Inhaled Lipid Nanoparticles Alleviate Established Pulmonary Fibrosis
Dongjun LiAng ZhaoJiafei ZhuChunjie WangJingjing ShenZixuan ZhengFeng PanZhuang LiuQian ChenYang Yang
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Abstract:
Abstract Pulmonary fibrosis, a sequela of lung injury resulting from severe infection such as severe acute respiratory syndrome‐like coronavirus (SARS‐CoV‐2) infection, is a kind of life‐threatening lung disease with limited therapeutic options. Herein, inhalable liposomes encapsulating metformin, a first‐line antidiabetic drug that has been reported to effectively reverse pulmonary fibrosis by modulating multiple metabolic pathways, and nintedanib, a well‐known antifibrotic drug that has been widely used in the clinic, are developed for pulmonary fibrosis treatment. The composition of liposomes made of neutral, cationic or anionic lipids, and poly(ethylene glycol) (PEG) is optimized by evaluating their retention in the lung after inhalation. Neutral liposomes with suitable PEG shielding are found to be ideal delivery carriers for metformin and nintedanib with significantly prolonged retention in the lung. Moreover, repeated noninvasive aerosol inhalation delivery of metformin and nintedanib loaded liposomes can effectively diminish the development of fibrosis and improve pulmonary function in bleomycin‐induced pulmonary fibrosis by promoting myofibroblast deactivation and apoptosis, inhibiting transforming growth factor 1 (TGFβ1) action, suppressing collagen formation, and inducing lipogenic differentiation. Therefore, this work presents a versatile platform with promising clinical translation potential for the noninvasive inhalation delivery of drugs for respiratory disease treatment.Keywords:
Nintedanib
Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease with a poor life expectancy. Nintedanib is a multiple tyrosine kinases inhibitor recently approved for the treatment of IPF, slowing disease progression by reducing the annual decline in lung function. Here we report the results of a large cohort of IPF patients who received nintedanib within a compassionate-use program (CUP) in Germany.
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Introduction: Idiopathic Pulmonary Fibrosis (IPF) is an interstitial lung disease characterized by the progressive loss of pulmonary function, ultimately leading to respiratory failure and death. Two novel compounds, nintedanib and pirfenidone, have shown efficacy in reducing the rate of decline of lung function in IPF patients. The multiple tyrosine kinase inhibitor nintedanib has extensively being studied as a potential angiogenesis inhibitor in clinical against various neoplastic disorders. Afterwards, this compound was successfully tested in IPF.Areas covered: Herein, the authors review the working mechanisms of nintedanib, its pharmacological profile, and its efficacy and safety for patients with IPF.Expert opinion: Nintedanib has shown to be safe and effective in patients with IPF, with a favorable long-term safety profile. There is a lack of comparative trials of pirfenidone and nintedanib, and the choice of treatment is left to the physicians' judgement. Future directions of nintedanib use are represented by the treatment of progressive fibrosing interstitial lung disease other than IPF, IPF with advanced functional impairment, and lung fibrosis secondary to connective tissue diseases. A promising safety profile for the combinational use of nintedanib and pirfenidone in IPF has also recently emerged.
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Acute Exacerbation of Idiopathic Pulmonary Fibrosis With Pirfenidone and Nintedanib: A Friend or Foe
Acute exacerbation (AE) in idiopathic pulmonary fibrosis (IPF) is unfortunate a deadly event with a very high mortality rate. Its occurrence is highly unpredictable, though few baseline risk factors have been identified. The revised definition of AE is more precise with clarity on defined parameters. However, no clear guidelines exist on treatment, with most therapies showing inconsistent benefits. Both the approved anti-fibrotic (pirfenidone and nintedanib) have shown equal efficacy in reducing the decline in lung functions, with few studies suggesting a drop in AE. We report a case of a patient with IPF with mildly impaired lung functions who was initiated on pirfenidone with dose titrated on a weekly basis but developed AE-IPF on day 10 of starting pirfenidone and after four days of doubling the dose from 600 mg/day to 1,200 mg/day. This raised the suspicion of whether pirfenidone played any role in this unfortunate event. With no response to conventional therapy of steroids and non-invasive ventilation for AE-IPF, initialization of nintedanib led to recovery with discharge of the patient in two weeks of hospitalization. This case highlights inadequacy in knowledge about the effects of these anti-fibrotics in IPF and recommends close monitoring in the future.
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FOR RELATED ARTICLE, SEE PAGE 1163In 2014, two landmark trials published in the New England Journal of Medicine drastically changed the treatment paradigm for patients with idiopathic pulmonary fibrosis (IPF). The Safety and Efficacy of BIBF 1120 at High Dose in Idiopathic Pulmonary Fibrosis Patients (INPULSIS) and Efficacy and Safety of Pirfenidone in Patients With Idiopathic Pulmonary Fibrosis (ASCEND) trials found that nintedanib and pirfenidone respectively slowed FVC decline.1Richeldi L. Du Bois R.M. Raghu G. et al.Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2071-2082Crossref PubMed Scopus (3188) Google Scholar,2King Jr., T.E. Bradford W.Z. Castro-Bernardini S. et al.A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2083-2092Crossref PubMed Scopus (2781) Google Scholar In an era when management of IPF was limited to lung transplantation and palliation, these two drugs were welcome additions to the pulmonologist. Since then, there has been growing evidence, mainly from pooled analyses of clinical trials, that nintedanib and pirfenidone reduce the risk of acute deteriorations in lung function and improve life expectancy.3Ley B. Swigris J. Day B.-M. et al.Pirfenidone reduces respiratory-related hospitalizations in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2017; 196: 756-761Crossref PubMed Scopus (140) Google Scholar, 4Richeldi L. Cottin V. Du Bois R.M. et al.Nintedanib in patients with idiopathic pulmonary fibrosis: combined evidence from the TOMORROW and INPULSIS® trials.Respir Med. 2016; 113: 74-79Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar, 5Guenther A. Krauss E. Tello S. et al.The European IPF registry (eurIPFreg): baseline characteristics and survival of patients with idiopathic pulmonary fibrosis.Respir Res. 2018; 19: 141Crossref PubMed Scopus (195) Google Scholar, 6Dempsey T.M. Sangaralingham L.R. Yao X. Sanghavi D. Shah N.D. Limper A.H. Clinical effectiveness of antifibrotic medications for idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2019; 200: 168-174Crossref PubMed Scopus (100) Google Scholar, 7Lancaster L. Crestani B. Hernandez P. et al.Safety and survival data in patients with idiopathic pulmonary fibrosis treated with nintedanib: pooled data from six clinical trials.BMJ Open Respir Res. 2019; 6e000397Crossref PubMed Scopus (115) Google Scholar FOR RELATED ARTICLE, SEE PAGE 1163 Limited data are available comparing the efficacy of nintedanib with that of pirfenidone. Although not directly comparable, the efficacy of slowing FVC decline appeared numerically similar between the antifibrotic trials. The adjusted annual rate of change in FVC was –114.7 mL with nintedanib vs –239.9 mL with placebo in INPULSIS-1 (52% relative risk [RR] reduction), and –113.6 mL vs –207.3 in INPULSIS-2 (45% RR reduction).1Richeldi L. Du Bois R.M. Raghu G. et al.Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2071-2082Crossref PubMed Scopus (3188) Google Scholar Similarly, in the ASCEND trial, the mean decline in FVC was 235 mL in the pirfenidone group vs 428 mL in the placebo group at 52 weeks (45% RR reduction).2King Jr., T.E. Bradford W.Z. Castro-Bernardini S. et al.A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2083-2092Crossref PubMed Scopus (2781) Google Scholar Subsequently, two small retrospective cohort studies from Italy compared outcomes of antifibrotic treatment, and neither study found a significant difference in the rate of FVC decline between patients taking nintedanib or pirfenidone.8Cerri S. Monari M. Guerrieri A. et al.Real-life comparison of pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis: a 24-month assessment.Respir Med. 2019; 159105803Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar,9Cameli P. Refini R.M. Bergantini L. et al.Long-term follow-up of patients with idiopathic pulmonary fibrosis treated with pirfenidone or nintedanib: a real-life comparison study.Front Mol Biosci. 2020; 7581828Crossref PubMed Scopus (47) Google Scholar One additional study compared the effects of pirfenidone and nintedanib in IPF patients with telomere-related gene mutations.10Justet A. Klay D. Porcher R. et al.Safety and efficacy of pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis and carrying a telomere-related gene mutation.Eur Respir J. 2021; 572003198Crossref PubMed Scopus (36) Google Scholar Using propensity score weighting, the authors found no statistically significant difference between antifibrotic cohorts, with a slope of FVC decline of 15 mL per month in the nintedanib group and 25 mL per month in the pirfenidone group. Taken together, there is no compelling evidence that one antifibrotic is more efficacious. We note that the clinical trials were not head-to-head comparisons, the Italian studies were small and single-center, and the study of patients with telomere-related gene mutations had limited generalizability. Nearly a decade since that issue of the New England Journal of Medicine, we still have not to our knowledge had a randomized clinical trial comparing treatments in IPF. Now, in clinical practice, we base the decision regarding which antifibrotic to start on side effects and patient preference. To improve our knowledge of whether one antifibrotic has better outcomes, in this issue of CHEST, Kim et al11Kim J.S. Murray S. Yow E. et al.Comparison of pirfenidone and nintedanib: post hoc analysis of the CleanUP-IPF study.Chest. 2024; 165: 1163-1173Abstract Full Text Full Text PDF Google Scholar compared outcomes of patients treated with nintedanib and pirfenidone from a recent clinical trial. The Clinical Efficacy of Antimicrobial Therapy Strategy Using Pragmatic Design in IPF (CleanUP-IPF) trial was a pragmatic clinical trial evaluating the efficacy of oral antibiotics in improving outcomes for patients with IPF, ultimately terminated for futility.12Martinez F.J. Yow E. Flaherty K.R. et al.Effect of antimicrobial therapy on respiratory hospitalization or death in adults with idiopathic pulmonary fibrosis.JAMA. 2021; 325: 1841Crossref PubMed Scopus (0) Google Scholar With most patients previously prescribed antifibrotics and a protocol that systematically collected serial FVC measurements, CleanUP-IPF provided a promising data set derived from multiple centers to compare outcomes in patients with IPF treated with antifibrotic medications. In this post hoc analysis, Kim et al11Kim J.S. Murray S. Yow E. et al.Comparison of pirfenidone and nintedanib: post hoc analysis of the CleanUP-IPF study.Chest. 2024; 165: 1163-1173Abstract Full Text Full Text PDF Google Scholar use a mixed-models approach to determine whether 12-month FVC differed between patients taking nintedanib and those taking pirfenidone. They found that patients taking nintedanib had a higher mean FVC at 12 months as compared with those taking pirfenidone (mean difference, 106 mL; 95% CI, 34-178 mL) and that the rate of FVC decline was slower in the nintedanib group (−6.2 mL/month vs −13.4 mL/month). The authors concluded that patients with IPF who used nintedanib had slower FVC decline than those who were taking pirfenidone. We congratulate Kim et al11Kim J.S. Murray S. Yow E. et al.Comparison of pirfenidone and nintedanib: post hoc analysis of the CleanUP-IPF study.Chest. 2024; 165: 1163-1173Abstract Full Text Full Text PDF Google Scholar on tackling an important clinical question in our field, but our excitement for the conclusions is tempered by details of the overall analyses. For example, when the authors compared outcomes in patients taking antifibrotics with those not using antifibrotics, the authors unexpectedly found no difference in the 12-month FVC between groups (difference of 14 mL; 95% CI, −120 to 91 mL). This is in stark contrast to results from the landmark antifibrotic trials, in which the antifibrotics reduced the rate of FVC decline by one-half over 1 year.1Richeldi L. Du Bois R.M. Raghu G. et al.Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2071-2082Crossref PubMed Scopus (3188) Google Scholar,2King Jr., T.E. Bradford W.Z. Castro-Bernardini S. et al.A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2083-2092Crossref PubMed Scopus (2781) Google Scholar In addition, the FVC difference was attenuated at 24 months and was no longer significant after propensity score matching. Furthermore, no significant difference was seen in diffusing capacity of the lungs for carbon monoxide or a composite outcome. These details raise concerns that there may be systematic differences between the patients included in this post hoc analysis and the patients who would have been randomized in an antifibrotic trial. These inconsistencies may be attributable to the major limitations aptly listed by the authors—selection bias, lack of data regarding antifibrotic duration or dosage, and missing outcome data. Considering the limitations of the findings, we remain uncertain whether there are efficacy differences between antifibrotic medications and will not be changing our approach for selecting antifibrotics when managing patients with IPF. In performing this investigation, Kim et al11Kim J.S. Murray S. Yow E. et al.Comparison of pirfenidone and nintedanib: post hoc analysis of the CleanUP-IPF study.Chest. 2024; 165: 1163-1173Abstract Full Text Full Text PDF Google Scholar highlight an important knowledge gap in our community—the lack of head-to-head trials comparing standard of care IPF treatments. This forces clinicians to turn to the next best thing—making clinical decisions based on old data, fraught with inherent biases that limit application of the results in clinic. Over the next decade, as new drugs are developed for patients with IPF, they should be compared with the existing standard of care to enable optimal treatment decisions moving forward. Just because we have the next best thing does not mean we should settle for it. The authors have reported to CHEST the following: P. W. reports grant support from Boehringer Ingelheim, Roche, Sanofi, Pliant and the NIH, and consulting fees from Blade Therapeutics. None declared (J. V. P.). Comparison of Pirfenidone and Nintedanib: Post Hoc Analysis of the CleanUP-IPF StudyCHESTVol. 165Issue 5PreviewPatients with IPF who used nintedanib had a slower 12-month FVC decline than pirfenidone in a post hoc analysis of a clinical trial. Full-Text PDF
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Introduction
Licensed anti-fibrotic medication (AFM) for IPF is limited to Pirfenidone and Nintedanib. Pirfenidone has been prescribed by the Newcastle Interstitial Lung Disease Service (NILDS) since March 2014 and Nintedanib since December 2015. Patients are referred to the NILDS by twelve regional trusts. Diagnosis of IPF is confirmed by the NILDS MDT before patient assessment for suitability of AFM.Methods
Multi-centre retrospective cohort review of all patients on Pirfenidone and Nintedanib since the beginning of local AFM prescription.Aims
Evaluation of the basic characteristics of non-trial, 'real life' patients on AFM in a North East cohort.Results
Up until June 2018, 194 patients had been prescribed Pirfenidone, 98 (50.5%) had stopped it, 45 (23.2%) were still taking it and 51 (26.3%) patients had died on Pirfenidone. Diagnoses for patients on Pirfenidone were definite IPF (n=107, 55.2%), working diagnosis IPF (n=21, 10.8%), probable IPF (n=45, 23.2%), Combined Pulmonary Fibrosis and Emphysema (n=20, 10.3%) and others (n=1, 0.5%). Of those stopping Pirfenidone, 37 (37.7%) patients switched to Nintedanib. Mean age for patients taking Pirfenidone was 73 years, 85% males. 212 patients had been prescribed Nintedanib, 62 (29.2%) had stopped it, 113 (53.3%) were still taking it and 37 (17.5%) patients had died on Nintedanib. Diagnoses for patients on Nintedanib were definite IPF (n=106, 50.0%), working diagnosis IPF (n=33, 15.6%), probable IPF (n=36, 17.0%), CPFE (n=36, 17%) and others (n=1, 0.4%). Of those stopping Nintedanib, 26 (41.9%) patients switched to Pirfenidone. Mean age for patients taking Nintedanib was 72 years, 81% males. In both treatment cohorts most patients had more than one side effect cited as the cause for stopping medication (see table 1). Mean treatment duration at last known patient contact was 12.2 months (range 1–46) for Pirfenidone and 10.1 months (range 1–34) for Nintedanib.Conclusions
Gender and age distribution for both AFM groups was similar to other UK IPF patient cohorts. Longer treatment duration in the Pirfenidone group may be due to increased length of medication availability. Side effects are often multiple in nature but both AFMs can be tolerated with specialist support for an extended period of time.Nintedanib
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In a small phase II trial in Japanese patients with IPF, there was a trend towards lower nintedanib exposure when nintedanib 150 mg bid was added to pirfenidone than when given alone.
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Pirfenidone and nintedanib are antifibrotic medications approved for idiopathic pulmonary fibrosis treatment by regulatory agencies and available for clinical use worldwide. These drugs have been shown to reduce the rate of decline in forced vital capacity and the risk of acute exacerbation among patients with idiopathic pulmonary fibrosis. Recent data suggest that different interstitial lung diseases with a progressive pulmonary fibrosis phenotype can share similar pathogenetic and biological pathways and could be amenable to antifibrotic therapies. Indeed, historical management strategies in interstitial lung disease have failed to identify potential treatments once progression has occurred despite available drugs. In this systematic review, we summarized data on the efficacy of pirfenidone and nintedanib in interstitial lung diseases other than idiopathic pulmonary fibrosis as well as ongoing and upcoming clinical trials. We identify two well-designed trials regarding nintedanib demonstrating the efficacy of this drug in slowing disease progression in patients with interstitial lung diseases other than idiopathic pulmonary fibrosis. On the other hand, results on the use of pirfenidone in interstitial lung diseases other than idiopathic pulmonary fibrosis should be interpreted with more caution on the basis of trial limitations. Several randomized control trials are underway to improve the quality of evidence in the interstitial lung disease field.
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Two antifibrotic medications (nintedanib and pirfenidone) were recommended (conditionally) for the treatment of patients with idiopathic pulmonary fibrosis (IPF) in the 2015 IPF evidence-based guidelines. These medications have been shown to reduce the rate of decline in forced vital capacity among patients with IPF over time and are the only two disease-modulating pharmacological agents approved by regulatory agencies and available for clinical use worldwide. With the evolved standard of care for interstitial lung disease evaluation including routine use of high-resolution computed tomography, fibrotic lung diseases other than IPF are increasingly recognised. In addition, it is becoming evident that genetic and pathophysiological mechanisms as well as disease behaviour in patients manifesting other "non-IPF progressive fibrotic interstitial lung diseases" (non-IPF-PF) may be similar to those in patients with IPF. Thus, it is biologically plausible that pharmacological agents with antifibrotic properties may be efficacious in non-IPF-PF. Indeed, studies are underway or planned to assess the safety and efficacy of nintedanib or pirfenidone among patients with several non-IPF fibrotic lung diseases. In this review, we briefly summarise the use of pirfenidone and nintedanib in IPF as well as the rationale and potential for use of these medications in non-IPF-PF that are being investigated in ongoing and upcoming clinical trials.
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Abstract Idiopathic pulmonary fibrosis ( IPF ) is an incurable condition that is characterized by progressive pulmonary fibrosis, architectural distortion of the lung and loss of gas exchange units. Until recently, there was no effective treatment for this condition. However, there were two landmark trials published earlier this year, which have changed the management of this condition. Pirfenidone ( A ssessment of P irfenidone to C onfirm E fficacy and S afety in I diopathic P ulmonary F ibrosis trial) and nintedanib ( E fficacy and S afety of N intedanib in I diopathic P ulmonary F ibrosis‐1 and ‐2 trials) have both demonstrated positive outcomes in patients with IPF . In this perspective, we critically discuss the role of these agents in IPF and in the broader pulmonary fibrosis population.
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