Tralokinumab is an anti-interleukin-13 human monoclonal antibody developed for the treatment of severe, uncontrolled asthma. These clinical trials aimed to assess the efficacy and safety of tralokinumab in this population. STRATOS 1 and STRATOS 2 were randomised, double-blind, parallel-group, placebo-controlled, phase 3 clinical trials that enrolled participants aged 12-75 years with severe asthma that was inadequately controlled despite use of inhaled corticosteroids (≥500 μg per day fluticasone or equivalent) and a long-acting β2 agonist (but not oral corticosteroids). STRATOS 1 was done at 246 sites in 14 countries, and STRATOS 2 was done at 242 sites in 13 countries. In STRATOS 1, participants were randomly assigned (2:1) to receive tralokinumab 300 mg or matching placebo subcutaneously every 2 weeks or every 4 weeks for 52 weeks. In STRATOS 2, participants were randomly assigned (1:1) to receive tralokinumab 300 mg or matching placebo subcutaneously every 2 weeks for 52 weeks. STRATOS 1 attempted to identify a biomarker-positive population with enhanced tralokinumab benefit, which was then tested in STRATOS 2. The primary endpoint was the annualised asthma exacerbation rate (AAER) reduction at week 52 in the all-comers population for STRATOS 1 and in the biomarker-positive population for STRATOS 2. All efficacy analyses for both trials were done on the full analysis set by an intention-to-treat approach. The safety analysis set comprised any participant who received the investigational drug and was categorised by treatment received. These trials are registered with ClinicalTrials.gov, numbers NCT02161757 (STRATOS 1) and NCT02194699 (STRATOS 2), and with the EU Clinical Trials Register, EudraCT 2013-005614-35 (STRATOS 1) and EudraCT 2013-005615-27 (STRATOS 2). STRATOS 1 was done between June 13, 2014, and Feb 28, 2017. 1207 participants were randomly assigned and 1202 treated as follows: tralokinumab every 2 weeks (n=398), tralokinumab every 4 weeks (n=404), or placebo (n=400). STRATOS 2 was done between Oct 30, 2014, and Sept 21, 2017. 856 participants were randomly assigned and 849 treated as follows: tralokinumab every 2 weeks (n=427) and placebo every 2 weeks (n=422). In the STRATOS 1 all-comers population, tralokinumab every 2 weeks did not significantly reduce AAER compared with placebo (7·0% reduction [95% CI -20·8 to 28·4]; rate ratio 0·93 [95% CI 0·72 to 1·21]; p=0·59). Baseline fractional exhaled nitric oxide (FENO) 37 ppb or greater was identified as the preferred biomarker in STRATOS 1; in FENO-high participants, tralokinumab every 2 weeks (n=97) reduced AAER by 44·0% (95% CI 6·0 to 66·0; rate ratio 0·56 [95% CI 0·34 to 0·94]; p=0·028) compared with placebo (n=102). In the STRATOS 2 FENO-high population, tralokinumab every 2 weeks (n=108) did not significantly improve AAER (15·8% reduction [95% CI -33·7 to 47·0]; rate ratio 0·84 [95% CI 0·53 to 1·34]; p=0·47) compared with placebo (n=121). The safety profile was consistent with that of previous tralokinumab trials. Tralokinumab reduced AAER in participants with severe asthma with baseline FENO 37 ppb or higher in STRATOS 1, but not in STRATOS 2. These inconsistent effects on AAER do not support a key role for interleukin 13 in severe asthma exacerbations. AstraZeneca.

Natural products (NPs) have long been used as a rich source of bioactive compounds for drug development. Recent technological advancements have revitalised natural products research as evidenced by increased publications in this field. In this editorial review, we highlight key points from the 2020 British Journal of Pharmacology (BJP) practical guide, which outlines standards for natural products research reports, and provide papers published in BJP between years 2020 to 2023 that demonstrate adherence to these guidelines. Looking ahead, we discuss the potential of chemical proteomics approaches to elucidate natural products mechanisms of action and identify therapeutic targets for future research. By fostering innovation, we aim to advance natural products research and contribute to the development of novel therapeutics that will have a significant impact on healthcare.

Among patients with asthma, heterogeneity exists regarding the pattern of airway inflammation and response to treatment, prompting the necessity of recognizing specific phenotypes. Based on the analysis of inflammatory cell counts in induced sputum, asthmatic patients can be classified into 4 unique phenotypes: eosinophilic asthma, neutrophilic asthma, mixed granulocytic asthma, and paucigranulocytic asthma (PGA). PGA is an asthma phenotype with no evidence of increased numbers of eosinophils or neutrophils in sputum or blood and in which anti-inflammatory therapies are ineffective at controlling symptoms. Although underinvestigated, PGA is the most common asthma phenotype in patients with stable asthma. However, PGA is sometimes underestimated because of the exclusive reliance on induced sputum cell counts, which are variable among cohorts of studies, prompting the necessity of developing improved biomarkers. Importantly, investigators have reported that inhaled corticosteroids had a limited effect on airway inflammatory markers in patients with PGA and therefore defining PGA as a potentially "steroid-insensitive" phenotype that requires exploration of alternative therapies. PGA manifests as an uncoupling of airway obstruction from airway inflammation that can be driven by structural changes within the airways, such as airway smooth muscle tissue hypertrophy. Animal models provide evidence that processes evoking airway hyperresponsiveness and airway smooth muscle thickening occur independent from inflammation and might be a consequence of a loss of negative homeostatic processes. Collectively, further understanding of PGA with a focus on the characterization, prevalence, clinical significance, and pathobiology derived from animal studies will likely provide precision therapies that will improve PGA clinical outcomes.

Bacterial-associated LPS drives oncostatin M–dependent airway inflammation and mucus hypersecretion in severe asthma.

The asthma-obesity syndrome represents a major public health concern that disproportionately contributes to asthma severity and induces insensitivity to therapy. To date, no study has shown an intrinsic difference between human airway smooth muscle (HASM) cells derived from nonobese subjects and those derived from obese subjects. The objective of this study was to address whether there is a greater response to agonist-induced calcium mobilization, phosphorylation of myosin light chain (MLC), and greater shortening in HASM cells derived from obese subjects. HASM cells derived from nonobese and obese subjects were age and sex matched. Phosphorylation of MLC was measured after having been stimulated by carbachol. Carbachol- or histamine-induced mobilization of calcium and cell shortening were assessed in HASM cells derived from nonobese and obese donors. Agonist-induced MLC phosphorylation, mobilization of calcium, and cell shortening were greater in obese compared with non-obese-derived HASM cells. The MLC response was comparable in HASM cells derived from obese nonasthma and nonobese fatal asthma subjects. HASM cells derived from obese female subjects were more responsive to carbachol than HASM cells derived from obese male subjects. Insulin pretreatment had little effect on these responses. Our results show an increase in agonist-induced calcium mobilization associated with an increase in MLC phosphorylation and an increase in ASM cell shortening in favor of agonist-induced hyperresponsiveness in HASM cells derived from obese subjects. Our studies suggest that obesity induces a retained phenotype of hyperresponsiveness in cultured human airway smooth muscle cells.

Significance: Stromal-interacting molecule 1 (STIM1) proteins are essential for the function of store-operated Ca ²⁺ entry (SOCE). Using transcriptomics, metabolomics, imaging, and inducible smooth muscle–specific STIM1 knockout mice expressing genetically encoded Ca ²⁺ sensors, we reveal a crucial function of STIM1 in airway remodeling and airway hyperresponsiveness in asthma. STIM1-mediated Ca ²⁺ oscillations in airway smooth muscle (ASM) cells are critical for ASM remodeling through metabolic and transcriptional reprogramming and cytokine secretion, including IL-6. These effects are driven by Ca ²⁺ -dependent activation of the transcription factor isoform NFAT4 specifically in ASM. Our data provide evidence that ASM STIM1 and SOCE are central triggers of asthma manifestations and advocate for the future use of STIM1 as a molecular target in asthma therapy.