Antibody-drug conjugates (ADCs) are complex molecules composed of a monoclonal antibody, a linker and a cytotoxic payload. Their design enables the selective delivery of cytotoxic agents to tumoral cells through antibody binding to a tumor-expressed antigen, followed by internalization, intracellular degradation and payload release, ultimately enabling the cytotoxic drug to exert its antitumor activity. ADCs have been evaluated in phase II and III trials in previously treated advanced non-small cell lung cancer (NSCLC), both in oncogene-addicted and in non-oncogene-addicted tumors, addressing resistance to standard therapies. Ongoing clinical trials are now expanding their use both in the first-line setting for advanced disease and in earlier disease stages. This narrative review summarizes the currently available data for ADC treatment in NSCLC, highlighting the need for improved patient selection to maximize benefit while limiting toxicity, incorporating clinical characteristics, pharmacogenomics and optimal treatment sequencing in the equation. Moreover, the understanding of resistance mechanisms and the development and validation of predictive biomarkers will be of utmost relevance to inform clinical practice.

Narsoplimab (narsoplimab-wuug; YARTEMLEA®) is a recombinant human immunoglobulin G4 monoclonal antibody targeted against mannan-binding lectin-associated serine protease2 (MASP-2) being developed by Omeros Corporation initially for the treatment of haematopoietic stem cell transplantation (HCT)-associated thrombotic microangiopathy (TA-TMA). MASP-2 inhibition by narsoplimab is thought to provide benefit in patients with TA-TMA by decreasing or preventing lectin complement pathway-mediated cellular injury. In December 2025, narsoplimab received its first approval, in the USA, for the treatment of adult and paediatric patients aged ≥ 2years with TA-TMA. Additionally, a Marketing Authorisation Application for narsoplimab for the treatment of TA-TMA is currently under regulatory review in the EU. This article summarises the milestones in the development of narsoplimab leading to this first approval for TA-TMA.

The 2026 report from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) introduces substantial conceptual and practical updates to the management of chronic obstructive pulmonary disease. While maintaining the established spirometric definition, the report emphasizes early diagnosis, multi-dimensional assessment, and personalized treatment strategies that move beyond a spirometry-centric approach. Key innovations include formally recognizing disease activity as a therapeutic target, refining the ABE classification with a lower threshold for patients prone to exacerbations (Group E), and integrating blood eosinophil counts to guide inhaled corticosteroid therapy. Nonpharmacologic interventions, such as pulmonary rehabilitation, vaccination, smoking cessation, structured self-management, and post-exacerbation care, are elevated to core disease-modifying strategies. Pharmacological escalation is structured around dual bronchodilation as the preferred initial step, with further intensification to biomarker-guided triple therapy, including inhaled corticosteroids or other anti-inflammatory agents, reserved for selected patients who remain symptomatic or experience exacerbations despite optimized dual therapy. GOLD 2026 also introduces biologics, dupilumab and mepolizumab, as an add-on therapy for exacerbation-prone eosinophilic chronic obstructive pulmonary disease. However, it also highlights ongoing limitations in efficacy, cost effectiveness, and generalizability. Artificial intelligence and emerging digital technologies are recognized as promising adjuncts in the management of chronic obstructive pulmonary disease, though their clinical implementation remains preliminary. Overall, GOLD 2026 advances precision medicine in chronic obstructive pulmonary disease by combining structured individualized assessments with early targeted interventions. However, significant uncertainties remain, including biological variability of biomarkers, limited evidence for emerging therapies, and barriers to equitable access to nonpharmacologic and advanced interventions. Careful context-sensitive application and continued validation are essential.

The EILAT Conferences on New Antiepileptic Drugs (AEDs), which have taken place biennially since 1992, have traditionally offered a forum for stakeholders from industry and academia to present updates on potential antiseizure medications (ASMs) in development. We reviewed publicly accessible data on compounds that were presented at EILAT conferences over this period but failed to reach the ASM market. The overarching aim was to determine the most likely reason(s) for terminating development and to provide potentially useful clues to improve the efficiency of ASM development in the future. We restricted our analysis to investigational compounds in clinical development that targeted common epilepsies. Of 56 such compounds, 15 reached the ASM market, 11 are still in development, and 30 had their development for epilepsy indications terminated. Compounds whose development was terminated include atimepazole, beprodone, cannabidivarin, carabersat, conantokin-G, dezinamide, elpetrigine, flunarizine, fluorofelbamate, ICA-105665, isovaleramide, JNJ-40411813, losigamone, naluzotan, padsevonil, pitolisant, ralitoline, remacemide, safinamide, soretolide, talampanel, tonabersat, T2000, T2007, valnoctamide, valrocemide, VX-765, zandatrigine, zuranolone, and 534U87. For most of these compounds, termination of development occurred during phase 1 or phase 2. Unfavorable pharmacokinetic properties, such as short half-life or high drug-drug interaction potential, were a common likely cause of early termination. Overall, the most common reason for terminating clinical development was lack of efficacy, possibly related, at least in some cases, to use of suboptimal trial designs. Review of preclinical data suggested that, for many compounds, suboptimal clinical efficacy was unlikely to be primarily explained by their mechanism of action. In some instances, failure to pursue an epilepsy indication could be explained by prioritization of development for other neurological or psychiatric conditions. This may reflect the perception of the drug market for common epilepsies being relatively crowded, and only attractive for compounds with outstanding safety or efficacy advantages over existing medications.

Antibody-drug conjugates (ADCs) represent a major advance in breast cancer therapy, with trastuzumab deruxtecan and sacituzumab govitecan emerging as leading agents targeting distinct tumor antigens and employing different linker-payload designs. Trastuzumab deruxtecan is a second-generation HER2-directed ADC composed of trastuzumab linked via a cleavable tetrapeptide linker to the camptothecin derivative exatecan, a highly potent topoisomerase I inhibitor. Its high drug-to-antibody ratio (DAR 8:1), membrane-permeable payload, and efficient lysosomal release confer strong antitumor activity, including a robust bystander effect in HER2-low tumors. By contrast, sacituzumab govitecan is a TROP-2-targeted ADC conjugated through a hydrolysable CL2A linker to SN-38, the active metabolite of irinotecan. Sacituzumab govitecan features a high DAR (7.6:1) and allows extracellular as well as intracellular release of SN-38, enhancing bystander killing in tumors with heterogeneous TROP-2 expression, while maintaining a favorable toxicity profile due to the lower intrinsic potency of SN-38 relative to exatecan. Since both these ADCs are conjugated to topoisomerase I inhibitors, concerns about potential cross-resistance regarding their sequencing in clinical practice are being raised, and currently there is a lack of predictive biomarkers providing a rational basis for their sequential administration. Resistance mechanisms exhibit significant heterogeneity: resistance to trastuzumab deruxtecan has been associated with mutations in TOPO I and SLX4, impaired lysosomal function, and efflux via ABC transporters. In contrast, resistance to sacituzumab govitecan is linked to overexpression of multidrug resistance proteins, particularly BCRP-mediated efflux. Clinically, trastuzumab deruxtecan has shown substantial efficacy in both HER2-positive and HER2-low breast cancer, whereas sacituzumab govitecan has demonstrated efficacy across triple-negative and hormone receptor-positive/HER2-negative breast cancers. Collectively, these agents highlight how variations in target antigen, linker chemistry, and payload potency impact ADC activity, therapeutic index, and potential strategies for sequential treatment in advanced breast cancer.Graphical

Rilzabrutinib (WAYRILZ™) is a small-molecule, reversible, highly specific, covalent BTK inhibitor being developed by Sanofi for the treatment of multiple immune-related and inflammatory disorders, including immune thrombocytopenia, warm autoimmune haemolytic anaemia, sickle cell disease, IgG4-related disease, asthma, chronic spontaneous urticaria, among others. As a BTK inhibitor, rilzabrutinib demonstrates multiple immunomodulatory effects, including reduced B cell activation and autoantibody production, inhibition of macrophage activity, and anti-inflammatory effects. In clinical trials, rilzabrutinib was associated with durable platelet responses in patients with previously treated immune thrombocytopenia. This article summarizes the milestones in the development of rilzabrutinib leading to its first approval for the treatment of adults with persistent or chronic immune thrombocytopenia who have had an insufficient response to previous treatment.

Elamipretide (Forzinity™) is a mitochondrial cardiolipin binder being developed by Stealth BioTherapeutics for the treatment of a range of disorders featuring mitochondrial dysfunction. In September 2025, elamipretide was granted accelerated approval in the USA for use to improve muscle strength in adult and pediatric patients with Barth syndrome weighing ≥30kg. With this accelerated approval, elamipretide became the first disease-specific treatment approved for Barth syndrome, an ultra-rare X-linked recessive genetic disorder. Elamipretide is also under phaseIII clinical development for use in the treatment of dry age-related macular degeneration and mitochondrial myopathies. This article summarizes the milestones in the development of elamipretide leading to this first approval for Barth syndrome.

Elinzanetant (Lynkuet™) is a non-hormonal, small-molecule neurokinin 1 (NK1) and 3 (NK3) antagonist being developed by Bayer for the treatment of vasomotor symptoms (VMS), which received its first approval in the UK in July 2025. As a neurokinin-targeted therapy, elinzanetant modulates the activity of hyperactive kisspeptin/neurokinin B/dynorphin neurones to reduce the frequency and severity of VMS, which was demonstrated during the OASIS clinical trials. This article summarizes the milestones in the development of elinzanetant leading to this first approval for the treatment of moderate to severe VMS associated with menopause.

Vitiligo is a common, chronic, immune-mediated disorder characterized by progressive skin depigmentation, often associated with significant psychosocial burden and impaired quality of life. Therapeutic management remains challenging, with limited effective options available. Although topical corticosteroids, calcineurin inhibitors, and narrowband ultraviolet B (NB-UVB) phototherapy constitute the mainstays of treatment, many patients, particularly those with extensive or refractory disease, fail to achieve satisfactory or durable repigmentation. The clinical course is further complicated by high relapse rates and heterogeneous treatment responses across different anatomical sites. Recent advances in the understanding of vitiligo pathogenesis have identified the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway as a central driver of immune-mediated melanocyte destruction. This pathway is activated by key cytokines involved in vitiligo, including interferon gamma (IFN-γ), interleukin 15 (IL-15), among others, which sustain cytotoxic T cell infiltration and melanocyte apoptosis. As a result, JAK inhibitors have emerged as promising targeted therapies for vitiligo. Several topical and JAK inhibitors are currently under clinical investigation, with one topical agent, ruxolitinib cream, already approved for the treatment of vitiligo. Topical ruxolitinib, a JAK1/2 inhibitor, has demonstrated consistent and clinically meaningful repigmentation, particularly in facial lesions, and is already approved for use in both adolescents and adults. Among oral agents, ritlecitinib (a JAK3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) inhibitor), upadacitinib and povorcitinib (JAK1 inhibitors) have shown the most promising efficacy, either as monotherapy or in combination with NB-UVB phototherapy. Ongoing phase III trials are expected to further define their role in clinical practice. Other agents, including tofacitinib, baricitinib, abrocitinib, among others, are currently under investigation or being used off-label in clinical practice. JAK inhibitors exhibit variable safety profiles depending on selectivity, formulation, and dose. Topical agents are generally well tolerated with minimal systemic absorption, whereas oral JAK inhibitors require monitoring owing to potential risks of infection, hematologic abnormalities, and cardiovascular events. In this article, we review the current evidence on the efficacy and safety of topical and oral JAK inhibitors for vitiligo and contextualize their role within the broader landscape of emerging therapeutic strategies.

Following announcements from professional and governmental bodies across a number of countries, modified-release (MR) opioids are no longer recommended in the routine management of acute pain, and so should not be initiated for this reason. The recommendations are not new, but a recent cluster of publications by key professional and governmental bodies has more clearly challenged their use and highlighted the need for change in guideline-driven and individual practice. The inclusion of MR opioids in many postoperative pain regimens relatively soon after they were first marketed for use in patients with chronic non-cancer pain, was not based on sound evidence, and there remains no evidence of benefit. In contrast, however, good evidence has accumulated that shows they not only provide less effective pain relief compared with immediate-release opioids, but that they lead to a higher risk of adverse effects including opioid-induced ventilatory impairment and persistent opioid use.