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Chronic hand eczema is a highly prevalent inflammatory skin disorder associated with substantial impairments in quality of life and social interactions. Topical corticosteroids and calcineurin inhibitors are conventional treatments often limited by the achievement of suboptimal disease control and concerns regarding long-term safety. Delgocitinib 2% cream, the first topical pan-Janus kinase inhibitor approved in Europe for adult patients with moderate-to-severe chronic hand eczema, represents a significant therapeutic advance. By simultaneously targeting multiple cytokine pathways implicated in chronic hand eczema pathogenesis, delgocitinib offers a corticosteroid-sparing alternative with minimal systemic absorption. Pivotal phase III clinical trials (DELTA 1, 2, and 3) demonstrated significant reductions in disease severity, itch, and pain compared with baseline, with a favorable safety profile sustained over long-term treatment. Recent investigations in adolescent and Asian populations are further expanding the therapeutic profile of topical delgocitinib across different age groups and ethnic backgrounds. Both the cream and ointment formulations have been assessed in clinical settings, with distinct utility depending on anatomical site and barrier integrity. Beyond chronic hand eczema, topical delgocitinib has shown efficacy in atopic dermatitis, and preliminary evidence is emerging in other inflammatory skin diseases, including vitiligo, lichenoid dermatoses, and hair disorders. This review provides an updated overview of the biological rationale for pan-Janus kinase inhibition, summarizes the most recent outcomes of topical delgocitinib in chronic hand eczema and atopic dermatitis management, and outlines its potential new applications in the landscape of immune-mediated skin diseases.

Trastuzumab rezetecan (Avida ^®) is a human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugate being developed by Jiangsu HengRui Medicine Co., Ltd. for the treatment of various solid tumours, including breast cancer, colorectal cancer, gastric cancer, gastroesophageal junction adenocarcinoma and lung cancer. In May 2025, it was approved by the National Medical Products Administration of China for the treatment of adults with unresectable locally advanced or metastatic non-small cell lung cancer (NSCLC) who have human epidermal growth factor receptor 2 (HER2) [ERBB2]-activating mutations and have received ≥ 1 previous systemic treatment. This article summarizes the milestones in the development of trastuzumab rezetecan leading to this first approval.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs)-along with the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA tirzepatide-are widely acknowledged for their efficacy in managing both type 2 diabetes mellitus and obesity, with expanding indications in cardiometabolic risk reduction. While their glycemic, weight-lowering, and cardiovascular benefits are well established through randomized trials and meta-analyses, concerns remain regarding their safety and tolerability across diverse populations and clinical settings. Gastrointestinal (GI) adverse events-particularly nausea, vomiting, diarrhea, and constipation-are the most common side effects, generally emerging during dose escalation and resolving over time. However, accumulating evidence has identified additional GI complications, including cholelithiasis, cholecystitis, gastroparesis, and bowel obstruction, which may warrant caution in susceptible individuals. Injection-site reactions and worsening of pre-existing diabetic retinopathy are also relevant clinical concerns. Although rare, associations with nonarteritic anterior ischemic optic neuropathy, pancreatitis, medullary thyroid carcinoma, and acute kidney injury (AKI) have been reported, primarily through pharmacovigilance and case-based evidence. Importantly, large-scale randomized trials, meta-analyses, and observational studies suggest that GLP-1RAs do not significantly increase AKI risk and may even confer renal benefits in high-risk populations. There is no confirmed elevated risk of suicidality, but surveillance remains warranted. Safety data in special populations-such as pregnant or lactating women, pediatric patients, and those with advanced renal or hepatic impairment-remain limited and require further study. This state-of-the-art narrative review synthesizes current evidence from clinical trials, pharmacovigilance databases, and real-world cohorts to provide a comprehensive evaluation of the safety and tolerability of GLP-1RAs and tirzepatide. We present clinical strategies for adverse event mitigation, monitoring recommendations, contraindications, and practical considerations for treatment discontinuation or switching. Although these agents offer transformative therapeutic potential, their optimal use requires individualized care, careful patient selection, and ongoing safety surveillance. Future research should prioritize long-term safety in underrepresented populations and strategies to mitigate lean mass loss during therapy.

Dordaviprone (MODEYSO^™) is a protease activator being developed by Chimerix for the treatment of various cancers, including glioma, glioblastoma, endometrial cancer, ovarian cancer, acute myeloid leukaemia, acute lymphoblastic leukaemia, myelodysplastic syndrome and colorectal cancer. On 6 August 2025, dordaviprone received accelerated approval in the USA for the treatment of adult and paediatric patients 1 year of age and older with diffuse midline glioma harbouring an H3 K27M mutation with progressive disease following prior therapy. This article summarizes the milestones in the development of dordaviprone leading to this first approval for glioma.

Aztreonam-avibactam (Emblaveo^™), a fixed-dose combination of the monobactam antibacterial agent aztreonam and the broad-spectrum β-lactamase inhibitor avibactam, has been developed as a treatment, administered intravenously, for serious bacterial infections caused by aerobic Gram-negative organisms. In the EU, aztreonam-avibactam is indicated in adults for the treatment of complicated intra-abdominal infection (cIAI); hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP); and complicated urinary tract infection (cUTI), including pyelonephritis; as well as for the treatment of other infections due to aerobic Gram-negative organisms in adult patients with limited treatment options. Adding to existing data on aztreonam and avibactam individually, the approval of aztreonam-avibactam was supported by a clinical development programme which included pharmacokinetic and pharmacodynamic modelling and probability of target attainment analyses together with evaluation of the combination in a range of clinical trials. Based on all available data, aztreonam-avibactam is a valuable addition to the treatment options for adults with serious bacterial infections caused by aerobic Gram-negative organisms. Furthermore, with in vitro data showing that the drug combination retains potent activity against metallo-β-lactamase (MBL)-producing Enterobacterales and Stenotrophomonas maltophilia, and noting the limited effective treatment options available for infections caused by such bacteria, aztreonam-avibactam is likely to be particularly useful in regions with a high prevalence of MBLs.

Benzodiazepines, first introduced in the 1960s as effective and safer alternatives to barbiturate sedative-hypnotics, are now widely viewed as having a high risk of overdose, abuse, addiction, and "dependency". These beliefs are contrary to extensive scientific evidence. Systematic research has shown that prescribed benzodiazepines are not prone to tolerance, dose-escalation, abuse, or addiction. Benzodiazepine abuse and overdose fatalities occur largely in the context of established polysubstance abuse. They are as effective as antidepressants and have fewer adverse effects but similar withdrawal syndromes. Major adverse effects are impairment of coordination, memory, and cognition, of most concern in older populations, and increased risk of motor vehicle accidents, especially when used along with alcohol. Most patients can be withdrawn from benzodiazepines without major difficulty using clinician supportiveness and flexible tapers. Reports of severe adverse reactions to benzodiazepines and of severe, prolonged difficulties withdrawing from them have not been subjects of systematic study and are poorly understood. In summary, the literature supports use of benzodiazepines on par with antidepressants for anxiety disorders, and for benzodiazepines and z-drugs for short-term mitigation of insomnia.

HER2 overexpression/amplification is a well-established oncogenic driver across several tumor types and has emerged as a therapeutically actionable biomarker in 3-5% of metastatic colon and rectal cancers (mCRCs). Based on increasing clinical evidence, several anti-HER2 therapeutic regimens have been incorporated into treatment guidelines. In this review, we provide a comprehensive overview of both established and emerging HER2-targeted strategies in mCRC, examining the mechanisms of action, toxicity profiles, and clinical efficacy of individual anti-HER2 drugs and their associations. As accurate and standardized HER2 testing remains critical, we also discuss current methodologies and challenges in HER2 screening for mCRC. In addition, we present an in-depth analysis of the relationship between HER2 amplification levels, co-occurring genomic alterations, and treatment outcomes across clinical trials, underscoring the importance of quantitative HER2 assessment and comprehensive tumor profiling. These data support the refinement of therapeutic strategies through more precise diagnostic approaches and improved patient selection, considering factors such as gene-dosage, toxicity, and coexisting mutations. Finally, the emerging role of anti-HER2 rechallenge strategies and the advent of novel HER2-directed therapies-including bispecific antibodies, novel tyrosine kinase inhibitors, antibody-drug conjugates, and immune-based therapies-are discussed as new opportunities to improve outcomes in this molecular subset of patients.

Imlunestrant (Inluriyo™), an oral, selective, estrogen receptor (ER) degrader (SERD), is being developed by Eli Lilly and Company for the treatment of ER-positive (ER+), human epidermal growth factor receptor 2 (HER2) negative (HER2-) breast cancer. In September 2025, imlunestrant was approved for the treatment of adults with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy in the USA. This article summarizes the milestones in the development of imlunestrant leading to this first approval for use in patients with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer.

An oral formulation of sepiapterin (Sephience™) is being developed by PTC Therapeutics for the treatment of phenylketonuria (PKU). Sepiapterin is a natural precursor of enzyme cofactor tetrahydrobiopterin (BH₄), which is required for phenylalanine hydroxylase (PAH)-mediated phenylalanine metabolism. Sepiapterin enhances PAH activity, which is deficient in patients with PKU. Sepiapterin received its first approval on 19 June 2025 in the European Union, for use in hyperphenylalaninaemia (HPA) in adult and paediatric patients with PKU. This was followed by approval in the USA on 28 July 2025, for the treatment of HPA in adult and paediatric patients ≥ 1 month of age with sepiapterin-responsive PKU. This article summarizes the milestones in the development of sepiapterin leading to its first approval for HPA in adult and paediatric patients with PKU.

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.