Boehringer Ingelheim (France)

Idiopathic pulmonary fibrosis (IPF) is characterised by progressive scarring primarily of the distal regions of the lung in a distinctive histological pattern. Consequently, drug discovery has focused on the activity of scar-forming fibroblasts, with some success shown by the pharmaceutical agents nintedanib and pirfenidone, and more recently nerandomilast. Yet an unmet medical need remains, pointing toward pathobiology not addressed by standard-of-care therapies. In recent years, single-cell sequencing of patient lung tissue has revealed several novel disease-associated epithelial populations. In addition, we are now beginning to understand, through functional co-culture studies, the importance of cellular crosstalk in both lung homeostasis and disease. Here, we review the advances made in “omic” technologies, the approaching spatial profiling revolution, current and future functional cell systems, novel in vivo models, how we assign disease-relevance to test systems via computational gene set enrichment analysis, and link all these elements to clinically relevant biomarkers. We show how epithelial populations, identified and validated through cutting-edge technologies, may provide targets for the next wave of therapeutics for patients with IPF.

Borderline personality disorder (BPD) is a significant cause of morbidity with no approved pharmacological treatment. We assessed treatment trajectories of patients with BPD in real-world clinical practice to help identify treatment gaps. This retrospective, observational, cohort study used de-identified MindLinc electronic health records data from the Holmusk NeuroBlu database (Version 21R2) to analyse the treatment journey of patients with BPD (aged ≥ 12 years with ≥1 diagnosis of BPD) that were prescribed pharmacological treatment within 14 days of diagnosis (baseline) and had treatment data for ≥12 months. Of those prescribed pharmacological treatment at baseline, 1461 patients (16.1%) had 12 months of follow-up data. Antidepressants were the most frequently prescribed medication at baseline (80.4%) either alone or in combination with other medication classes, followed by second-generation antipsychotics (SGAs), anxiolytics and mood stabilisers. In the 12 months post-baseline, the most frequently recorded treatment pathway was a switch from 1 antidepressant to another. Sertraline (5.5%), fluoxetine (5%), and citalopram (5%) were the most-prescribed antidepressants; lamotrigine (24.9%), gabapentin (15.4%), and valproate (7.1%) were the most prescribed mood stabilisers; and quetiapine (22.1%) and aripiprazole (19.0%) were the most prescribed SGAs. Polypharmacy (defined as the prescription of ≥ 1 psychotropic medication) was observed in 83.1% of patients at baseline and increased with follow-up time and age. The high rates of polypharmacy observed suggest that current clinical practices may not fully align with treatment guidelines for BPD, and that patients with BPD experience a considerable treatment burden. Limitations of this study include the absence of psychotherapy data and the use of prescription records without information on treatment adherence. Nonetheless, the diversity of treatment patterns observed reflects the complex symptomatology of BPD and highlights the need to deepen our understanding of its neurobiology to improve pharmacological treatment strategies and translate to meaningful patient outcomes. Not applicable.

Material-sparing tablet development (MSTD) describes an approach to tablet formulation development that uses the active pharmaceutical ingredient's (API) material properties to guide formulation design. The work presented here expands on this methodology and demonstrates its application for any API. Four APIs were randomly selected from the Boehringer Ingelheim opnMe platform to demonstrate the universal applicability of the MSTD regardless of the API properties. Small batches of each API (<20 g of API) were used to mimic early-phase development. Each API was analyzed for particle morphology, flowability, density, and compression behavior. Formulations were then designed to complement these API properties using standard tableting excipients. The powder blends were tested for flowability (≤ 12 mm Flodex) and tensile strength (> 2 MPa) to ensure manufacturability. Tablet disintegration (< 15 min) and friability (NMT 0.8 % loss) were tested to verify tablets met current federal performance standards. Stability testing was done to determine excipient compatibility and overall drug product stability (NMT 0.3 % API loss). This work demonstrated that for a wide variety of different APIs, formulations could be designed and tested for critical manufacturing attributes, and possible failure points could be determined using less than 20 g of API in less than 14 days.

<bold>Introduction:</bold> Nerandomilast is a preferential inhibitor of phosphodiesterase 4B with antifibrotic and immunomodulatory effects. In the Phase III FIBRONEER-IPF trial in patients with IPF, nerandomilast significantly reduced the decline in forced vital capacity (FVC) over 52 weeks. <bold>Aim:</bold> To assess the efficacy of nerandomilast in subgroups by baseline characteristics in the FIBRONEER-IPF trial. <bold>Methods:</bold> Patients with IPF were randomised 1:1:1 to receive nerandomilast 9 mg bid, nerandomilast 18 mg bid, or placebo, stratified by background antifibrotic therapy (nintedanib/pirfenidone vs none). In pre-specified analyses, we assessed the absolute change from baseline in FVC (mL) at week 52 in subgroups by sex, age (<65, ≥65 years), weight (<65, ≥65 kg), race (White, Asian, Black/African-American), ethnicity (Hispanic or Latino [yes/no]), and FVC % predicted (≤70, >70) at baseline. Interaction p-values were calculated to assess potential heterogeneity in the effect of nerandomilast versus placebo across subgroups. <bold>Results:</bold> A total 1177 patients received nerandomilast or placebo. Interaction p-values did not identify differences in the effect of nerandomilast vs placebo across subgroups (Figure). <bold>Conclusions:</bold> In patients with IPF, a consistent effect of nerandomilast on slowing disease progression was observed across subgroups based on demographic characteristics and FVC at baseline. <fig><object-id>erj;66/suppl_69/OA1253/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig>

<bold>Introduction:</bold> Antifibrotics (AF) significantly enhance patient survival, yet low treatment persistence rates may lead to unsatisfactory outcomes. <bold>Aims and Objectives:</bold> This nationwide study aimed to assess AF treatment persistence and identify factors associated with non-persistence in real-life settings. <bold>Methods:</bold> Using the SNDS healthcare database, we identified all patients who initiated AF treatment between 2019 and 2021 in France, and calculated their persistence rate until lung transplantation, death, or end of study (December 31, 2022). A Fine and Gray regression model was used to account for the competing risks of lung transplantation and death. <bold>Results:</bold> 4,935 patients were included, including 69.7% diagnosed with idiopathic pulmonary fibrosis, 5.0% with systemic sclerosis, and 25.3% with other diagnoses. Patients were treated with nintedanib (n=3,351, 67.9%) or pirfenidone (n=1,584, 32.1%). At 12 months, persistence rates were 68.1% for nintedanib and 61.3% for pirfenidone. A persistence decrease of nearly 15% was observed between months 6 and 12, followed by a slower decline, reaching 53.1% (nintedanib) and 50.7% (pirfenidone) at month 30. Persistence was significantly lower (p<0.001) in patients with oxygen therapy during follow-up (sHR=1.22), those with <2 pulmonary function tests (sHR=3.25), or followed outside expert centers (sHR=1.61). <bold>Conclusion:</bold> This real-life study, encompassing 99% of the French population, highlighted that one-third of AF-treated patients discontinued therapy within the first year. Persistence was influenced by clinical status and care pathways, underscoring the need for longitudinal follow-up to improve long-term persistence.