Efficacy In Idiopathic Pulmonary Fibrosis Research Articles

Inhaled nintedanib nanoparticles for enhanced efficacy in idiopathic pulmonary fibrosis (IPF) treatment – Evidence in disease-relevant in-vitro models

Idiopathic pulmonary fibrosis (IPF) is a fatal and progressive interstitial lung disease with a high mortality rate due to limited prognosis. According to the National Institutes of Health (NIH), approximately 100,000 people in the United States suffer from IPF, and around 50% likelihood of dying within 2–3 years. Currently, nintedanib (Nint) is one of the only 2 FDA-approved drugs for the treatment of IPF, with anti-fibrotic and anti-inflammatory activities. However, Nint oral capsules have some undesirable limitations such as low bioavailability and high dose requirement for sufficient therapeutic efficacy, leading to various side effects associated with oral delivery. To address these shortcomings and enhance the therapeutic potential, Nint was loaded into PLGA nanoparticles (Nint NPs) for localized pulmonary delivery. In-vitro cell culture studies indicated that nano-sized particles (179 ± 3 nm) of Nint NPs enhanced cellular uptake in airway epithelial cells and normal human lung fibroblasts, while readily avoiding macrophage phagocytosis. Transforming growth factor-beta (TGF-β) (10 ng/mL) was selected to establish IPF in cells, which resulted in proliferation and rapid wound healing, whereas Nint NPs showed superior ability in inhibiting these pathological phenomena compared to free Nint. Upon further evaluation of pathological mechanisms of IPF, Nint NPs remarkably attenuated epithelial-to-mesenchymal transition (EMT) by elevating epithelial marker E-cadherin level and reducing extracellular matrix (ECM) deposition by evidence of reduced collagen production and fibroblast-to-myofibroblast differentiation marker, α-SMA. Nint NPs also decreased expression of inflammatory cytokine IL-17A and indicated autophagy as a separate anti-fibrotic mechanism. Finally, Nint NPs proved their superior efficacy in a novel IPF cell model using diseased lung ECM substrates. Hence, inhalation therapy of Nint NPs is a promising alternative tool for oral capsules in IPF therapy.

Pirfenidone: Molecular Mechanisms and Potential Clinical Applications in Lung Disease.

Pirfenidone (PFD) is a pharmacological compound with therapeutic efficacy in idiopathic pulmonary fibrosis. It has been chiefly characterized as an antifibrotic agent, although it was initially developed as an antiinflammatory compound because of its ability to diminish the accumulation of inflammatory cells and cytokines. Despite recent studies that have elucidated key mechanisms, the precise molecular activities of PFD remain incompletely understood. PFD modulates fibrogenic growth factors, thereby attenuating fibroblast proliferation, myofibroblast differentiation, collagen and fibronectin synthesis, and deposition of extracellular matrix. This effect is mediated by suppression of TGF-β1 (transforming growth factor-β1) and other growth factors. Here, we appraise the impact of PFD on TGF-β1 production and its downstream pathways. Accumulating evidence indicates that PFD also downregulates inflammatory pathways and therefore has considerable potential as a viable and innovative antiinflammatory compound. We examine the effects of PFD on inflammatory cells and the production of pro- and antiinflammatory cytokines in the lung. In this context, recent evidence that PFD can target inflammasome pathways and ensuing lung inflammation is highlighted. Finally, the antioxidant properties of PFD, such as its ability to inhibit redox reactions and regulate oxidative stress-related genes and enzymes, are detailed. In summary, this narrative review examines molecular mechanisms underpinning PFD and its recognized benefits in lung fibrosis. We highlight preclinical data that demonstrate the potential of PFD as a nonsteroidal antiinflammatory agent and outline areas for future research.

Endotype-phenotyping may predict a treatment response in progressive fibrosing interstitial lung disease.

BackgroundSome interstitial lung disease (ILD) patients develop a progressive fibrosing-ILD phenotype (PF-ILD), with similar persistent lung function decline suggesting common molecular pathways involved. Nintedanib, a tyrosine kinase inhibitor targeting the PDGF, FGF, VEGF and M-CSF pathways, has shown comparable efficacy in idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated ILD (SSc-ILD). We hypothesize that Nintedanib targeted molecular pathways will be augmented to a similar degree across PF-ILD regardless of aetiology.MethodsWe collected explanted lung tissue at the time of lung transplantation from 130 PF-ILD patients (99 (76%) IPF, 14 (11%) SSc-ILD, 17 (13%) other PF-ILD), and wedge biopsies from 200 donor lungs and measured PDGF, FGF, VEGF and M-CSF concentrations by Luminex.FindingsThe concentrations of PDGF-AA, PDGF-BB, FGF-2, VEGF and M-CSF were significantly increased in PF-ILD lungs compared to donor lungs (PDGF-AA 93·0 pg/ml [±97·2] vs. 37·5 pg/ml [±35·4], p < 0·001; PDGF-BB 102·5 pg/ml [±78·8] vs. 61·9 pg/ml [±47·0], p < 0·001; FGF-2 1442·4 pg/ml [±426·6] vs. 1201·7 pg/ml [±535·2], p = 0·009; VEGF 40·6 pg/ml [±20·1] vs. 24·9 pg/ml [±29·5], p < 0·001; and M-CSF 25526 pg/ml [±24,799] vs. 6120 pg/ml [±7245], p < 0·001). There were no significant differences in these growth factor/angiogenic molecules/cytokine concentrations when segregated by IPF, SSc-ILD and other PF-ILDs.InterpretationNintedanib specific targeted molecular pathways are augmented to a similar magnitude in all PF-ILD lung tissue as compared to controls, suggesting that Nintedanib treatment may be efficacious in PF-ILD regardless of aetiology. We speculate that clinical trials using Nintedanib for PF-ILD with or without IPF or SSc-ILD should show a similar relative reduction in FVC decline as seen in IPF and SSc-ILD (∼45–50%).FundingHealth Grant P01-HL108793 (JAB), South-Eastern Norway Regional Health Authority Grant 2018072 (AMHV).

Effects of nintedanib on the microvascular architecture in a lung fibrosis model.

Nintedanib, a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis, has anti-fibrotic, anti-inflammatory, and anti-angiogenic activity. We explored the impact of nintedanib on microvascular architecture in a pulmonary fibrosis model. Lung fibrosis was induced in C57Bl/6 mice by intratracheal bleomycin (0.5mg/kg). Nintedanib was started after the onset of lung pathology (50mg/kg twice daily, orally). Micro-computed tomography was performed via volumetric assessment. Static lung compliance and forced vital capacity were determined by invasive measurements. Mice were subjected to bronchoalveolar lavage and histologic analyses, or perfused with a casting resin. Microvascular corrosion casts were imaged by scanning electron microscopy and synchrotron radiation tomographic microscopy, and quantified morphometrically. Bleomycin administration resulted in a significant increase in higher-density areas in the lungs detected by micro-computed tomography, which was significantly attenuated by nintedanib. Nintedanib significantly reduced lung fibrosis and vascular proliferation, normalized the distorted microvascular architecture, and was associated with a trend toward improvement in lung function and inflammation. Nintedanib resulted in a prominent improvement in pulmonary microvascular architecture, which outperformed the effect of nintedanib on lung function and inflammation. These findings uncover a potential new mode of action of nintedanib that may contribute to its efficacy in idiopathic pulmonary fibrosis.

S134 Kinase Selectivity Profiles Of Nintedanib And Imatinib

<h3>Introduction</h3> Tyrosine kinase inhibition has shown inconsistent success in the treatment of idiopathic pulmonary fibrosis (IPF). While a study of imatinib showed no impact on survival or lung function in a placebo-controlled study, two recently announced placebo-controlled phase 3 trials of nintedanib demonstrated statistically significant impact on forced vital capacity. Comparing the kinase target profiles could inform future target selection for drugs in IPF. <h3>Methods</h3> <i>In vitro</i> kinase selectivity data of nintedanib and imatinib were collected using the kinomescan platform (DiscoveRx Inc). Binding data (% binding) for 451 human kinases (~80% of the human kinome) were initially collected at a single concentration (10 uM). For kinases that displayed significant binding, potencies (K_D) were measured in dose-response format. <h3>Results</h3> At a common concentration of 100 nM, imatinib and nintedanib bound to 12 and 50 kinases, respectively. Maximal drug concentrations (C_max) observed in patients were used to project therapeutically relevant kinase inhibition for both drugs. Using these criteria, nintedanib binds 44 kinases at drug levels seen in patients (K_D &lt; C_maxof 64 nM). Imatinib binds 34 kinases at drug levels seen in patients (K_D &lt; C_maxof 7500 nM). 14 kinases were bound by both compounds, including PDGFRA, PDGFRB and VEGFR2. <h3>Conclusions</h3> Our results suggest that nintedanib and imatinib have partially overlapping inhibition profiles; the kinases that are targeted by both agents are unlikely to be responsible for efficacy differences. Further work is required to identify which of the remaining kinase target (s) are responsible for efficacy in IPF and could therefore represent targets for follow-up compounds.

The European IPF Network: towards better care for a dreadful disease

Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of diffuse parenchymal lung disease (DPLD) and probably affects up to 340,000 people in Europe and North America 1. Despite extensive research over the past 25 yrs, considerable investment in controlled clinical trials, and significant progress in defining appropriate outcome measures and surrogates of disease progression, IPF remains a progressive and invariably fatal disease with a mean survival of ∼3 yrs from diagnosis. With the exception of pirfenidone 2, which is now on the way of being approved in Europe, and N-acetylcysteine 3, which has shown some signs of therapeutic efficacy in IPF, no other investigational agents, including bosentan 4, imatinib 5 and interferon-γ 6, have proven to be beneficial in phase III studies performed over the last decade. IPF, therefore, remains a dismal disease for which new effective therapeutic approaches are urgently needed. Despite this, we would argue that there is much cause to be optimistic in terms of the current climate for scientists and clinicians striving to develop novel therapeutic strategies for this devastating disease. The last 5 yrs or so have seen major advances, including the definition of novel paradigms of disease pathogenesis and the discovery of novel biomarkers. Pharmaceutical interest and investment from both academia and industry are at unprecedented levels. We must, however, be careful to heed the lessons we have learned from our past experience. There are many possible answers to these important questions. First, we need to deconstruct the way IPF has been approached in terms of controlled clinical trials. Most of the trials conducted to date were based on an “opportunistic approach”, using drugs or investigational compounds developed for other disease indications rather than agents which emerged from a systematic programme for the development of novel …