prior systemic therapies)	1 study (FAERS)	yes (see teclistamab)	no	CRS; new: vasogenic cerebral edema, second malignant neoplasms	n/e	monitoring for delayed neurologic symptoms and CRS	[107, 115]
Tebentafusp (Kimmtrak®) bispecific fusion protein	HLA-A*02:01-positive unresectable or metastatic uveal melanoma	1 study (FAERS)	yes (see teclistamab)	no	CRS, vascular disorders, reproductive system and breast disorders	n/e	monitoring for vascular complications, delayed ADRs, and CRS	[107, 116]
Fruquintinib (Fruzaqla®) kinase inhibitor	metastatic colorectal cancer in patients treated previously with standard therapies (fluoropyrimidine-, oxaliplatin-, and irinotecan-based), anti-VEGF and anti-EGFR agents, who have progressed on/are intolerant to trifluridine-tipiracil or regorafenib	2 studies (FAERS)	yes (other tyrosine kinases)	yes (male patients more likely to develop dysphonia and myelosuppression; females - hypertension, diarrhea, nausea, and pain; elderly - more susceptible to asthenia)	fatigue, hypertension, diarrhea, asthenia, dysphonia, stomatitis; neurological, renal, and cardiovascular toxicities; new: dehydration; myelosuppression, peripheral neuropathy, posterior reversible encephalopathy syndrome; intestinal and biliary obstruction; thrombotic microangiopathy (kidney)	n/e	early monitoring (first month of therapy) for hypertension, dehydration, neurological symptoms, renal dysfunction, and hematologic toxicity	[117–119]
Futibatinib (Lytgobi®) kinase inhibitor	locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or rearrangement that have progressed after at least one prior line of systemic therapy	1 study (FAERS)	yes (other FGFR inhibitors)	limited; mortality ↑ in patients ≤ 65	hyperphosphatemia, hypercalcemia, nail toxicity, diarrhea; new: hypomagnesemia	n/e	lab monitoring, early toxicity management	[120, 121]
Ritlecitinib (Litfulo®) kinase inhibitor	severe alopecia areata in adults and adolescents 12 years of age and older	3 studies (FAERS)	yes (other JAK inhibitors)	limited; infections more common among females	skin disorders, infections, hypercholesterolemia, GI ADRs, CK ↑; new: hair color changes, herpes simplex reactivation, laryngitis, diabetes mellitus, thyroid disorder	n/e	monitor GI symptoms and CK levels	[122–125]
Ripretinib (Qinlock®) kinase inhibitor	advanced GI stromal tumor in patients who have received prior treatment with three or more kinase inhibitors, including imatinib	5 studies (FAERS)	yes (avapritinib, imatinib, sunitinib)	yes (male patients more frequently reported alopecia, tumor progression, abnormal hair texture, and fatigue; females - hyperkeratosis, and tumor-associated pain; elderly - more susceptible to ADRs)	GI disorders (constipation, diarrhea), skin and subcutaneous tissue disorders (alopecia, dry skin, PPES), pruritus, muscle spasms, hypertension, appetite↓, fatigue; new: hepatic neoplasm, hepatic lesion, liver abscess; skin papillomas, melanocytic nevi, abnormal hair texture; pleural mass, electrolyte abnormalities, hypersomnia, coagulation-related bleeding	n/e	regular monitoring of hepatic function, dermatologic changes, blood pressure, electrolytes, coagulation parameters, and tumor-related symptoms	[126–131]
Desvenlafaxine (Desveneurax®) small molecule	major depression	1 study (FAERS)	yes (fluoxetine)	yes; lower suicidality risk vs fluoxetine in the entire population and in ≤ 18 and ≥65 year old patients	lower suicidality risk vs fluoxetine	n/e	consider in patients at high risk for suicidality	[12, 132]
Tirzepatide (Mounjaro®) peptide	type 2 diabetes mellitus in patients ≥ 10 years of age as an adjunct to diet and exercise; weight management in patients with initial BMI ≥ 30 kg/m2 (obesity) or ≥27 kg/m2 to < 30 kg/m2 (overweight) in the presence of at least one weight-related comorbid condition (e.g. hypertension)	16 studies (including 1 FAERS- & VigiBase4-based & 9 FAERS-based)	yes (GLP-1 analogues, e.g., semaglutide; insulin)	yes; higher frequency of GI issues, sleep disorders and medullary thyroid carcinoma (males) and of ketoacidosis and injection site reactions (females)	GI issues; new: gastroesophageal reflux disease, blood glucose ↑, postmenopausal hemorrhage, menstrual disorder, sleep disorder, Wernickeʼs encephalopathy, non-arteritic anterior ischemic optic neuropathy; additional problems: injection site reactions, incorrect dose administration, off-label use	yes; frequency of some ADRs of tirzepatide < semaglutide (e.g., GI issues, pancreatico-biliary disorders, acute kidney injury, suicidality, diabetic retinopathy) or even beneficial effect of tirzepatide (promotion of bone formation)	gradual dose escalation, GI monitoring	[133–149]
Etrasimod (Velsipity®) small molecule	ulcerative colitis (moderately to severely active) in patients aged 16 and older who have had an inadequate response, lost response, or were intolerant to conventional therapy or a biological agent	2 studies (FAERS)	yes (other S1P modulators, fingolimod and ozanimod)	limited (male-specific hepatobiliary risk)	general disorders and administration site conditions, GI, ocular, metabolic, and immune system disorders; new: drug ineffectiveness and ulcerative colitis exacerbation; headache, dizziness, fatigue, diarrhea, blurred vision	yes, shorter half-life, improved safety vs other S1P modulators	lymphocyte and liver monitoring	[150–152]
Sparsentan (Filspari®) small molecule	primary immunoglobulin A nephropathy	3 studies (including 1 FAERS- & VigiBase5-based & 2 FAERS-based)	yes (irbesartan)	yes (ADRs slightly more common in males and elderly patients)	hypotension, dizziness, fatigue, nausea, peripheral edema, hyperkalemia, headache, renal impairment; new: somnolence, loss of consciousness; renal pain, abnormal creatinine metabolism, fluid retention; hepatic dysfunction; ear disorders, musculoskeletal chest pain	n/e	regular monitoring of blood pressure, renal and hepatic function, electrolytes, and fluid retention; individualized dose adjustment and close surveillance	[153–156]
Zilucoplan (Zilbrysq®) peptide	generalized myasthenia gravis (as add-on to standard therapy)	1 study (FAERS)	yes (other new drugs used for treatment of myasthenia gravis)	limited	injection site reactions; new: weight gain or loss	n/e	continued long-term monitoring	[157, 158]

The table comprises drugs for which at least one comprehensive post-approval pharmacovigilance study is available. Drugs are arranged as in Table 2, i.e., (i) ADCs, (ii) bispecific antibodies, (iii) kinase inhibitors, and (iv) other drugs. For each drug, the indication is given; if not stated otherwise, the respective drug was approved for use in adults only; n/e, not established

¹for more details regarding indications please see respective summaries of product characteristics, EMA

²FAERS, Food and Drug Administration Adverse Event Reporting System

³JADER, Japanese Adverse Drug Event Report database

⁴sex differences may largely reflect underlying disease epidemiology rather than true biological variability

⁵VigiBase, WHO (World Health Organization) counterpart of the FAERS, aggregating reports from over 180 countries

ADC(s), antibody-drug conjugate(s); ADR(s), adverse drug reaction(s); BMI, body mass index; CD38, cluster of differentiation 38; CK, creatine kinase; CRS, cytokine release syndrome; DLBCL, diffuse large B-cell lymphoma; EGFR, epidermal growth factor receptor; EMA, European Medicines Agency; FGFR(2), fibroblast growth factor receptor (2); GI, gastrointestinal; GLP-1, glucagon-like peptide 1; HLA, human leukocyte antigen; HR, hormone receptors (estrogen and progesterone receptors); ICANS, immune effector cell-associated neurotoxicity syndrome; INN, international nonproprietary name; JAK, Janus non-receptor tyrosine kinase; MM, multiple myeloma; NSCLC, non-small cell lung cancer; PML, progressive multifocal leukoencephalopathy; PPES, palmar-plantar erythrodysesthesia syndrome; S1P, sphingosine-1-phosphate; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; VEGF, vascular endothelial growth factor; ↑, increase; ↓, decrease

To the best of our knowledge, 8 MTDLs authorized in 2022–2024 still lack comprehensive post-approval safety analyses (i.e., studies focused on a wide spectrum of ADRs, and not limited to a specific organ or system), including drugs approved for the treatment of cancer (momelotinib [13]), primary biliary cholangitis (elafibranor [13]), hand eczema (delgocitinib [13]), and insomnia (daridorexant [12]). In the case of the anti-cancer agent loncastuximab tesirine [13], only hematological ADRs were considered [159]. Similarly, in the case of another anti-cancer agent, capivasertib [13] only ADRs within the oral cavity were analyzed [160]. In both instances, new safety signals were not observed. In the case of vamorolone (indicated for the treatment of Duchenne muscular dystrophy in patients ≥ 2 years of age [13]), the analysis of the FAERS database was performed in the context of drug-induced urinary incontinence only; pediatric urinary incontinence was identified as a new signal [161]. The post-marketing safety of faricimab (indicated for the treatment of age-related macular degeneration [12]) was assessed only in a small case-series study focusing on the eye which revealed sterile intraocular inflammation as a so far unknown ADR [162].

The post-marketing safety analysis of the anti-HER2 (see glossary in Table 1) ADC trastuzumab deruxtecan showed high rates of grade ≥ 3 adverse events (Table 1) in real-world settings, particularly interstitial lung disease, necessitating dose adjustments and careful monitoring [93–95]. In the case of another ADC, enfortumab vedotin, indicated for advanced urothelial carcinoma [12], the studies focused on dermatologic and cardiovascular toxicity [93, 99, 100] and revealed severe cutaneous reactions such as Stevens-Johnson syndrome (SJS) as new signals (Table 3).

The bispecific antibody amivantamab was approved for the treatment of some forms of advanced NSCLC [12]. Its use has been associated with several serious ADRs, such as pneumonitis, pneumonia, and dermatological complications. Safety concerns are particularly pronounced in older male patients, who appear to be at an increased risk of pulmonary complications. In addition, amivantamab has raised concerns regarding cardiovascular safety, with cardiovascular adverse events accounting for a substantial proportion of fatal outcomes (16.3%). Major adverse cardiovascular events were associated with particularly poor prognosis, with mortality reaching up to 60% in reported cases [102–105].

Another six bispecific antibodies (teclistamab, talquetamab, elranatamab, glofitamab, epcoritamab [13], and mosunetuzumab [12]) and a fusion protein (tebentafusp [12]) are also anti-tumor drugs (for indications, see Table 3). They share a similar mechanism of action involving simultaneous binding to a tumor antigen and to CD3 on cytotoxic T cells, which results in the activation of the latter and subsequent tumor cell lysis. T-cell activation is associated with the release of proinflammatory cytokines, explaining why T-cell engagers can elicit a CRS and an immune effector cell-associated neurotoxicity syndrome (ICANS; for glossary, see Table 1). The ADRs of the seven drugs were compared to each other in a FAERS-based study [107] and many common properties but also marked differences were found (Table 3). Moreover, their safety profiles vary, according to target antigen and pharmacokinetic properties. Agents directed against BCMA (teclistamab, elranatamab) and G protein-coupled receptor class C group 5 member D (GPRC5D) (talquetamab) are more often associated with delayed-onset toxicities, including CRS, ICANS, and organ-specific signals such as ocular, skin, and, in some cases, novel malignancy or renal-related events. CD20-directed bispecific antibodies (glofitamab, epcoritamab, mosunetuzumab) show more heterogeneous profiles, with glofitamab demonstrating earlier toxicity onset due to a shorter half-life, while epcoritamab and mosunetuzumab are associated with delayed inflammatory and multi-organ immune-related ADRs. Tebentafusp, not targeting BCMA, GPRC5D or CD20, shows an early onset toxicity profile dominated by vascular events with fewer infectious complications [107]. Concerning the severity of ADRs, approximately 50% of the reports for epcoritamab, elranatamab, and mosunetuzumab involved hospitalization, indicating the potential seriousness of these events. Conversely, talquetamab demonstrated relatively lower hospitalization and mortality rates, suggesting a more favorable safety profile [107]. New safety signals were detected for glofitamab (hypogammaglobulinemia), epcoritamab (hydronephrosis, progressive multifocal leukoencephalopathy (PML), see glossary in Table 1), mosunetuzumab (vasogenic cerebral edema, second malignant neoplasms), and tebentafusp (vascular, breast and reproductive system disorders) [107].

Four small molecules targeting different sets of kinases were considered as well. FAERS-based studies for fruquintinib, approved for the treatment of metastatic colorectal cancer [13], revealed new hematological, neurological, GI, renal, and cardiovascular ADRs (Table 3). Post-marketing data for futibatinib (indicated for the treatment of advanced bile duct cancer [13]) revealed new safety concerns such as hypomagnesemia and a higher mortality signal in younger patients [120] (Table 3). The increased mortality was not shared by another two FGFR inhibitors, erdafitinib and pemigatinib [120]. For ritlecitinib, approved for the treatment of severe alopecia areata [13], FAERS data revealed drug-specific safety signals, including GI events and elevated creatine kinase, with early onset after treatment initiation, supporting the need for monitoring; new signals were also identified (Table 3). Ripretinib, indicated for the treatment of advanced GI stromal tumors [12], frequently led to disorders of the GI tract and of the skin and subcutaneous tissue. As novel safety signals abnormalities of the liver, skin, and hematologic system were identified [126–130] (Table 3).

Desvenlafaxine is an antidepressant that simultaneously inhibits the neuronal serotonin and noradrenaline transporters [12]. With respect to the treatment of children and adolescents, antidepressants, except for fluoxetine, do not offer a clear advantage over placebo, and some antidepressants might increase the risk of suicidality (suicidal ideation, suicide attempt, completed suicide) [163]. If one considers antidepressant effectiveness plus effect on suicidality, fluoxetine is relatively favorable in this age group. Fluoxetine (approved for antidepressant treatment in children and adolescents both by the FDA and the EMA) served as the comparator in a FAERS analysis in which desvenlafaxine and another 37 antidepressants as well as lithium were considered [132]. Only desvenlafaxine and vilazodone were able to outperform fluoxetine with a reduced risk of reporting suicidality in the entire study population; desvenlafaxine was superior to fluoxetine also in the group of children and adolescents (Table 3).

Tirzepatide, approved for type 2 diabetes and weight management [13], is one of the most extensively characterized agents in the post-marketing setting, supported by multiple pharmacovigilance real-world studies (Table 3). Post-marketing data confirm the profile of ADRs and have further expanded their list [133–135]. A notable real-world issue with tirzepatide is the increasing frequency of dosing errors, underscoring the importance of patient education and structured therapeutic support [136]. Real-world pharmacovigilance analyses have demonstrated lower reporting odds for heart failure with tirzepatide, without significant signals for ischemic or arrhythmic events in healthcare professional reports [137]. These findings are especially relevant given the growing interest in tirzepatide for heart failure with preserved ejection fraction [164].

Comparative analyses suggest a favorable safety profile of tirzepatide in comparison to semaglutide. This is remarkable since tirzepatide (an analogue of both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)) causes an even higher weight loss (by ~ 5%) than semaglutide (GLP-1 analogue only) [165]. (i) The frequency of many ADRs is similar for tirzepatide vs semaglutide (e.g. [133, 138]). (ii) Lower reporting rates of acute kidney injury, and no significant signal of suicidality were published for tirzepatide when compared to semaglutide [139–141]. (iii) In marked contrast to semaglutide, tirzepatide has even a beneficial effect on bone (suppression of bone resorption and increase in bone formation) [142].

Among drugs indicated for the treatment of diseases of the immune system, etrasimod, a sphingosine-1-phosphate (S1P) modulator, is indicated for the treatment of ulcerative colitis [13] (Table 3). This drug exhibited a favorable lymphocyte safety signal relative to other S1P modulators, alongside a shorter half-life and reduced risk of prolonged immunosuppression; hepatobiliary adverse events were noted predominantly in male patients. Interestingly enough, the drug frequently proved to be ineffective or even aggravated ulcerative colitis [150, 151]. In the case of sparsentan, indicated for immunoglobulin A nephropathy [13], new safety signals comprise neurological, renal, and hepatic ADRs [153–155] (Table 3). Zilucoplan was approved for the treatment of myasthenia gravis [13]. Post-marketing safety analysis confirmed that injection site reactions are common ADRs (probably due to the subcutaneous mode of administration) and revealed weight gain or, even more often, its loss as new signals (Table 3 [157]). Zilucoplan is just one of 5 new drugs for the treatment of myasthenia gravis (see glossary, Table 1), and serious reports of events were 82%, as compared to ravulizumab (33%), eculizumab (38%), rozanolixizumab (78%) and efgartigimod (93%) [157].

Across studies, consideration of demographic variables such as sex and age was inconsistent. While some analyses identified clinically relevant differences, including sex-specific ADRs and age-related variability in outcomes, the lack of systematic stratification represents a major limitation. Additional constraints include reliance on FAERS data, underreporting, reporting bias, reporting by health professionals vs patients, and the absence of denominator data, precluding incidence estimation and causal inference.

Practical clinical actions proposed in the literature include gradual dose escalation, routine laboratory monitoring, early recognition of ADRs, and structured patient education (Table 3). These strategies underscore the importance of multidisciplinary collaboration in post-marketing pharmacovigilance, involving physicians, nurses, clinical pharmacists, and other healthcare professionals working closely with patients. Such integrated cooperation may help to reduce the burden on healthcare systems by supporting adverse event reporting, maintaining real-world data registries, facilitating early signal detection, and improving treatment adherence and patient awareness of potential therapy-related risks [166].

Conclusions

Polypharmacology is an emerging paradigm in drug design, development, and clinical implementation, which involves MTDLs, able to interact with multiple molecular targets simultaneously, as a more optimal alternative to single-target-based therapy, especially in the context of chronic multifactorial diseases. Among the 38 substances approved by the EMA and introduced in Germany in 2025, 11 were classified as MTDLs, i.e., antibody-drug conjugates, bispecific antibodies, and small molecules. There is minimal year-to-year fluctuation in the number of polypharmacological drugs brought to the market (11 substances approved in 2024, 7 in 2023, and 10 in 2022 (Ryszkiewicz et al., 2023 [12], 2025 [13]) and their primary indication, as most of them are tailored for cancer treatment. Eight of the 11 drugs approved by the EMA in 2025 were rated as step or disruptive innovations according to Pharmazeutische Zeitung, a German journal for pharmacists. Another rating in Germany (by Joint Federal Committee) revealed a considerable additional benefit of inavolisib over the standard therapy regarding PIK3CA-mutated breast cancer in patients not treated previously with a CDK4/6 inhibitor, and a non-quantifiable benefit in the case of mirdametinib, vorasidenib, and tiratricol.

Post-marketing pharmacovigilance studies remain essential for optimizing the safe use of newly authorized therapies, including those with polypharmacological mechanisms of action. Despite some methodological weaknesses, such studies are particularly important since they reflect real-world conditions and encompass far higher numbers of treated persons than in clinical phases 1–3. For such studies, the real-world databases such as FAERS are of utmost importance. As expected, ADRs listed in the EMA summaries of product characteristics occurred, but also new safety signals, including the potentially fatal SJS and PML, were identified. It is intriguing that the dual GLP-1 and GIP analogue not only reduces weight more strongly than a selective GLP-1 analogue, but also has a more favorable safety profile (e.g., lower frequency of acute kidney injury and no significant suicidality signal).

Abbreviations

2-HG

2-hydroxyglutarate

ADC(s)

Antibody-drug conjugate(s)

ADCC

Antibody-dependent cellular cytotoxicity

ADCP

Antibody-dependent cellular phagocytosis

ADR(s)

Adverse drug reaction(s)

AI

Artificial intelligence

AKT

Protein kinase B

ALK

Anaplastic lymphoma kinase

ALT

Alanine aminotransferase

AST

Aspartate aminotransferase

ATC

Anatomical therapeutical chemical classification

ATP

Adenosine triphosphate

BCMA

B-cell maturation antigen

BMI

Body mass index

CD3, 20, 38

Cluster of differentiation 3, 20, 38

CDK4/6

Cyclin-dependent kinase 4/6

CGRP

Calcitonin gene-related peptide

CK

Creatine kinase

CRISPR

Clustered regularly interspaced short palindromic repeats

CRS

Cytokine release syndrome

DLBCL

Diffuse large B-cell lymphoma

DXd

Deruxtecan

EGFR

Epidermal growth factor receptor

EMA

European Medicines Agency

ERK

Extracellular signal-regulated kinase

EU

European Union

FAERS

Food and Drug Administration Adverse Event Reporting System

Fc

Fragment crystallizable region of an antibody

FDA

Food and Drug Administration

FGF

Fibroblast growth factor

FGFR2, 3

Fibroblast growth factor receptor 2, 3

GGT

Gamma-glutamyltransferase

GI

Gastrointestinal

GIP

Glucose-dependent insulinotropic polypeptide

GLP-1

Glucagon-like peptide-1

GPRC5D

G protein-coupled receptor class C group 5 member D

HER2

Human epidermal growth factor receptor 2

HER2/neu

Receptor tyrosine kinase within the erb-b2 family

HLA

Human leukocyte antigen

HPV

Human papillomavirus

HR

Hormone receptors (estrogen and progesterone receptors)

ICANS

Immune effector cell-associated neurotoxicity syndrome

IDH1, 2

Isocitrate dehydrogenase 1, 2

IgG1

Immunoglobulin G1

IgG4

Immunoglobulin G4

IL-6

Interleukin 6

INN

International nonproprietary name

JAK

Janus non-receptor tyrosine kinase

JCV

Human polyomavirus 2

MCT8

Monocarboxylate transporter 8

MEK1, 2

Mitogen-activated protein kinase 1, 2

MHC

Major histocompatibility complex

MM

Multiple myeloma

MMAE

Monomethyl auristatin E

MRI

Magnetic resonance imaging

MTDL(s)

Multi-target-directed ligand(s)

mTOR

Mammalian target of rapamycin serine/threonine protein kinase

NF1

Neurofibromin 1 gene

NSCLC

Non-small cell lung cancer

NTRK

Neurotrophic receptor tyrosine kinase

PABA

p-aminobenzoic acid

PD-1

Programmed death receptor 1

PD-L1

Programmed death receptor 1 ligand 1

PI3K

Phosphatidylinositol-3-kinase

PIK3CA, p110α

Phosphatidylinositol-4, 5-bisphosphate-3-kinase catalytic subunit alpha gene/protein

PML

Progressive multifocal leukoencephalopathy

PPES

Palmar-plantar erythrodysesthesia syndrome

RAF

Rapidly accelerated fibrosarcoma serine/threonine protein kinase

RAS

Ras (rat sarcoma virus) GTPase

ROS1

ROS proto-oncogene 1 receptor tyrosine kinase

S1P

Sphingosine-1-phosphate

SGB V

German Social Code Book Five

SJS

Stevens-Johnson syndrome

SLC16A2

Monocarboxylate transporter 8 gene

T3

Triiodothyronine, liothyronine

T4

L-thyroxine, levothyroxine

TEN

Toxic epidermal necrolysis

TF

Tissue factor

TKI(s)

Tyrosine kinase inhibitor(s)

TRK

Tropomyosin receptor tyrosine kinase

TRKA, B, C

Tropomyosin receptor tyrosine kinase A, B, C

TROP2

Trophoblast cell surface antigen 2

TRα, β

Thyroid hormone receptors α, β

VEGF

Vascular endothelial growth factor

Author contributions

Piotr Ryszkiewicz (PR): conceptualization, data curation, funding acquisition, methodology, project administration, resources, software, visualization, writing – original draft, writing – review and editing, Marta Baranowska-Kuczko (MB-K): data curation, writing – original draft, writing – review and editing, Barbara Malinowska (BM): writing – review and editing

Eberhard Schlicker (ES): supervision, writing – review and editing

Funding

The study was supported by the Medical University of Białystok, Poland (B.SUB.26.129).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethical approval

Not applicable.

Disclosure of using artificial intelligence (AI) in the writing process

No AI or AI-assisted technologies were used in the preparation of this manuscript.

Competing interests

The authors declare no competing interests.