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Ziftomenib (KOMZIFTI^™) is an oral, selective, once-daily menin inhibitor in development by Kura Oncology for the treatment of NPM1-mutated (NPM1-m) or KMT2A-rearranged (KMT2A-r) acute myeloid leukaemia (AML), KMT2A-r acute lymphoblastic leukaemia and gastrointestinal stromal tumours (GIST). The menin-KMT2A complex and mutated NPM1 proteins co-occupy specific gene promoter sites and increase transcription of leukaemogenic genes. By blocking the interaction between menin and KMT2A, ziftomenib downregulates transcription of key leukaemogenic factors and restores differentiation pathways to exert anti-leukaemic effects in NPM1-m and KMT2A-r AML. Ziftomenib received its first approval on 13 Nov 2025 in the USA for the treatment of adults with relapsed or refractory AML with a susceptible NPM1 mutation who have no satisfactory alternative treatment options. This article summarises the milestones in the development of ziftomenib leading to this first approval for relapsed or refractory AML associated with an NPM1 mutation.

Uncontrolled gout (UG) is a progressive arthropathy that develops as a consequence of sustained hyperuricemia. Recombinant uricases can profoundly lower serum urate (SU) and reverse the clinical manifestations of uncontrolled gout. However, therapeutic uricases are highly immunogenic and can provoke the development of anti-drug antibodies (ADAs), resulting in a loss of effect and potentially severe allergic reactions. Pegloticase is currently the only US Food and Drug Administration-approved uricase indicated for the treatment of UG. The Food and Drug Administration recently approved the co-administration of methotrexate with pegloticase to inhibit ADA formation and enhance the efficacy and tolerability of pegloticase. Nanoencapsulated sirolimus plus pegadricase (NASP) is a novel every-4-week treatment delivered as a sequential two-component infusion consisting of nanoencapsulated sirolimus immediately followed by pegadricase, a novel PEGylated uricase. NASP mitigates ADA formation by promoting uricase-specific immunotolerance, thereby obviating the need for systemic immunomodulatory drugs. Phase I trials demonstrated that NASP inhibited ADA development, allowing sustained pegadricase control and SU lowering for up to 30 days. The dose-finding (phase II) study showed NASP (nanoencapsulated sirolimus 0.1-0.15 mg/kg and pegadricase 0.2 mg/kg) reduced ADA development and supported durable SU lowering. The phase II COMPARE trial demonstrated that monthly NASP was as effective as twice-monthly pegloticase in achieving SU targets at 6 months. Combined phase III DISSOLVE trial data confirmed that NASP significantly lowered SU and increased SU responses in participants with UG. All phase I-III trials demonstrated that NASP was generally well tolerated with no specific safety signals. Overall, NASP has demonstrated robust and durable SU lowering, which ultimately reduced disease burden, supporting positive health-related quality-of-life outcomes. This review summarizes the clinical development of NASP with particular reference to the targeted immunotolerizing strategy that diminishes its immunogenicity. Video abstract available online. Video Abstract.

Objective: The aim of this meta-analysis was to compare the efficacy of PCSK9 and ANGPTL3 inhibitors in patients with homozygous familial hypercholesterolemia (HoFH).

Methods: We systematically searched selected electronic databases until 30 November 2024. Main end point was the effect of lipid lowering therapy on lipid profile: total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and lipoproteins levels. The secondary end point was adverse clinical effects.

Results: A total of 12 trials involving 392 patients with HoFH, were finally included in the meta-analysis. At a median follow-up of 12 months, ANGPTL3 inhibitors achieved greater reductions in TC (- 49.9% versus - 21.2%; p _{for subgroup} < 0.001), LDL-C (- 50.77% versus - 17.88%; p _{for subgroup} < 0.001) and TG (- 48.9% versus - 8.2%; p _{for subgroup} < 0.001) compared with PCSK9 inhibitors, but had a smaller impact on HDL-C (- 28.9% versus + 5.2%; p _{for subgroup} = 0.001). Apolipoprotein B decreased more with ANGPTL3i (- 26.9% versus - 13.2%; p _{for subgroup} < 0.001), while lipoprotein(a) reductions were similar between groups, and apolipoprotein A remained unaffected with PCSK9i but slightly decreased with ANGPTL3i. In meta-regression, ANGPTL3i produced a greater LDL-C reduction in the negative LDL receptor (LDLR) genotype (- 34.5%; p = 0.04) and showed a trend toward significance in the defective genotype (- 23.1%; p = 0.07), with no significant difference in the heterozygous type. The rates of adverse events and discontinuations were not significantly different between the groups.

Conclusions: PCSK9 inhibitors have lower efficacy in reducing lipid levels in HoFH compared with ANGPTL3 inhibitors, with the greatest difference seen in patients with the negative LDLR genotype. Further studies are needed to clarify efficacy across LDLR functional variants.

Obstructive sleep apnoea (OSA) is a common, chronic respiratory disorder associated with major co-morbidity and adverse safety consequences. New research has highlighted the heterogeneity of OSA pathogenesis and the importance of non-anatomical contributors beyond the primary cause-impaired pharyngeal anatomy. For > 40 years, continuous positive airway pressure (CPAP), which works downstream from the causes of OSA, has been the mainstay therapeutic approach. While efficacious when used, CPAP is associated with poor tolerance and acceptance which limits real-world clinical effectiveness. Non-CPAP therapies that target the primary anatomical cause such as oral appliances and upper airway surgery, reduce OSA severity by ~ 50%. Given that obesity increases the anatomical predisposition for OSA, new weight loss drugs can reduce OSA severity in the ~ 50% of patients who are obese. Thus, although these therapies can resolve OSA for certain patients, overall efficiency varies and is challenging to predict with currently available clinical tools. Recent translation of OSA pathogenesis research has unlocked new pharmacotherapy targets beyond impaired pharyngeal anatomy. These include drugs to activate the pharyngeal dilator muscles, reduce unstable respiratory control and promote deeper, more stable sleep and breathing. Accordingly, the sleep medicine field is undergoing a paradigm shift as OSA pharmacotherapy becomes a reality. This article outlines the latest OSA pathophysiology knowledge and accompanying recent major developments in OSA pharmacotherapy. Practical, readily available, clinical tools for OSA endotyping to help move beyond the current problematic one-size-fits-all, trial-and-error treatment model towards a targeted paradigm tailored to underlying mechanisms that include emerging pharmacotherapy are also included.

Mu-opioid receptor (MOR) agonists remain the cornerstone of pain management but are limited by respiratory depression, tolerance, dependence, and mood disturbances. Kappa-opioid receptor (KOR) agonists offer complementary analgesic mechanisms with minimal abuse potential, yet clinical utility is restricted by dysphoria, sedation, and anxiety. This review critically evaluates emerging strategies that leverage both receptor systems through G-protein-biased KOR agonists and bifunctional KOR/MOR ligands. While preclinical evidence suggests that these approaches may provide additive analgesia with reduced adverse effects, significant challenges remain in translating these findings to clinical practice. The controversy surrounding G-protein bias measurement and the limited clinical data available highlight the need for cautious optimism regarding these novel therapeutic approaches.

Background: Elevated lipoprotein(a) [Lp(a)] is a genetically determined, causal risk factor for atherosclerotic cardiovascular disease, but effective therapies remain limited. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are primarily used to lower low-density lipoprotein cholesterol (LDL-C), yet their effects on Lp(a) have been inconsistently reported. This umbrella review synthesizes meta-analytic evidence on PCSK9 inhibitors and Lp(a).

Methods: We systematically searched PubMed, Embase, Web of Science, and Cochrane Library through April 2025 for meta-analyses of randomized controlled trials (RCTs) comparing PCSK9 inhibitors (alirocumab, evolocumab, inclisiran) with placebo or standard therapy. The primary outcome was mean percentage change in Lp(a). Methodological quality was assessed using the Assessment of Multiple Systematic Reviews 2 (AMSTAR-2), and evidence certainty was graded with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Overlap of primary trials was quantified using the Corrected Covered Area (CCA), and sensitivity analyses were performed to account for overlapping evidence.

Results: Twenty-one meta-analyses (116 RCTs; 231,796 participants) were included. The PCSK9 inhibitors consistently reduced Lp(a): evolocumab (29.68-46.68%; high certainty), alirocumab (18.55-26.46%; high certainty), and inclisiran (18.00%; high certainty). Higher biweekly doses yielded larger decreases (e.g., alirocumab 150 mg: 24.6%; evolocumab 140 mg: 26.8%, high certainty). Reductions were dose-dependent and broadly consistent across populations, comparators, follow-up durations, and baseline Lp(a). The Lp(a) reductions correlated modestly with LDL-C (β = 0.28; 95% CI 0.07-0.49) and apolipoprotein B (apoB) (β = 0.33; 95% CI 0.03-0.63). Concomitant reductions in LDL-C, apoB, and major adverse cardiovascular events were supported by high and moderate certainty evidence. Safety was favorable, with injection-site reactions being the most common adverse event. Sensitivity analyses confirmed robustness of findings after accounting for overlapping trials.

Conclusions: The PCSK9 inhibitors, particularly evolocumab 140 mg every 2 weeks, significantly lower Lp(a) alongside LDL-C and apoB. These findings highlight the consistent Lp(a)-lowering effect of PCSK9 inhibitors. However, the observed cardiovascular benefits are largely attributable to concomitant LDL-C reduction, and the incremental contribution of Lp(a) lowering remains uncertain. Confirmation from outcome trials specifically designed to target Lp(a) is required.

Registration: PROSPERO CRD420251048597.

Taletrectinib [DOVBLERON ^® (China); IBTROZI^TM (USA)] is an oral, potent, next-generation proto-oncogene tyrosine-protein kinase-1 (c-Ros oncogene-1; ROS1) inhibitor developed by Nuvation Bio China Ltd., a Nuvation Bio Inc. company, for the treatment of advanced ROS1-positive non-small cell lung cancer (NSCLC). Taletrectinib received its first approval on 20 December 2024 in China for the treatment of adults with locally advanced or metastatic ROS1-positive NSCLC who have previously been treated with ROS1 inhibitors. Subsequently, taletrectinib was approved on 3 January 2025 in China and on 11 June 2025 in the USA for the treatment of adults with locally advanced or metastatic ROS1-positive NSCLC, and then on 19 September 2025 in Japan for the treatment of adults with unresectable advanced and/or recurrent ROS1-positive NSCLC. Additional global filings for taletrectinib are underway. This article summarizes the milestones in the development of taletrectinib leading to these first approvals.

Brensocatib (BRINSUPRI™), an oral, small molecule, reversible inhibitor of dipeptidyl peptidase 1 (DPP1), is being developed by Insmed Incorporated under license from AstraZeneca for the treatment of neutrophil-mediated diseases, including non-cystic fibrosis bronchiectasis (NCFB), chronic rhinosinusitis without nasal polyps (CRSsNP) and hidradenitis suppurativa (HS). Brensocatib received its first approval on 12 August 2025 in the USA for the treatment of NCFB in adult and paediatric patients 12 years of age and older. Brensocatib received a positive opinion in the EU on 17 Oct 2025 and is also under regulatory review in the UK for this indication. This article summarizes the milestones in the development of brensocatib leading to this first approval for the treatment of NCFB.

Chronic kidney disease (CKD) increases the risk of cardiovascular disease (CVD), with dyslipidemia being a contributing risk factor. In patients with CKD, diminished antioxidant, anti-inflammatory, and cholesterol transport capacities of high-density lipoprotein cholesterol (HDL-C) may contribute to atherosclerosis and poor CVD outcomes. Different lipid-lowering therapies (LLTs) have demonstrated efficacy in correcting dyslipidemia in patients without kidney disease, including substantial elevations in HDL-C levels with triglyceride-lowering therapies, such as fibrates and niacin, as well as novel HDL-targeted therapies, including cholesterol-ester transfer protein inhibitors. However, the effects of HDL-elevating therapies in populations without kidney disease may not readily be extrapolated to patients with CKD, given the distinct dyslipidemia patterns and the lack of high-quality clinical trials in this population. Despite plausible mechanisms of HDL-elevation to improve clinical outcomes, current clinical guidelines only recommend statin use for the treatment of hyperlipidemia in patients with non-dialysis-dependent CKD. In this narrative review, we discuss how HDL-C functionality is affected in patients with CKD and explore evidence investigating different LLTs for HDL elevation and improved clinical outcomes in this population. In patients with CKD, we recommend further investigation of HDL-targeted therapies, comparative effectiveness evaluation of HDL-elevating LLTs versus statins across various clinical endpoints, and whether HDL-C elevation mediates these outcomes.

Treatment paradigms for advanced urothelial carcinoma have evolved rapidly with the introduction of antibody-drug conjugates and novel immunotherapy combinations. Enfortumab vedotin plus pembrolizumab has redefined first-line therapy, demonstrating unprecedented survival benefits compared with platinum-based chemotherapy. However, high cost and limited availability remain major barriers to its global implementation. Accordingly, gemcitabine-cisplatin with nivolumab and platinum-based chemotherapy followed by maintenance avelumab remain validated evidence-based alternatives, particularly for cisplatin-eligible patients or in regions where enfortumab vedotin plus pembrolizumab is not readily accessible. These advances have created new challenges in treatment sequencing, particularly for patients who progress after enfortumab vedotin plus pembrolizumab, where prospective evidence remains limited. Enfortumab vedotin monotherapy retains activity post-platinum and immune checkpoint inhibition, erdafitinib provides a targeted benefit in fibroblast growth factor receptor 3-altered tumors, and trastuzumab deruxtecan has emerged as a later-line option for HER2-positive disease. In parallel, circulating tumor DNA is an emerging biomarker with potential to individualize sequencing strategies, although its clinical application remains investigational. This review synthesizes current evidence and highlights practical considerations, emphasizing the need to balance therapeutic innovation with cost effectiveness, equitable access, and global applicability, while identifying critical research priorities in the post-enfortumab vedotin plus pembrolizumab era.