Vertex Pharmaceuticals

Think bronchoscopy is just for samples? Think again. It impacts clinical management in >50% of bronchiectasis cases with a high safety profile: moving from expert opinion to data-driven care. https://bit.ly/3NYVAM3.

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has demonstrated efficacy in people with cystic fibrosis (pwCF) aged ≥6 years with ≥1 F508del allele in clinical trials. This registry-based cohort study aimed to describe real-world use and outcomes up to 36 months post-treatment initiation among pwCF aged ≥6 years treated with ELX/TEZ/IVA in France. Outcomes included per cent predicted forced expiratory volume in 1 s (ppFEV1), intravenous-treated pulmonary exacerbations (PEx), hospitalisations, nutrition, lung transplantation, mortality and, among pwCF ≥18 years, quality of life (CFQ-R). All results are presented by population (≥12 years and 6-11 years). In the ≥12 years cohort, a subgroup analysis of pwCF with advanced lung disease (ALD), defined as ppFEV1 <40% at baseline, is presented. The study included 553 pwCF aged 6-11 years, with a mean±sd age of 8.8±1.9 years at baseline, ppFEV1 of 91.3±17.6% and mean follow-up of 8.9 months. In addition, 3313 pwCF aged ≥12 years were included, with a mean±sd age at baseline of 27.6±11.7 years, ppFEV1 of 65.4±24.8% and mean follow-up of 21.2 months. In the cohort aged 6-11 years, ppFEV1 improved by +9.6% (95% CI: 7.6-11.6) at 12 months and i.v.-treated PEx annual rate decreased from 0.15 (95% CI: 0.11-0.18) to 0.02 (0.00-0.04) after 0 to 12 months post-ELX/TEZ/IVA initiation. Among pwCF ≥12 years ppFEV1 improved post-ELX/TEZ/IVA initiation by +16.2% (95% CI: 15.6-16.8) at 24 months. i.v.-treated PEx annual rate decreased from 0.92 (95% CI: 0.88-0.95) during baseline to 0.14 (95% CI: 0.12-0.15) after 12 to 24 months post-ELX/TEZ/IVA initiation. Similar benefits to those in the ≥12 years population were observed in the ALD subgroup. This study confirms the longer term, transformational clinical benefit of ELX/TEZ/IVA in pwCF aged ≥6 years in a French population, demonstrating sustained improvements across multiple health outcomes, including in pwCF with ALD that were not part of the pivotal clinical trials.

Breathlessness is a common symptom in long COVID (LC). Using hyperpolarised xenon magnetic resonance imaging (129Xe-MRI), we assessed whether this symptom could be attributed to abnormalities in the alveolar-capillary membrane not detected by standard investigations. We focused on never-hospitalised individuals without an identified cause for breathlessness. In this prospective, multicentre study, we compared 129Xe-MRI, lung function, exercise capacity and symptom questionnaires in LC patients with breathlessness (BLC) to those without breathlessness (NBLC) and healthy controls. Primary outcome was whether BLC demonstrated measurable impairments in gas exchange focusing on dissolved-phase 129Xe-MRI metrics: red blood cell to membrane ratio (RBC:M) and red blood cell to gas ratio (RBC:Gas). We also explored associations between symptoms and physiological measures. Of 269 participants recruited, 196 were included in the analysis (109 BLC, 43 NBLC, 44 controls), with age and sex well matched across groups. BLC had a significantly longer interval from infection to MRI (median 632 days; p<0.001). No significant differences in global or regional RBC:M or RBC:Gas were observed across groups. BLC showed lower forced expiratory volume in 1 s, forced vital capacity, transfer factor of the lung for carbon monoxide (T L CO), and carbon monoxide transfer coefficient (K CO) z-scores compared to controls, though >90% of values remained within normal range. A subset of BLC participants with low T L CO (14 out of 109) showed reduced 129Xe-MRI metrics and higher breathlessness scores. Most nonhospitalised LC participants exhibited no detectable pulmonary abnormalities, including those with breathlessness. However, ∼13% of breathless individuals demonstrated minor reductions in T L CO and 129Xe-MRI gas exchange suggesting a potential pulmonary contribution for symptoms in this subgroup.

Sickle cell disease remains a major cause of childhood morbidity and mortality, particularly in sub-Saharan Africa. In September, 2025, WHO convened the Paediatric Drug Optimization for Sickle Cell Disease process to review approved therapies, pipeline candidates, and potentially curative approaches, and define priorities for children and adolescents. Hydroxyurea (hydroxycarbamide) was confirmed as the leading near-term priority, with age-appropriate soluble or dispersible formulations identified as essential to improve equitable paediatric access; preferred and minimum characteristics were defined through a formal target product profile. Among investigational agents, pyruvate kinase activators and decitabine plus tetrahydrouridine (NDec) emerged as promising candidates for paediatric investigation on the basis of emerging efficacy data and programmatic potential. Intersecting research priorities included identifying appropriate clinical trial endpoints, strengthening early and inclusive paediatric investigation, and proactively ensuring that the promise of potential cure through gene therapy does not delay investment in scalable disease-modifying treatments.

Notalgia paresthetica is a sensory neuropathy characterized by severe pruritus, pain, and hyperpigmented patches in the T2-T6 distribution. Despite multiple treatment options, there are no established guidelines to manage this challenging sensory neuropathy. A 64-year-old man presented to the pain clinic with persistent notalgia paresthetica for 5 years. He was unable to tolerate oral neuropathic agents, and insurance coverage for capsaicin cream and botulinum toxin injections was denied. He was treated with suzetrigine, a novel NaV1.8 channel inhibitor, for 1 month and experienced complete resolution of symptoms. The etiology of notalgia paresthetica has not been fully elucidated, but it is thought to involve irritation and aberrant firing of the thoracic spinal nerves. This response to suzetrigine suggests that it may act as a peripheral nerve membrane stabilizer and may be a treatment option for this condition.

Crohn's disease is an inflammatory bowel disease (IBD) commonly treated through anti-TNF blockade. However, most patients still relapse and inevitably progress. Comprehensive single-cell RNA-sequencing (scRNA-seq) atlases have largely sampled patients with established treatment-refractory IBD, limiting our understanding of which cell types, subsets, and states at diagnosis anticipate disease severity and response to treatment. Here, through combining clinical, flow cytometry, histology, and scRNA-seq methods, we profile diagnostic human biopsies from the terminal ileum of treatment-naive pediatric patients with Crohn's disease (pediCD; n = 14), matched repeat biopsies (pediCD-treated; n = 8) and from non-inflamed pediatric controls with functional gastrointestinal disorders (FGIDs; n = 13). To resolve and annotate epithelial, stromal, and immune cell states among the 201,883 baseline single-cell transcriptomes, we develop a principled and unbiased tiered clustering approach, ARBOL. Through flow cytometry and scRNA-seq, we observe that treatment-naive pediCD and FGID have similar broad cell type composition. However, through high-resolution scRNA-seq analysis and microscopy, we identify significant differences in cell subsets and states that arise during pediCD relative to FGID. By closely linking our scRNA-seq analysis with clinical meta-data, we resolve a vector of T cell, innate lymphocyte, myeloid, and epithelial cell states in treatment-naive pediCD (pediCD-TIME) samples, which can distinguish patients along the trajectory of disease severity and anti-TNF response. By using ARBOL with integration, we position repeat on-treatment biopsies from our patients between treatment-naive pediCD and on-treatment adult CD. We identify that anti-TNF treatment pushes the pediatric cellular ecosystem toward an adult, more treatment-refractory state. Our study jointly leverages a treatment-naive cohort, high-resolution principled scRNA-seq data analysis, and clinical outcomes to understand which baseline cell states may predict Crohn's disease trajectory.

Non-transfusion-dependent β-thalassemia (NTDT) was historically regarded as a relatively mild form of thalassemia because patients survive without regular transfusion therapy. However, growing evidence has challenged this perception and uncovered substantial morbidity and premature mortality driven by chronic anemia, iron overload, and hypercoagulability. This review examines three major clinical paradoxes that have reshaped the understanding of NTDT: the anemia paradox, whereby transfusion-independent patients may actually benefit from anemia correction; the iron overload paradox, characterized by clinically significant iron accumulation despite minimal or no transfusion exposure; and the hypercoagulability paradox, whereby chronic anemia coexists with a prothrombotic state. These evolving concepts have transformed NTDT from a condition traditionally managed through observation into a disease requiring proactive, risk-based intervention.