RCC management has evolved toward immunotherapy-based strategies, with adjuvant anti-PD-1 therapy after nephrectomy and immune-VEGF TKI combinations in the metastatic setting now representing standards of care. Outcomes remain variable because of biological heterogeneity, treatment resistance, and the limited performance of currently available biomarkers. This review synthesizes contemporary standards of care together with advances in tumor biology and biomarker development, and appraises investigational modalities across immune, targeted, and cellular platforms. We analyze how standards of care and translational insights have evolved in recent years, outlining the principal directions of current and investigational treatments. The field is moving toward biology-informed treatment selection. Priorities include prospective validation of biomarker strategies, standardization of assay platforms, and integration of dynamic response measures to refine treatment selection, sequencing, and combinations. Molecularly defined subsets and less common histologies warrant dedicated, adequately powered studies. With rigorous methodology and standardized testing methods, emerging approaches have the potential to translate current signals into more consistent and durable clinical benefits in RCC. Renal cell carcinoma is the most common form of kidney cancer in adults. Over the past decade, treatment options have expanded remarkably, leading to major improvements in patient survival and quality of life. The use of immune checkpoint inhibitors, often combined with tyrosine kinase inhibitors that block tumor blood-vessel growth, has become the standard of care for advanced diseases. Pembrolizumab is also approved as an adjuvant therapy after surgery to reduce the risk of relapse.Despite these advances, some patients do not respond or develop resistance. New investigational agents are now being studied, including HIF-2α inhibitors, such as belzutifan, MET, and AXL inhibitors, that target resistance pathways and antibody–drug conjugates or cell-based immunotherapies designed to attack tumor-specific targets.At the same time, research on biomarkers is becoming central to the future of RCC care. Genetic alterations such as PBRM1, SETD2, and BAP1 are being investigated as potential predictors of response to immunotherapy or targeted agents, while molecular signatures derived from RNA sequencing may help classify tumors into biologically distinct subtypes. In parallel, circulating and urinary biomarkers – including soluble proteins and tumor DNA – offer promising tools for noninvasive disease monitoring and early detection of relapse.Together, these innovations are moving RCC treatment toward a more precise, biology-driven approach that tailors therapy selection and follow-up to each patient’s unique tumor profile.
Myelofibrosis (MF) is a clonal myeloproliferative neoplasm driven by dysregulated JAK-STAT signaling and epigenetic alterations, characterized by chronic inflammation, marrow fibrosis, and limited disease-modifying treatment options. Bromodomain and extra-terminal (BET) proteins regulate transcriptional programs implicated in MF pathogenesis, making BET inhibition a rational therapeutic strategy. This review discusses the biological rationale for BET inhibition in MF and critically appraises clinical development from January 2015 to November 2025. We summarize preclinical evidence and clinical trial data of BET inhibitors, including pelabresib, INCB057643, BMS-986158, and other investigational agents, both as monotherapy and in combination with JAK inhibitors. The literature search included international clinical trial registries (ICTRP, Clinical trial.gov), databases, conference abstracts, and peer-reviewed publications, focusing on efficacy, safety, and potential disease-modifying effects. BET inhibitors represent a promising investigational class with the potential to complement JAK inhibition by targeting inflammatory, fibrotic, and proliferative pathways. Pelabresib has demonstrated clinically meaningful activity in phase 2-3 trials, supporting its potential role in first-line combination therapy. However, hematologic toxicities, durability of responses, and the impact on survival and leukemic transformation remain unresolved. Biomarker-driven patient selection and rational combination strategies will be essential to optimize the clinical integration of BET inhibitors in MF.
Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm (MPN) driven by recurrent acquired somatic mutations in hematopoietic stem cells and characterized by progressive bone marrow fibrosis, cytopenias, and extramedullary hematopoiesis. Janus kinase inhibitors (JAKi) improve splenomegaly and MF symptom burden but without achieving molecular remission or clear disease course modification. Novel therapies targeting epigenetic dysregulation through bromodomain and extra-terminal domain (BET) proteins have emerged as a key therapeutic approach, aimed at reducing pro-inflammatory and oncogenic transcription to deepen clinical responses in combination with JAKi therapy. This review summarizes the biology, preclinical data, and emerging clinical data in the development of novel BET inhibitor (BETi). Trials assessing the efficacy of pelabresib, ABBV-744, INCB057643, BMS-986158, and OPN-2853 are detailed herein. BET protein inhibition is a promising therapeutic target complementing JAK inhibition by co-targeting inflammatory pathways, fibrosis, and clonal proliferation. Pelabresib is a pan-BETi furthest in development demonstrating clinical benefit with ongoing trials. Research into novel pan-and selective-BETis both as monotherapy and in combination with JAKis or other mechanism-based therapies is ongoing. Whether BETi therapy in MF will ultimately deliver substantial anti-clonal activity to modify disease biology and meaningfully impact clinical outcomes is yet to be determined.
Over the past decade, the therapeutic landscape for sickle cell disease (SCD) has expanded beyond hydroxyurea to targeted small molecules, monoclonal antibodies, and transformative cellular and gene therapies. However, not every investigational approach survives the rigor of randomized trials, post-marketing surveillance, and commercial realities. High-profile discontinuations and trial failures have important implications for a disease community with longstanding unmet needs and a historical mistrust of biomedical research. This review analyzes the proximate causes of discontinuation of SCD therapies, highlighting recurrent themes such as overreliance on surrogate endpoints, trial design limitations, post-marketing safety surveillance gaps, enrollment challenges, and corporate reprioritization, and draws lessons for future drug development. We place the most consequential cases in context and discuss how next-generation agents, trial design innovations, biomarker-based strategies, and equitable deployment might reduce the likelihood and impact of future discontinuations. Finally, we propose pragmatic recommendations to maximize patient benefit while minimizing avoidable harms. Recent advances in sickle cell therapies bring real promise alongside setbacks. Failures are part of progress, but better trial design, transparency, patient partnership, and shared data can reduce harm, strengthen trust, and ensure innovation translates into meaningful, durable patient benefit.
The systemic administration of cytokines is constrained by their pleiotropic activity, dose-dependent toxicities, and short serum half-life, limiting their therapeutic window in cancer treatment. To overcome these challenges, strategies that restrict cytokine signaling to defined immune cell subsets within the tumor microenvironment have been developed to enhance efficacy while minimizing off-target effects. Among these, antibody-cytokine fusion proteins represent a rational design platform that enables selective and localized cytokine delivery to specific immune populations. This report outlines the design principles underlying tumor-associated antigen-targeted and cis-delivered IL-2- and IL-15-based immunocytokine platforms, with particular emphasis on the PD-1-directed cis-signaling strategy. Preclinical data on SOT201 are summarized, highlighting how its affinity optimized IL-15 mutein promote selective proliferation and enhanced effector function of PD-1+ CD8+ T cells. Cis-acting immunocytokines represent a promising class of advanced therapeutics that selectively direct cytokine payload to tumor infiltrating lymphocytes. This strategy has been shown to induce durable antitumor immunity and, in some cases, promote immune memory formation while limiting systemic toxicity. Ongoing clinical evaluation and rational combination approaches will ultimately define its therapeutic positioning in precision cancer immunotherapy.
Asthma is a chronic and heterogeneous airway disease in which epithelial-derived cytokines - TSLP, IL-33, and IL-25-act as upstream drivers of inflammation. Over the past decade, these alarmin cytokines have become key therapeutic targets, leading to the development of a new generation of biologics designed to intervene early in the inflammatory cascade. This review discusses findings from Phase I and II clinical trials investigating anti-alarmin therapies, including monoclonal antibodies and novel delivery platforms targeting TSLP, IL-33, and IL-25. A comprehensive literature search was conducted across PubMed, ClinicalTrials.gov, and recent conference proceedings to summarize safety, pharmacokinetic, and efficacy outcomes, as well as emerging biomarkers and genetic insights related to treatment response. Early-phase studies confirm that alarmin blockade is safe, biologically relevant, and efficacious for improving airway inflammation across multiple asthma phenotypes. TSLP inhibition is an approved and clinically available therapy, while IL-33 and IL-25 remain in earlier development. Future progress will rely on optimized airway-focused dosing strategies such as biomarker-guided patient selection and genetic profiling, to achieve optimal personalized therapy. Anti-alarmin biologics are poised to redefine asthma management by addressing inflammation at the epithelial origin of common asthma triggers and advancing clinical care toward precision medicine.
Alpha-1 antitrypsin (AAT) is an acute-phase glycoprotein belonging to the serine protease inhibitor (SERPIN) superfamily. An advanced understanding of functional and post-translational modifications highlighted a broad range of AAT effects on inflammation, metabolism, and cell survival. AAT's SERPIN activity is important to inhibit overactivation of several endogenous proteases, a crucial function evidenced by the fact that mutant AAT isoforms can promote lung and liver disease. However, recent research highlighted that AAT's physiological and pathophysiological functions extend beyond SERPIN function. AAT isolated from healthy donors' plasma is approved for augmentation therapy and remains the only disease-modifying therapy approved for patients with severe AAT deficiency. We searched PubMed and Google Scholar to review the current literature on AAT function, the pathophysiology of AAT deficiency, and the growing evidence of additional biological effects independent of protease inhibition. Preclinical and clinical studies highlighted that AAT is more than a SERPIN. AAT can regulate cell function, inflammation, and response to injury. AAT showed a disease-modifying effect in cellular, animal, and human studies. In addition, novel recombinant isoforms or peptides that mimic some of AAT's properties, are the focus of preclinical and clinical research as an alternative to plasma-derived AAT.
Estrogen receptor-positive, HER2-negative (ER+/HER2-) metastatic breast cancer represents a major therapeutic challenge due to the frequent development of endocrine resistance. This review focuses on ESR1 mutations as key drivers of resistance and examines the evolving therapeutic strategies designed to overcome this mechanism. The authors discuss current standards of care in the first- and second-line settings, with a focus on molecularly guided therapeutic strategies. The literature was identified through a targeted search of PubMed and ClinicalTrials.gov, focusing on English-language publications from peer-reviewed journals with additional reference to current ESMO and ASCO clinical practice guidelines. Particular attention was given to emerging oral ER-targeting agents. Key clinical trial data supporting ctDNA-based monitoring of ESR1 mutations and treatment adaptation were also reviewed. Routine assessment of ESR1 mutations using liquid biopsy should be integrated into clinical practice to enable dynamic, molecularly guided treatment optimization. The expanding arsenal of ER-targeted therapies supports personalized sequencing strategies that move beyond rigid temporal cutoffs and improve outcomes in ET‑resistant disease.
Allergic rhinitis (AR) is a prevalent IgE-mediated inflammatory disease with significant global health and economic burdens. Common treatments include pharmacotherapy and allergen-specific immunotherapy (AIT), but challenges remain in managing some of the moderate-to-severe patients, driving development on targeted biologics. This review covers recent advances in AR management, including optimized pharmacotherapy, biologics targeting type 2 inflammation and innovations in AIT. The management toward AR should fully consider the phenotypic and endotypic characteristics of the patients and develop stepwise, comprehensive, and personalized care pathways that combine pharmacotherapy, AIT, and biologics. Further studies are needed to validate long-term efficacy and safety and optimize precision medicine approaches.
Endometriosis is a chronic, estrogen-dependent inflammatory disease affecting up to 10% of reproductive-aged women. Current therapies are predominantly hormone-based and offer symptomatic relief without correcting the immune dysregulation and inflammation that drive lesion persistence, pain, and infertility. This review summarizes emerging strategies that directly target inflammatory pathways in endometriosis. Key mechanisms involved in lesion survival and symptom generation include cytokine signaling (TNF-α, IL-1, IL-6), oxidative stress, immune-checkpoint dysregulation, and activation of the JAK/STAT pathway. Therapeutic approaches discussed comprise biologic agents (infliximab, etanercept, adalimumab, anakinra, tocilizumab), small-molecule JAK inhibitors (tofacitinib), and antioxidant compounds such as N-acetylcysteine, resveratrol, and vitamins C and E. Targeting inflammation represents a promising shift in endometriosis management, particularly for women who do not respond to hormonal therapies or aim to conceive. Preclinical studies consistently demonstrate reductions in lesion size, inflammatory cytokines, oxidative stress, and neuroangiogenic signaling. Early clinical evidence - especially for TNF-α and IL-1 blockade and for N-acetylcysteine - suggests improvements in pain and, in selected cases, reproductive outcomes. Although preliminary, these findings support the rationale for inflammation-directed therapies. Future research should prioritize randomized trials, long-term safety and fertility assessment, and biomarker-guided patient stratification to identify responders and optimize precision use of these agents.
Neurodegenerative and demyelinating diseases represent major unmet medical needs, with existing therapeutics demonstrating limited efficacy and significant safety concerns. Drug repurposing offers accelerated development timelines and established safety profiles. GV1001, a 16-amino acid telomerase-derived peptide originally developed as a cancer vaccine, has emerged as a promising multi-mechanism neuroprotective agent. This review examines preclinical evidence demonstrating GV1001 efficacy across Alzheimer's disease, stroke, experimental autoimmune encephalomyelitis, and depression models. Convergent mechanisms include gonadotropin-releasing hormone receptor-mediated neuroprotection, mitochondrial stabilization, modulation of glial functional states away from tissue-damaging inflammation, and promotion of remyelination. Clinical translation through Phase 2 trials in Alzheimer's disease demonstrated statistically significant cognitive improvements consistent with neurotrophic benefit, with excellent safety profiles lacking amyloid-related imaging abnormalities. The network pharmacology approach of GV1001-simultaneously addressing multiple pathological processes-positions it as a differentiated alternative to single-target therapeutics. The dual anti-inflammatory and pro-remyelination profile of the peptide addresses critical unmet needs in progressive multiple sclerosis. Phase 3 confirmation, biomarker-driven patient stratification, and combination therapy investigations represent critical development priorities. Successful development may help validate multi-mechanism approaches in neurodegeneration, potentially catalyzing paradigm shifts from reductionist single-target strategies.
Current standard-of-care for idiopathic pulmonary fibrosis is limited to nintedanib and pirfenidone, which only slow the progressive loss of lung function and have significant adverse effects that are intolerable to many patients. There is therefore a significant unmet need for alternative treatments for this incurable disease. This review describes emerging evidence implicating dysregulation of the renin-angiotensin system in IPF pathogenesis, and both pre-clinical and recent clinical data supporting activation of the anti-fibrotic AT2R as a promising therapeutic strategy. The efficacy of AT2R agonists across pre-clinical models of both IPF and relevant lung diseases is discussed, with a particular focus on favorable findings with the AT2R agonist C21 (buloxibutid), leading to its current clinical trials for IPF. Rapid translation of C21 (now named buloxibutid), the first-in-class orally available AT2R agonist, to early phase clinical trials for IPF have established its safety and disease-modifying potential. Ongoing development of novel, more highly selective AT2R agonists may deliver the same clinical benefit as C21 with reduced off-target effects. The AT2R drug class offers great promise as novel therapeutics, potentially extending beyond IPF to other inflammatory and fibrotic lung diseases.
Narcolepsy is a debilitating chronic neurological disorder, and currently, there is no cure. Activation of the histaminergic system through the blockade of histamine 3 (H3) autoreceptors promotes wakefulness. Blockade of H3 heteroreceptors modulates adrenergic, serotonergic, cholinergic, and dopaminergic systems. These properties of H3 receptors may offer therapeutic options for managing the symptoms of narcolepsy. Samelisant is an investigational H3 receptor inverse agonist/antagonist being developed for the treatment of hypersomnia disorders. This review includes an evaluation of the nonclinical and clinical profiles of samelisant. Samelisant's inverse agonism property at the H3 receptor may be ideal for addressing challenges associated with the constitutive activity. A key distinguishing feature of samelisant is its cleaner drug-drug interaction and cardiovascular safety profile compared to existing treatments. This is particularly important for women of childbearing potential, considering the known interactions of current treatments (e.g. pitolisant and modafinil) with hormonal contraceptives, as well as the common occurrence of polypharmacy and comorbidities in narcolepsy. Additionally, as samelisant may act downstream of orexinergic pathways, it presents an opportunity to complement orexin-based therapies. The potential of samelisant in combination with other narcolepsy treatments represents an important area for future research.
Rifaquizinone (RQZ, TNP-2092) is a novel drug for treating hepatic encephalopathy (HE). This study assessed the safety, pharmacokinetics (PK), and efficacy of RQZ capsules in healthy participants and cirrhosis patients with hyperammonemia. We conducted three double-blind, randomized, placebo-controlled trials. Trials 1 and 2 enrolled healthy participants, while Trial 3 involved 36 cirrhosis patients with hyperammonemia. In healthy participants and liver cirrhosis patients with hyperammonemia, RQZ was safe and well tolerated. Adverse events were generally mild or moderate. Both food and liver cirrhosis disease status increased the exposure of RQZ, which was around 1% of that of the corresponding doses after intravenous administration. The effect in lowering blood ammonia was dose-dependent. The changes from baseline in blood ammonia levels at day 15 were -14.1 and 0.5 μmol/L in 600 mg and placebo cohort. The percentage of achieving normal blood ammonia during treatment were 31.9% and 7.4% in 600 mg and placebo cohort. Although this study enrolled a relatively small cohort of cirrhotic patients with hyperammonemia, RQZ demonstrated an excellent safety profile as an intestinally restricted agent and showed promising potential for lowering blood ammonia and treating hepatic encephalopathy.
Delayed onset and/or protracted labor progression is a relatively common obstetrical condition. The hypothesis that low molecular weight heparins may induce positive effects on uterine tissues in promoting and shortening delivery time was advanced in the last few years through several retrospective studies in pregnant women treated for thrombotic disorders. Tafoxiparin, a depolymerized form of heparin with a molecular structure created to eliminate the anticoagulant effects of heparins, is under investigation as a potential tool to promote labor activation and progression. The authors conducted a critical review on current pharmacological and clinical evidence of tafoxiparin effects on labor. To date, available results may indicate potential benefits of using tafoxiparin for cervical ripening and labor augmentation, but several aspects need further clarifications and investigations. Clinical evidence is still weak to generalize the results of the trials and support the introduction of the drug into daily medical practice because few studies specifically focussing on this topic were published until now. In addition, many queries are left to be explored with future research, including optimal timing and doses, better route of administration, patient and physician acceptability, target pregnant populations, and cost-effectiveness aspects.
'Maximum tolerated dose' (MTD) was historically used to maximize clinical efficacy. However, there is a drive to optimize dose selection to improve safety/tolerability, while maintaining efficacy. This paradigm is increasingly important in oncology clinical development, leading to a focus on careful early-phase trial design to ensure that appropriate dose - or exposure-response data are obtained to guide dose selection. We describe the development pathway and risk-benefit considerations for clinical dose selection for giredestrant, a next-generation, highly potent, non-steroidal oral selective estrogen receptor antagonist and degrader, under development for estrogen receptor-positive breast cancer. This included evaluating low-grade adverse events to potentially improve tolerability, long-term compliance, and giredestrant combination therapy use; using pharmacodynamic markers for early drug activity assessment; and testing multiple dose levels during dose-escalation and -expansion phases. Data were leveraged from preclinical and phase I/II studies in metastatic and early breast cancer, as a single agent with palbociclib, to inform giredestrant dose selection. Our learnings challenge the MTD paradigm in drug development, particularly in targeted therapies, and demonstrate the importance of basing dose selection on the totality of evidence, including preclinical data, and may help inform the clinical development of future targeted therapies.
IMNN-001 is designed for local and durable delivery of a pluripotent anti-tumor cytokine, IL-12, using an expression plasmid and a synthetic lipopolymer delivery system. IMNN-001, delivered intraperitoneally in combination with chemotherapy, is currently in a Phase 3 trial for the front-line treatment of advanced epithelial ovarian cancer. This report details IMNN-001 preclinical and clinical development, demonstrating local and durable production of IL-12, minimal systemic exposure and manageable safety profile, as well as its antitumoral effects in a total of six completed trials in ovarian cancer. In the OVATION-2 Phase 2 randomized trial, neo- and adjuvant chemotherapy combined with IMNN-001 produced a numerical 13 month increase in overall survival, with even greater benefit in tumors that lacked DNA homologous repair activity. In translational studies, IMNN-001-induced changes in the tumor microenvironment are consistent with the observed induction of IL-12 and IFN-γ levels at the tumor site and support the hypothesis that IMNN-001 treatment alters the tumor microenvironment in favor of broad immune stimulation and inhibition of immunosuppressive mechanisms. IMNN-001 gene therapy could add clinically meaningful IL-12-driven immunotherapy to newly diagnosed ovarian cancer patients. IMNN-001 holds promise for synergistic combinations with immunotherapies requiring intrinsic immune activity. The recent ability to harness a patient’s own immune system to control or destroy a tumor has revolutionized the care and outcomes in many types of cancers. Unfortunately, up to this time, such efforts have been unsuccessful in ovarian cancer, where the standard of care has not improved for 25 or more years. The barrier in ovarian cancer is that the tumor is not recognized by the body’s defense mechanism. IMNN-001 represents a new and promising approach to this problem. IMNN-001 is designed to stimulate tumor cells and the cells surrounding the tumor to make IL-12, a natural molecule which strongly activates the body’s natural response against the tumor, resulting in the destruction of the malignant cells. In previous and ongoing studies, beneficial outcomes of IMNN-001 on tumor response and survival have been observed with a manageable safety profile. A large clinical trial is ongoing, with the hope that IMNN-001 could provide a new, safe, and novel treatment for women with advanced ovarian cancer.
Specifically Targeting the ABL1 Myristoyl Pocket inhibitors (STAMPi) have reshaped the management of chronic myeloid leukemia (CML). Yet, major challenges remain, including resistance and compound mutations, cross-intolerance, and long-term toxicities. Asciminib has shown efficacy in heavily pretreated patients and in the first-line setting, but resistance and limited benefit after ponatinib highlight the need for new therapeutic options. This review summarizes preclinical and early clinical evidence on next-generation STAMPi. TGRX-678 exhibits potent activity against wild-type and mutant ABL1, including T315I, synergism with orthosteric tyrosine kinase inhibitors (TKIs), central nervous system (CNS) penetration, and encouraging phase Ia/Ib clinical activity in heavily pretreated CML. Early but promising data are also emerging for TERN-701 from the CARDINAL trial. Next-generation STAMPi may extend therapeutic options beyond asciminib by addressing resistant mutations and enabling rational dual-site inhibition. TGRX-678 ability to achieve CNS exposure raises potential in blast phase CML and Ph+ acute lymphoblastic leukemia. Key questions regarding durability, long-term safety, and optimal integration with ATP-competitive TKIs remain open. Ongoing trials will define the clinical role of these STAMPi and their potential to advance cure-directed strategies, including treatment-free remission.
Darigabat is a selective γ-aminobutyric acid type A (GABA-A) receptor positive allosteric modulator targeting α2, α3, and α5 subunits, developed to preserve anxiolytic and anticonvulsant effects while reducing α1-mediated sedation and cognitive adverse events. Subtype-selective modulation represents a strategy to improve the safety of GABAergic therapies. A literature search in PubMed, Embase, CENTRAL, and ClinicalTrials.gov up to June 2025 identified 20 preclinical and clinical studies. Darigabat demonstrated dose-proportional pharmacokinetics, high brain penetration, and overall acceptable tolerability, with dose-dependent central nervous system adverse effects at higher exposures. Preclinical models showed anticonvulsant and anxiolytic activity. However, clinical trials reported heterogeneous and inconsistent efficacy across indications. Darigabat supports the feasibility of subtype-selective GABA-A modulation. Early-phase studies in healthy volunteers suggested improved acute tolerability compared with nonselective benzodiazepines. In contrast, repeated-dose studies in patients revealed dose-dependent central nervous system adverse effects, including somnolence, psychomotor slowing, and cognitive impairment, indicating that α1-sparing reduces but does not eliminate these effects. Current evidence does not support a clear therapeutic role in chronic central nervous system disorders. Future research should focus on exposure-response relationships, identification of responsive subgroups, and biomarker integration. The ability to retain efficacy with improved safety remains uncertain.
Behçet syndrome (BS) is a multisystem variable-vessel vasculitis characterized by recurrent mucocutaneous manifestations and severe organ involvement affecting the eyes, blood vessels, nervous system, and gastrointestinal tract. Although therapeutic advances over the past two decades have significantly improved outcomes, important clinical questions remain regarding optimal treatment selection, sequencing, durability, and long-term safety. This narrative review summarizes current evidence on established and emerging therapies for BS, focusing on unresolved aspects of management. We discuss comparative data between infliximab and adalimumab, the evolving role of cyclophosphamide in major vascular involvement, treatment strategies in colchicine-resistant mucocutaneous and joint disease, the use of combination therapy with conventional immunosuppressives, and considerations for tapering or discontinuing biologics. We also review available evidence for alternative biologic and targeted therapies, including interleukin (IL)-1, IL-6, IL-12/23, IL-17 inhibitors, JAK inhibitors, and novel phosphodiesterase-4 inhibitors, as well as investigational agents. This review is based on a targeted literature search and the authors' expertise, including recent work for the updated 2025 EULAR recommendations for the management of BS. Monoclonal anti-TNF antibodies remain the most supported biologic option across all disease manifestations. Emerging therapies show promise, but their long-term efficacy and safety require confirmation in controlled trials.