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Sebetralstat (EKTERLY^®), an orally available plasma kallikrein inhibitor, is being developed by KalVista Pharmaceuticals for the on-demand treatment of acute attacks of hereditary angioedema (HAE). On 7 July 2025, sebetralstat received its first approval in the USA for the treatment of acute attacks of HAE in adult and pediatric patients aged 12 years and older. The drug has since been approved on 15 July 2025 in the UK for the treatment of HAE attacks in adults and adolescents aged 12 years and older. Sebetralstat has also received a positive opinion in the EU for the symptomatic treatment of acute attacks of HAE in adults and adolescents aged 12 years and older. This article summarizes the milestones in the development of sebetralstat leading to this first approval for HAE.

Background: Resistant hypertension (RHT) is a challenging clinical condition characterized by persistently elevated blood pressure despite adherence to lifestyle modifications and the use of at least three antihypertensive agents, including a high-dose diuretic. RHT is a heterogeneous condition, influenced by multiple pathophysiological mechanisms such as sodium retention, sympathetic overactivity, and vascular dysfunction. Among these, hyperaldosteronism plays a pivotal role in a subset of patients.

Methods: This systematic review examines in depth the pharmacokinetic properties of aldosterone synthase inhibitors (ASIs), with a focus on their therapeutic potential in patients with RHT. A comprehensive literature search was conducted to identify clinical trials and pharmacological studies investigating ASIs, including baxdrostat, dexfadrostat, lorundrostat, LY3045697, and osilodrostat (LCI699).

Results: ASIs have shown compelling efficacy in lowering both office-based and 24-h ambulatory blood pressure, particularly in patients with elevated aldosterone levels. These findings underscore the critical role of aldosterone-mediated mechanisms in the pathophysiology of RHT. The inhibitors differ substantially in their metabolic pathways, selectivity profiles, and pharmacokinetic characteristics.

Conclusions: Emerging data support the potential of ASIs as a therapeutic option for RHT, particularly when treatment is individualized based on renal function, dietary sodium intake, and comorbidities. Personalized treatment strategies may enhance efficacy, improve tolerability, and support durable blood pressure control in this difficult-to-treat population.

Registration: PROSPERO identifier number CRD42024522918 [Graphical abstract available].

Vasomotor symptoms (VMS) are considered the cardinal symptoms of menopause, affecting up to 80% of American women at some point during the menopausal transition. VMS, particularly if they are moderate to severe, frequent, or cause sleep disturbances, can have a negative impact on a woman's quality of life, physical and mental health, and professional life. Furthermore, VMS have been associated with negative health outcomes, including an increased risk of coronary heart disease and cognitive impairment. Menopausal hormonal therapy (MHT) is supported by level 1 evidence and can address many of the negative impacts associated with menopause, including VMS. However, not all women can take MHT (owing to having contraindications to their use) or choose not to take MHT. In addition to MHT, non-hormonal therapy options, which include neurokinin (NK)-targeted therapies, are also available. Fezolinetant (NK3 receptor antagonist) and the newly approved elinzanetant (NK1 and NK3 receptor antagonist) are non-hormonal treatment options approved for the treatment of VMS associated with menopause. These approvals expand the treatment options for women. A number of investigational agents are currently in phase 2 trials for potential future use for VMS; these include Q-122, PhytoSERM, NOE-115, GS1-144, and HS-10384. In this review, we highlight the recent advancements in our understanding of the pathophysiology of VMS and consider the current, new, and investigational treatment options for the treatment of VMS.

Tyrosine kinase inhibitors (TKIs) have revolutionised systemic therapy for advanced thyroid cancers, including radioiodine-refractory differentiated thyroid cancer (RR-DTC), anaplastic thyroid cancer (ATC) and medullary thyroid cancer (MTC), which respond poorly to conventional cytotoxic chemotherapy. The treatment of advanced thyroid cancer is also increasingly personalised, with recent advances in genomic-driven, highly selective targeted therapies. This review summarises contemporary evidence regarding the efficacy, safety and clinical application of drug therapies in thyroid cancers, whilst exploring their evolving role in the age of personalised medicine. Multikinase inhibitors (MKIs) such as sorafenib, lenvatinib, vandetanib and cabozantinib have demonstrated significant improvements in progression-free survival and objective response rates in patients with RR-DTC and MTC. In ATC-a highly lethal tumour-BRAF-directed therapies have shown promising efficacy in patients harbouring the BRAF V600E mutation, yielding enhanced survival outcomes. Moreover, highly-selective inhibitors targeting RET, NTRK and other actionable alterations have refined treatment paradigms by increased integration of molecular testing via next-generation sequencing, ensuring treatments are tailored to the genetic profile of an individual tumour. Despite significant progress, management of advanced thyroid cancer remains challenged by drug resistance and toxicity, underscoring the need for ongoing research and innovation. Furthermore, vast improvements are still required to ensure universal access to molecular testing and targeted therapies.

Gepotidacin (BLUJEPA), a small molecule triazaacenaphthylene bacterial type II topoisomerase inhibitor (BTI) antibacterial, has been developed by GSK for the treatment of uncomplicated urinary tract infections (uUTIs) and uncomplicated urogenital gonorrhoea (uUGC). In March 2025, gepotidacin was approved for the treatment of uUTIs caused by susceptible isolates of Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii complex, Staphylococcus saprophyticus and Enterococcus faecalis in female adult and paediatric patients aged ≥ 12 years and weighing ≥ 40 kg in the USA. This article summarizes the milestones in the development of gepotidacin leading to this first approval for the treatment of bacterial uUTIs.

This narrative review explores current pharmacological treatments for agitation in Alzheimer's disease (AD). Agitation, a common and difficult-to-manage symptom in AD, often requires targeted intervention. While nonpharmacological methods, such as behavioral therapy and environmental modifications, are considered first line, they may not always be effective. In cases where these approaches fail, pharmacological treatment can become a necessary component of care. Historically, antipsychotics have been the mainstay of pharmacological treatment for agitation in AD; however, safety and efficacy concerns have prompted exploration into alternative treatments. The purpose of this narrative review is to synthesize current literature on pharmacological treatments for agitation in AD with a focus on new and repurposed drugs. It also examines agents that have failed to demonstrate clinical benefit, offering insights into the ongoing challenges of drug development in this area. This review synthesizes recent findings on various drug classes, including anticonvulsants, antipsychotics, selective serotonin reuptake inhibitors (SSRIs), atypical antidepressants, sedatives, anti-dementia drugs, dextromethorphan, and cannabinoids. Both brexpiprazole and risperidone have demonstrated efficacy and received approval from government agencies, including brexpiprazole in the USA and risperidone in parts of Europe. Despite these advances, concerns remain regarding their long-term use and safety profiles. As a result, multiple other therapies are currently being studied as possible alternative solutions. However, no other pharmacological agents are currently approved, underscoring the need for further research on safe and effective options for this vulnerable population.

Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra-rare acquired genetic stem cell disorder based on a mutation in the PIGA gene that results in susceptibility of resulting blood cells to complement-mediated intravascular haemolysis (IVH). In countries where anti-complement therapy is available, pharmacological treatments have transformed this disease from a highly morbid and sometimes lethal disorder. The first treatment developed was the terminal complement (C5) monoclonal antibody inhibitor eculizumab, in 2002. This has been largely supplanted by a longer-acting antibody, ravulizumab, targeting the same binding site on C5. These agents significantly modify the natural history of the disease by reducing the risk of thrombosis, the most lethal complication of PNH, as well as reducing transfusion dependence and improving renal function, quality of life and probably, survival. Other terminal inhibitors available include eculizumab biosimilars, crovalimab, pozelimab and cemdisiran (combination). Despite this, a proportion of patients develop extravascular haemolysis (EVH) based on the accumulation of C3 components on these PNH blood cells, which no longer undergo IVH because of C5 inhibition. This has led to the development of proximal complement inhibitors, which have been generally successful at reducing this iatrogenic complication, improving haemoglobin concentrations, reducing transfusion dependency and improving quality of life. Currently available proximal inhibitors (and their targets) are pegcetacoplan (C3), danicopan (Factor D) and iptacopan (Factor B). While effective, as with all other complement inhibitors, there is a risk of breakthrough IVH with their use and approaches to manage this complication are being developed.

Avutometinib and defactinib (AVMAPKI^™ FAKZYNJA^™ CO-PACK) is a co-packaged rapidly accelerating fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK) inhibitor (avutometinib) and focal adhesion kinase (FAK)/proline-rich tyrosine kinase-2 (Pyk2) inhibitor (defactinib) being developed by Verastem Oncology for the treatment of RAS/MAPK pathway-driven cancers. In May 2025, avutometinib and defactinib was approved in the USA for the treatment of adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy. This article summarizes the milestones in the development of avutometinib and defactinib leading to this first approval for KRAS-mutated recurrent LGSOC.