Chronic Obstructive Pulmonary Disease (COPD) and lung cancer (LC), both predominantly linked to smoking, exhibit a poorly understood relationship. Current hypotheses suggest that oxidative stress and sustained inflammation induced by cigarette smoke create a favourable environment for the development of both diseases. Repeated cycles of injury and repair seen in COPD may also contribute to the onset of Tumorigenesis. This study aims to unravel the molecular mechanisms underlying the transition from COPD to LC through a combination of in silico analyses and animal experiments. In silico study included a total of 18 BioProjects for Non-small cell lung cancer (NSCLC) and 7 BioProjects for COPD derived from the National Center for Biotechnology Information-Sequence Read Archive (NCBI-SRA). The differential gene expression analysis, enriched pathway analysis and network analysis were performed using the patients' transcriptomic Next-generation sequencing (NGS) data from both diseases. The study suggested that the Tumor Necrosis Factor (TNF), a pro-inflammatory cytokine, as a potential link between COPD and NSCLC. In vivo experiments were performed with vitamin C-deficient guinea pigs exposed to para-benzoquinone (p-BQ), a component of cigarette smoke and quinone pollution that causes emphysematous damage, while lower doses potentially promote cellular proliferation, making it a good animal model. Histological analyses and immune-detection-based protein analyses reveal a heterogeneous distribution of p-BQ-induced oxidative stress, thereby creating distinct inflammatory states simultaneously. Biphasic activation of TNF-α plays a dual role, showing two opposing phenomena in different phases: acute, with apoptosis and chronic, with proliferation, by activating Caspase 8 and NF-κB, respectively. Gradual remodeling of tissue remodeling sheds light on pre-malignant changes in the chronic phase. As COPD and lung cancer co-exist clinically, this observation potentially contributes to the development of targeted therapies for patients with both diseases.
Asthma and COPD are chronic respiratory conditions characterised by persistent airway inflammation, elevated inflammatory biomarkers (CRP, TNF-α, IL-6, IL-10), and frequent hypomagnesaemia, which worsens disease severity despite standard treatments. This study evaluates the efficacy and safety of Magnesium glycinate (440 mg/day) as add on therapy in the management of asthma and COPD. This randomised, double-blind, placebo-controlled trial enrolled 224 adults (112 Asthma and 112 COPD) with confirmed hypomagnesemia (Serum magnesium < 1.6 mg/dL) at Arogyavaram Medical Centre, India. Participants received oral magnesium glycinate 440 mg daily (n = 112) or placebo (n = 112) for 12 months alongside standard therapy. Primary outcomes were changes in CRP, TNF-α, IL-6, and IL-10. Secondary outcomes included FEV1/FVC ratio, serum magnesium, quality of life, medication adherence, and adverse drug reactions. Mixed-effects models and t-tests were used (P < 0.05). Magnesium glycinate supplementation significantly reduced systemic inflammation and improved pulmonary function in both asthma and COPD patients compared with placebo, as demonstrated by reductions in CRP (asthma: -0.97 mg/L, 95% CI -1.34 to -0.61, P < 0.001; COPD: -3.42 mg/L, 95% CI -4.23 to -2.61, P < 0.001) and improvements in FEV1 (asthma: +0.23 L, p = 0.002; COPD: +0.19 L, p = 0.004). Alongside an increase in the anti-inflammatory cytokine IL-10 (+2.8 pg/mL, 95% CI + 0.61 to +4.99, p = 0.013) and the intervention was well tolerated with no serious adverse events compared to placebo. Adjunctive magnesium glycinate safely reduces inflammatory biomarkers, particularly CRP, in hypomagnesemic asthma and COPD patients, with stronger cytokine modulation in COPD.
Cystic fibrosis (CF) has become increasingly treatable with Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-targeted therapies. However, the availability and efficacy of these treatments depend on each patient's CFTR genotype, necessitating careful follow-up to detect effective benefits. This study builds on our previous findings by applying the Optical Beta-Adrenergic Sweat Test (OBAST) as a complement to the classical sweat Cl- testing (ST) to better evaluate the restoration of CFTR activity in vivo. We quantified the sweat droplet number (SDN) and the ratio between CFTR-dependent (beta-adrenergic Cocktail-induced, C-phase) and the CFTR-independent (Methacholine-induced, M-phase) sweat rates (C/M ratio) in 128 non-CF subjects and 143 people with CF (PwCF). Among the PwCF, 39 were treated with various combinations of the CFTR modulators, including Lumacaftor/Ivacaftor (LI), Tezacaftor/Ivacaftor (TI) and/or Elexacaftor/Tezacaftor/Ivacaftor (ETI). SDN detected an earlier response to CFTR modulators, yielding lower p-values than the C/M rate ratio, particularly during ETI therapy. Thus, SDN counting provides a simpler and faster method than C/M ratio for monitoring the effects of CFTR modulators on CFTR function, without compromising sensitivity or reliability. This enables more precise tracking of drug efficacy in individual subjects. In six PwCF, who underwent at least two different CFTR-targeted therapies, we also assessed lung function and nasal potential difference (NPD) in addition to ST, SDN, and the C/M ratio. We propose OBAST as a reliable complementary tool to standard tests, especially valuable when CFTR-targeted drugs are not approved for rare CFTR genotypes, when clinical response appears limited, and/or when sweat [Cl-] results are inconclusive.
Brain-derived neurotrophic factor (BDNF) is classically recognized for its role in neuronal survival and synaptic plasticity; however, increasing evidence highlights its important regulatory functions within the respiratory system. In the lung, BDNF and its receptors, particularly tropomyosin receptor kinase B (TrkB), are expressed by airway epithelial cells, airway smooth muscle, immune cells, fibroblasts, and neurons, positioning BDNF as a central mediator of neuroimmune-epithelial crosstalk. Activation of BDNF-TrkB signaling engages multiple intracellular pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), phospholipase C-γ (PLCγ), and small GTPase-dependent cascades, thereby regulating epithelial repair, airway contractility, inflammation, fibrosis, and neural plasticity. Dysregulation of this signaling axis has been implicated in the pathogenesis of major respiratory diseases. In asthma, excessive BDNF activity contributes to airway hyperresponsiveness and remodeling, whereas in chronic obstructive pulmonary disease reduced BDNF signaling is associated with impaired epithelial regeneration. In idiopathic pulmonary fibrosis, BDNF promotes fibroblast activation and extracellular matrix deposition, while in acute lung injury and acute respiratory distress syndrome its effects appear context dependent, supporting epithelial survival during acute injury but exacerbating pathology when persistently elevated. Emerging evidence further implicates epigenetic mechanisms, microRNAs, and cellular heterogeneity revealed by single-cell transcriptomics in shaping disease-specific BDNF responses. Collectively, these findings identify BDNF as a context-dependent regulator of pulmonary homeostasis and disease. Targeted modulation of BDNF-TrkB signaling therefore represents a promising, yet complex, therapeutic avenue for chronic and acute respiratory disorders.
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by neutrophil-dominant inflammation, disruption of the alveolar-capillary barrier, and severe hypoxemia, with persistently high mortality in infection-associated etiologies, including severe COVID-19 pneumonia. Neutrophil elastase (NE) is a central mediator of lung tissue destruction and inflammatory amplification in these conditions. However, currently available NE inhibitors such as Sivelestat have shown limited clinical efficacy. Here we evaluated the therapeutic potential of PD-05, a novel NE inhibitor, in murine model of ALI. ALI was induced in female C57BL/6 mice using intratracheal LPS (1 mg/kg), followed by oral administration of PD-05 (5 mg/kg). PD-05 significantly attenuated NE activity and reduced neutrophilic infiltration in lung tissue. Mechanistically, PD-05 suppressed NF-κB activation and reduced pro-inflammatory cytokines (TNF-α, IL-6, and Kc) levels, while decreasing ICAM-1 expression, consistent with reduced leukocyte recruitment and improved barrier integrity. PD-05 increased heme oxygenase-1 (HO-1) expression and restored surfactant protein C levels. These molecular changes translated into significant structural and functional improvement, evidenced by reduced septal thickening, preserved alveolar architecture, decreased HIF-1α expression, attenuation of airway hyperresponsiveness, and improved lung mechanics. Histological analysis further confirmed reduced lung injury and improved epithelial integrity in PD-05-treated mice. Collectively, PD-05 exerts coordinated anti-inflammatory and barrier-protective effects in experimental ALI, underscoring its translational potential for ALI and ARDS.
Severe eosinophilic asthma is driven by interleukin (IL)-5-mediated type 2 inflammation and frequently requires long-term biologic therapy. Depemokimab was designed to achieve sustained IL-5 neutralization with a twiceyearly dosing schedule, addressing key unmet needs related to treatment burden and adherence. This review summarizes the molecular design, preclinical pharmacology, model-informed drug development (MIDD) strategy, Phase I-III clinical trial program, and regulatory approvals of depemokimab in asthma and chronic rhinosinusitis with nasal polyps. Depemokimab exemplifies how rational antibody engineering, including Fc modification and high-affinity IL-5 binding, can enable sustained pharmacodynamic activity and ultra-longacting cytokine inhibition. A twice-yearly dosing regimen may offer advantages in terms of treatment adherence, patient convenience, and long-term disease control. The application of MIDD approaches facilitated efficient clinical development and supported the progression of pivotal trials, potentially shortening development timelines by approximately two to three years. Although efficacy and safety data are encouraging, longer-term real-world evidence will be necessary to better define immunogenicity, rare adverse events, and adherence patterns. Comparative effectiveness studies of depemokimab versus other approved anti-IL-5 therapies and type 2-targeted biologics will be critical to establish its relative clinical value. Further investigation into additional eosinophilic diseases, pediatric populations, and diverse healthcare settings may expand its therapeutic utility, positioning depemokimab as a representative example of next-generation long-acting biologics that target cytokine-mediated inflammatory diseases.
Lung cancer remains a leading healthcare challenge due to its high mortality and incidence. To develop a new therapeutic approach, dihydroartemisinin (DHA) was combined with chrysin (CRS) to test their effects on both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cells. The results demonstrated that the DHA + CRS combination not only significantly reduced the effective concentrations of both drugs but also robustly induced apoptosis in both cancer types. Utilizing next-generation sequencing, topoisomerase II alpha (TOP2A) was identified as a critical molecular target mediating the apoptosis-enhancing effects of this combination therapy. Validation experiments, including TOP2A overexpression and siRNA-mediated silencing, confirmed TOP2A's pivotal role in the apoptotic pathway activated by DHA + CRS. Mechanistically, the combination therapy reduced TOP2A expression, leading to DNA damage accumulation (evidenced by increased γH2A.X) and p53 upregulation. This study established a novel therapeutic strategy for treating the two major lung cancer subtypes by DHA and CRS combination at lower concentrations. The discovery of TOP2A as a therapeutic target opens new avenues for drug discovery, potentially expanding the development of TOP2A-targeted therapies.
Lung ischemia-reperfusion (I/R) injury is a major driver of acute lung dysfunction after procedures such as lung transplantation, yet effective pharmacological strategies remain limited. We evaluated whether evodiamine (EVO) mitigates lung I/R injury and explored potential mechanisms. Male C57BL/6 mice underwent left pulmonary hilar occlusion (60 min) followed by reperfusion (120 min) and received EVO, the SYK inhibitor BAY61-3606, or the combination. Compared with I/R alone, treatment reduced histopathological damage, inflammatory cytokine expression, apoptosis, and ferroptosis-associated marker changes (iron overload, PTGS2 induction, and loss of GPX4/SLC7A11). EVO was associated with decreased activation of the SYK/TLR4/NLRP3 inflammasome axis, and BAY61-3606 recapitulated several protective effects. Because the mechanistic inference is based on pharmacological inhibition, these findings support—rather than definitively prove—SYK-linked TLR4/NLRP3 signaling as an important node in EVO-mediated protection. Together, the data suggest that evodiamine alleviates acute lung I/R injury in part by restraining inflammatory signaling and modulating ferroptosis-related markers.
BACKGROUND:The positive effects of modulator therapies (MT) on various symptoms have been proven. There is no clear recommendation for stopping or reducing the dose of other therapies after using modulators. However, patients may feel better and stop their other therapies. The aim of this study was to compare Medication Regimen Complexity Index (MRCI) and Treatment Complexity Score (TCS) scores of adult CF patients before and after 1 year of their MT use and also to compare them with non-MT patients. METHODS:The medications and forced expiratory volume in 1 s (FEV1) of patients using MT were recorded on the first day and after 1 year, and those non-MT were recorded at 1-year intervals. MRCI and TCS were recorded simultaneously. RESULTS:In total, 105 patients were included (48.6% MT). Dornase alfa use decreased significantly in the MT group (p < 0.001), while azithromycin use increased significantly in the non-MT group (p = 0.016). No significant change was observed in the use of other therapies. In the MT, mean (SD) MRCI and TCS decreased significantly [28.37 (10.39) vs 23.77 (10.90); p < 0.001 and 8.86 (3.37) vs 7.51 (3.29); p < 0.001]. In the non-MT, mean (SD) MRCI and TCS increased significantly [23.65 (12.86) vs 26.13 (14.68); p < 0.001, and 7.29 (4.21) vs 7.79 (4.61) p = 0.021]. A negative significant correlation was observed between MRCI (p < 0.001), TCS (p < 0.001) and FEV1% at baseline and after 1-year. CONCLUSION:A decrease in the use of inhaled therapy was observed in MT group after 1 year. Our study demonstrates that patients receiving MT exhibit a reduction in medication use, whereas those not receiving MT show an increase, suggesting that MT may contribute to decreased treatment burden without worsening clinical outcomes in CF management.
Sepsis is a severe systemic inflammatory response in which the lungs are often the first organ affected. Given the known inhibitory effects of nicotinamide N-oxide (NAMO) on inflammatory cell activation, this study sought to assess its protective function in a mouse model of acute lung damage generated by sepsis. The caecal ligation and puncture (CLP) technique was employed to induce sepsis, and 40, 80, and 160 mg/kg NAMO were given intraperitoneally. In a dose-dependent manner, NAMO dramatically reduced inflammatory cell infiltration, interstitial lung oedema, neutrophil aggregation, and macrophage activation. In lung tissues and cells, NAMO therapy decreased lipid peroxidation (MDA), increased the activities of antioxidant enzymes (CAT, GSH-Px, and T-AOC), and decreased the mRNA expression levels of proinflammatory cytokines. Western blot analysis revealed that NAMO modulates the protein levels of GPX4 and SLC7A11, thereby reducing cell death, Fe2+ accumulation, and ROS levels. Mechanistically, silencing SIRT1 attenuated NAMO-induced activation of the AKT signalling pathway, indicating that SIRT1 is required for NAMO-mediated AKT activation. Moreover, NAMO effectively mitigated sepsis-induced ferroptosis by modulating iron metabolism-related markers through the SIRT1/AKT signalling pathway. In conclusion, NAMO inhibits ferroptosis and alleviates sepsis-induced acute lung injury by activating the SIRT1-mediated AKT signalling pathway.
The clinical use of the anti-cancer drug arsenic trioxide (ATO) has been limited due to its side effects and the development of cancer cell resistance, highlighting the need for combination therapy. In this study, we optimized and characterized the combination of antifungal drug posaconazole (PCZ) and ATO in A549 lung cancer cells using single-drug monotherapy and sequential/pretreatment combination assays. In the pretreatment approach, the cells were incubated with PCZ for 6 h, followed by incubation with ATO for 48 h. MTT assay indicated that the sequential (pretreatment) combination of ATO and PCZ produced an IC50 value of 25 μmol/L, whereas PCZ and ATO alone exhibited IC50 values of 100 μmol/L and 75 μmol/L, respectively. qRT-PCR analysis showed that treatment at the IC50 concentration of ATO upregulated HMGA2 and Bcl-2 gene expression, while the combination of ATO with PCZ significantly countered these effects. Additionally, overexpression of HMGA2, VEGF, and MMP-9 indicated a high potential for invasion and metastasis, particularly at 75 μmol/L ATO, as demonstrated by wound healing and transwell invasion assays. In contrast, the pretreatment combination showed high efficacy in inducing cytotoxicity in lung cancer cells with minimal risk of invasion and metastasis. The results indicated that this enhanced cytotoxicity occurs through apoptosis induction and modulation of the Hedgehog signaling pathway via targeting SMO and Gli1. Furthermore, flow cytometry and colony formation assays revealed that PCZ attenuates and reduces the apoptotic/necrotic effects of ATO. In conclusion, PCZ synergistically and effectively reduces the adverse cytotoxic effects of ATO in lung cancer cells, providing a promising new therapeutic strategy for lung cancer treatment.
Chronic airway diseases (CAD), including asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, and cystic fibrosis, are increasingly recognized as heterogeneous and overlapping syndromes that share treatable biological and clinical characteristics. The Treatable Traits (TT) approach is a precision medicine framework that transcends diagnostic labels. It identifies and targets modifiable pulmonary, extrapulmonary, and behavioral characteristics in each patient. Biomarkers are central to this paradigm, translating latent endotypes into measurable traits that inform diagnosis, treatment selection, and longitudinal monitoring.This review synthesizes contemporary evidence on the role of biomarkers in implementing the TT model across CAD. Peripheral and airway biomarkers, including blood eosinophil count (BEC), fractional exhaled nitric oxide (FeNO), and sputum cell profiles, enable the identification of type 2 inflammatory traits and the prediction of corticosteroid or biologic responsiveness. Imaging and quantitative computed tomography metrics extend trait definition to structural and functional domains. Meanwhile, multi-omic and microbiome signatures reveal the molecular endotypes that underpin disease heterogeneity. Canonical examples include BEC predicting the benefit of inhaled corticosteroids in COPD and FeNO indicating steroid responsiveness in asthma. Additionally, emerging data suggest that rapid trait identification during acute exacerbations may facilitate targeted biologic therapy, extending precision care into acute management contexts.Integrating biomarker-guided assessment with individualized therapy redefines the management of CAD by offering a pathway toward biologically precise, dynamically adaptive care. Continued research should focus on standardizing biomarker thresholds, validating composite panels, and translating omic and imaging discoveries into routine clinical tools to optimize outcomes across the chronic airway disease spectrum.
BACKGROUND:Severe asthma is characterized by impaired lung function and elevated cardiovascular risk. Type 2 inflammation, primarily mediated by IL-4 and IL-13, contributes to both airway and cardiac remodeling. Dupilumab, an IL-4Rα antagonist, has shown efficacy in improving respiratory outcomes; however, its impact on cardiac function remains insufficiently studied. OBJECTIVE:To assess the 12-month effects of dupilumab on echocardiographic parameters and evaluate its potential association with clinical remission in patients with severe type 2 asthma. METHODS:This single-centre observational study enrolled 24 patients with severe type 2 asthma receiving dupilumab. Echocardiographic assessments and lung function tests were conducted at baseline and after 12 months. Clinical remission was defined by meeting all of the following: zero exacerbations, zero OCS use, ACT score ≥20, and pre-bronchodilator FEV1 ≥ 80 % predicted. RESULTS:Twelve-month dupilumab therapy led to significant improvements in both cardiac and respiratory parameters. LV-GLS improved from -17.00 % to -19.00 % and RV-GLS from -17.33 % to -19.11 % (both p < 0.0001). TAPSE and TAPSE/S-PAP ratio also increased significantly (p < 0.0001). Lung function showed notable gains in FEV1 and FEF25-75, alongside reductions in residual volume and airway resistance. Clinical remission was achieved by 45.83 % of patients. Baseline LV-GLS emerged as a strong predictor of remission (AUC = 0.832), unlike RV-GLS (AUC = 0.545). CONCLUSIONS:Dupilumab markedly improved cardiac and pulmonary function and may promote clinical remission. Baseline LV-GLS may serve as a predictive marker, supporting cardiovascular assessment in asthma management.
Idiopathic pulmonary fibrosis is a progressive interstitial lung disease associated with poor prognosis and high mortality rate. It is a chronic irreversible lung disorder, mainly characterized by matrix stiffening. This study aims to investigate the therapeutic potential of targeting ELK-1 transcription factor and mechanosensitive MDM4 receptor using Ivabradine (IVA), an HCN channel blocker, in bleomycin (BLM)-induced pulmonary fibrosis (PF) rat model. Total, differential cell counts and LDH activity were assessed in bronchoalveolar lavage fluid. Pulmonary levels of MDA, GSH, IL-1β, α-SMA, COL1A1, ELK-1, MDM4, p-53, caspase-3, cleaved caspase-3, and CX3CL-1 were measured. Our study demonstrated that IVA induced a marked decrease in MDA and increase in GSH levels. Also, rats treated with IVA revealed a significant reduction in inflammation scores, LDH, IL-1β, α-SMA and COL1A1 levels. IVA-treated group showed a marked downregulation of MDM4 and ELK-1 along with significant upregulation of p-53, caspase-3, cleaved caspase-3, and CX3CL-1 levels when compared to BLM-induced PF group. In conclusion, these findings highlight the therapeutic potential of IVA in the treatment of pulmonary fibrosis. The antifibrotic effects of IVA in the bleomycin-induced rat model may be attributed to restoring redox balance, alleviation of aberrant inflammatory response, sensitizing lung myofibroblasts to apoptosis and promoting their clearance by macrophages.
BACKGROUND:Oral selexipag, a prostacyclin receptor agonist, has been shown to delay pulmonary arterial hypertension (PAH) progression and reduce the risk of hospitalization for PAH. To ensure optimal patient outcomes with selexipag, careful treatment titration and expected side effect (SE) management are required. This study aimed to obtain expert consensus on the appropriate management of patients with PAH treated with selexipag. METHODS:United States (US) healthcare professionals (N = 17, 11 physicians; 5 nurse practitioners; 1 registered nurse) participated in this modified-Delphi panel comprising two online surveys and a consensus meeting. Consensus was defined as ≥80% panelists agreeing using a 9-point Likert scale. RESULTS:Panelists prescribed selexipag according to FDA label recommendations to patients with PAH. Panelists acknowledged considerations prompting adjustment in titration speed, agreeing that individual maximum dose is based on SE tolerability. It was agreed that the duration of SEs is variable and patient-specific, however, SEs often become manageable over time. Panelists identified methods for managing SEs, agreeing this should be proactive. Panelists highlighted the importance of communicating with patients to set expectations, to enhance engagement and adherence. Panelists agreed that treatment initiation, titration, and SE management should be individualized to suit each patient, with decision-making primarily based on patient characteristics and treatment preference. DISCUSSION:This panel provided expert opinions on the clinical use of and best practices for treatment titration and management of expected SEs for oral selexipag. Insights are valuable for developing standardized clinical guidelines and best practices, as well as ensuring personalized treatment to improve patient care.
Background The coexistence of asthma and chronic obstructive pulmonary disease (COPD), known as asthma-COPD overlap (ACO), presents unique diagnostic and therapeutic challenges. Although biological therapies such as Mepolizumab and Dupilumab have transformed the management of severe eosinophilic asthma, their role in ACO remains poorly defined due to the exclusion of this phenotype from most clinical trials. Methods This retrospective observational study aimed to evaluate the real-world effectiveness of Mepolizumab and Dupilumab in patients with ACO compared to those with severe uncontrolled asthma (SUA). We included 212 patients treated in a specialized asthma unit between 2017 and 2024, all with at least 12 months of follow-up. Treatment response was assessed using clinical tools (EXACTO scale and SEPAR-REMAS criteria). Results Among Mepolizumab-treated patients (ACO n = 10; SUA n = 132), those with ACO had significantly lower baseline FEV1 and lower rates of good/complete response (14.2% vs. 60%, p < 0.03) and clinical remission (0% vs. 20.9%). In the Dupilumab group (ACO n = 10; SUA n = 60), ACO patients showed lower baseline ACT scores and FEV1, with reduced response rates (25% vs. 55%) and no clinical remission, although differences were not statistically significant. Despite limited power due to small ACO sample sizes, the magnitude of these differences suggests a clinically relevant reduction in biologic effectiveness in ACO. Conclusion These findings emphasize the urgent need for dedicated studies in ACO, a population with a high disease burden and limited treatment guidance. Individualized therapeutic approaches should be prioritized until robust clinical trial data becomes available.
Staccato alprazolam (STAP) is a hand-held device that can provide rapid systemic delivery of alprazolam via pulmonary inhalation. UP0099/NCT04802746, a phase 1, randomized, double-blind, placebo-controlled trial, evaluated pulmonary safety of two consecutive doses of STAP administered 72 h apart (days 1, 4). Part A evaluated STAP 1 mg and 2 mg vs. placebo in a three-way crossover design in healthy adults. Part B evaluated STAP 2 mg vs. placebo in a two-arm parallel-group design in adults with mild asthma. In Part A (n = 30 randomized) on day 1, mean change from baseline in forced expiratory volume in 1 s (FEV1) showed a statistically significant decrease vs. placebo at 5 min postdose for STAP 1 mg and 5/20 min for STAP 2 mg. On day 4, there were no statistically significant negative changes from baseline in FEV1. Respiratory treatment-emergent adverse events (TEAEs) were reported by 8/29 and 12/29 participants on STAP 1 mg/2 mg, respectively (day 1), and 8/29 and 9/28 (day 4) (placebo: 0). In Part B (n = 25 placebo, n = 23 STAP) on days 1 and 4, mean change from baseline in FEV1 showed a statistically significant decrease for STAP 2 mg vs. placebo at 5/20 min and 6 h postdose. Respiratory TEAEs were reported by 16/23 participants on STAP 2 mg on day 1, 15/22 on day 4 (placebo: 0). Most respiratory TEAEs were mild in intensity. No evidence of clinically relevant airway obstruction or respiratory TEAEs indicative of bronchospasm with STAP were observed. Two doses of STAP (1 mg/2 mg) administered 72 h apart were well tolerated in healthy participants and those with mild asthma.
