Boehringer Ingelheim (South Korea)

<bold>Background</bold> Neutrophil elastase (NE) is activated by CatC, and increased airway NE activity is linked to poor outcomes in people with bronchiectasis (BE). We report the effects of the CatC inhibitor BI 1291583 on NE activity in people with BE in the AIRLEAF^® study. <bold>Methods</bold> AIRLEAF^® enrolled 322 adults with BE, examining once-daily BI 1291583 administration (1/2.5/5 mg doses) vs placebo up to 48 weeks. Participants had a history of pulmonary exacerbations (PExs) requiring antibiotic treatment in the year prior to screening (≥2 PExs or 1 PEx with St. George’s Respiratory Questionnaire [SGRQ] Symptoms score >40). Free sputum NE activity was measured at baseline and over time, using a fluorescent substrate-based enzymatic activity assay. Descriptive statistics for absolute NE activity over time were calculated; change from baseline in sputum NE activity and corresponding NE inhibition were estimated using a mixed model with repeated measures. <bold>Results</bold> At baseline, mean sputum NE activity was similar across all treatment groups, with no differences in participants who had ≥2 PExs or 1 PEx with SGRQ Symptoms score >40. Higher baseline NE activity (p<0.01) was observed in those positive for <italic>P. aeruginosa</italic> and those from East Asia. At Weeks 12 and 24, placebo-corrected-mean-adjusted NE inhibition was 24.1% and 44.9%, 78.4% and 78.9%, and 80.2% and 90.8% in the BI 1291583 1 mg, 2.5 mg, and 5 mg groups, respectively. <bold>Conclusions</bold> Dose-dependent NE inhibition was seen with BI 1291583. However, the 2.5 mg dose achieved the greatest clinical efficacy in AIRLEAF^®;¹ several mechanisms may be responsible for this. ¹Chalmers JD, <italic>et al.</italic> Eur Respir J 2025;65:2401551

Idiopathic pulmonary fibrosis (IPF) presents with dysregulated alveolar repair and accumulation of aberrant cell fates supposedly driving the onset and progression of the disease. Standard of care therapies only achieve to decelerate fibrosis, while regeneration of the gas-exchange unit continues to pose a significant challenge. To address the unmet medical need for regenerative concepts, we designed an organoid model of the human alveolar epithelium for the identification of novel pathobiology in dysregulated lung repair. The model was established using co-cultured human primary alveolar type 2 (AT2) cells and lung fibroblasts in a miniaturized 384-well format. Alveolar budding organoids develop bud-like epithelial monolayers, demonstrating alveolar differentiation, apical-basal polarization and surfactant production. A cytokine cocktail, representative of the pro-fibrotic microenvironment in IPF, was used to simulate dysregulated alveolar repair, with disease-specific phenotypes confirmed via gene expression and proteomics. Pro-fibrotic stimulation of organoids led to suppressed bud formation, increased extracellular matrix generation and significant release of clinically relevant IPF biomarkers (e. g. MMP7, sICAM1). Decreased levels of alveolar markers, such as surfactant proteins, and the rise in aberrant gene signatures (e. g. KRT17), suggest disease-specific phenotypic shifts of epithelial cells under pro-fibrotic conditions. In summary, the alveolar budding organoid model demonstrates IPF-relevant phenotype shifts in a pro-fibrotic environment, offering a drug discovery platform to address novel therapeutic concepts in dysregulated alveolar repair.

ObjectiveA phase 2 trial tested different doses of the anti‐CD40 monoclonal antibody BI 655064 as an add‐on therapy to the standard of care in patients with class III or IV lupus nephritis (LN) with active disease. A post hoc analysis showed a potential benefit of the higher tested doses (180 and 240 mg) versus a low dose (120 mg) or placebo. We investigated whether the treatment effect of BI 655064 on kidney outcomes may be modified by the presence of glomerular monocytes, a target for this drug with a well‐known role in LN pathogenesis.MethodsOne hundred one renal biopsies of patients with LN enrolled in the BI 655064 trial were scored centrally. The estimated glomerular filtration rate (eGFR), spot urine protein/urine creatinine ratio (UP/UC), and complete renal response (CRR) were evaluated over 52 weeks. Patients were divided according to a “better” or “worse” performance than the average of all patients in the cohort, predicted by a mixed model for repeated measurements. Logistic regression models adjusted for potential confounders were used to assess the association between different treatment doses and outcomes according to the presence or absence of monocytes.ResultsA higher BI 655064 dose (180 or 240 mg) was associated with better outcomes of UP/UC and CRR when glomerular monocytes were present in kidney biopsy samples (odds ratio [OR] 3.66 [95% confidence interval (CI) 1.09–12.3], P = 0.04; OR 4.58 [95% CI 1.24–16.9], P = 0.02). A trend toward improved eGFR was also observed in these patients (at 52 weeks, P = 0.08).ConclusionIn LN kidney biopsy samples with glomerular monocytes, high‐dose BI 655064 treatment improved proteinuria at 52 weeks and resulted in a higher CRR compared to biopsy samples without glomerular monocytes. Histologic features may guide the choice of treatment for individual patients with LN.

A novel pre-clinical method for collecting breath samples from intubated mice is presented, which can be tailored to respiratory disease research. Integrated with gold-standard respiratory mechanics equipment (flexiVent®), the approach captures volatile organic compounds (VOCs) onto industry-standard sorbent tubes, resulting in mouse breath samples that can be transported and analysed through TD-GC-MS and other central lab technologies. Background levels originating from the intubation equipment are shown to be low enough to effectively distinguish on-breath VOCs from background compounds. Quantitative analysis reveals a distinct number of compounds at elevated levels in mouse breath, despite their lower abundance compared to human breath samples. It is proposed that this method provides a route for translating pre-clinical findings and biomarkers into human clinical studies, particularly in the context of respiratory disease.

Despite an appetite among UK veterinarians (vets) and farmers to improve calf health, vets face challenges in delivering and sustaining proactive calf health services. Forty-six vets and 10 veterinary technicians (techs) participated in a project to determine what makes calf health services successful while improving their own services. In four facilitated workshops and two seminars, carried out between August 2021 and April 2022, participants described their approaches to calf work, discussed measures of success, identified challenges and success factors, and addressed knowledge gaps. Many approaches to calf health services were described, and these could be categorised into three overlapping models. Success involved enthusiastic, knowledgeable vets/techs, supported by their practice team, fostering positive attitudes among farmers by providing the services they need, creating a tangible return on investment for farmers and the practice. Lack of time was identified as the most prominent challenge to achieving success. Participants were self-selected from one nationwide group of practices. Successful calf health services depend on identifying the needs of calves, farmers and veterinary practices, and delivering measurable benefits to each. More calf health services embedded as a core part of farm veterinary practice could bring wide ranging benefits to calves, farmers and vets.

BackgroundVascular involvement in Systemic Sclerosis (SSc) is known to start even before clinical diagnosis, to drive Digital Ulcer disease and later in the disease natural history to cause Pulmonary Artery Hypertension, among other manifestations. Despite the proven immune origin of Scleroderma, vascular involvement is not currently targeted by immune driven interventions. Similarly, little data is available on immune or inflammatory biomarkers and outcome measures of vascular disease in SSc. Digital Artery Volume Index (DAVIX) has been recently proposed as imaging surrogate outcome measure of vascular disease activity in SSc [1].ObjectivesHere we aimed to determine the value of DAVIX as overall biomarker of vascular involvement and its correlation with Type I IFN activation in patients with SSc.MethodsEighty-six patients attending our Scleroderma Program were consecutively enrolled for the evaluation of serum IFN score as previously described [2]. Clinical features including presence or history of Digital Ulcers, Presence of Pulmonary Artery Hypertension (PAH) and DLCO, were recorded. Digital Artery Vascular Index (DAVIX) of the dominant hand’s fingers was calculated using time of flight magnetic resonance images analysed through IAG proprietary algorithm, as previously described [1]. Medians were compared by Mann-Whitney-Wilcoxon test, correlation with clinical parameters was performed using Spearman’s or Pearson test, as appropriate (R).ResultsSixty-two patients fulfilled the 2013 ACR/EULAR classification criteria for SSc (diffuse cutaneous 24.6%, limited cutaneous 75.4%) whereas 23 were classified as Very Early Diagnosis of Scleroderma (Criteria score between 6 and 8). Twenty-three patients had DU disease (History of DUs in the previous 24 weeks, presence of DUs at baseline assessment, or onset of new DUs during the following 24 weeks). Eighteen patients had reduced DLCO (<70) with FVC/DLCO>1.8 (suspected PAH). DAVIX showed a negative correlation with disease duration (r=-0.33 and p=.003) and with FVC/DLCO ratio (r=-0.34 and p=.009). Patients with DU disease presented lower DAVIX than patients without (p=.018).DAVIX showed a significant correlation with Serum IFN score (r=-0.24, p<0.032). Accordingly, patients classified as IFN-HI had lower DAVIX than those within the IFN-LO group (p=0.016).ConclusionDAVIX correlated both with presence of Digital Ulcer disease, DLCO and disease duration. The correlation of DAVIX and Serum IFN score does support the notion of innate immune involvement in vascular disease manifestations of SSc. Prospective testing in the context of Randomised controlled trial will determine the value of DAVIX as surrogate outcome measure of vascular disease severity in SSc.

ABSTRACTAims/IntroductionWe investigated the utilization of healthcare resources in patients with type 2 diabetes treated with empagliflozin, a sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor, versus dipeptidyl peptidase‐4 (DPP‐4) inhibitors in clinical practice in Japan, South Korea, and Taiwan.Materials and MethodsWe analyzed the Japanese Medical Data Vision database (December 2014–April 2018), the South Korean National Health Information Database, and the Taiwanese National Health Insurance claims database (both May 2016–December 2017). Patients with type 2 diabetes starting empagliflozin, 10 or 25 mg, or a DPP‐4 inhibitor were matched 1:1 via propensity scores (PS). We compared inpatient care needs, emergency room (ER) visits, and outpatient visits between the treatment groups using Poisson regression and Cox proportional hazards models, pooled across countries by random‐effects meta‐analysis.ResultsWe identified 28,712 pairs of PS‐matched patients; the mean follow‐up was 5.7–6.8 months. Empagliflozin‐treated patients had a 27% lower risk of all‐cause hospitalization compared with DPP‐4 inhibitor–treated patients (rate ratio [RR] 0.73, 95% CI 0.67–0.79), and 23% reduced risk for first hospitalization (hazard ratio 0.77, 95% CI 0.73–0.81). The risk for an ER visit was 12% lower with empagliflozin than with DPP‐4 inhibitors (RR 0.88, 95% CI 0.83–0.94) while the risk for outpatient visit was 4% lower (RR 0.96, 95% CI 0.96–0.97). These findings were generally consistent across countries, regardless of baseline cardiovascular disease, and in the subgroup starting empagliflozin with the 10 mg dose.ConclusionsEmpagliflozin treatment was associated with lower inpatient care needs and other healthcare resource utilization than DPP‐4 inhibitors in routine clinical practice in East Asia in this study.

:Fibrosing interstitial lung diseases have a variable clinical course. Regular monitoring is important to assess disease progression and inform patient care and counseling. NPs play a key role in helping patients understand their disease and its treatment and manage the adverse reactions of pharmacologic therapies.

Abstract This study provides insight into the relationship between the photochemical reactivity and the photonic parameters of an acrylate formulation usable in digital light processing (DLP) 3D printing. First the photoreactivity of riboflavin tetrabutyrate (RFT) used as a non‐toxic photoinitiator is assessed by laser flash photolysis in the absence and in the presence of an amine as co‐initiator. RFT alone is able to photopolymerize the acrylate formulation at a rate which is drastically increased when the co‐initiator is added. Then, the depth of light penetration (Dp) and the critical energy (Ec) to form a polymer film were measured and compared to those determined from the Bouguer‐Lambert‐Beer law for Dp and from the Stockmayer equation and photopolymerization experiments for Ec. A new proposed model is able to predict the in‐depth acrylate conversion within a printed part with a relatively low input of experimental parameters. Confocal Raman microscopy is used to discuss the effect of the photobleaching of RFT in the absence of co‐initiator on the photopolymerized films. Finally, it is shown that this formulation performs quite well for 3D printing with a resolution close to the best performance of the DLP printer.