Nintedanib with Add-on Pirfenidone in Idiopathic Pulmonary Fibrosis. Results of the INJOURNEY Trial

Vancheri, Carlo; Kreuter, Michael; Richeldi, Luca; Ryerson, Christopher J.; Valeyre, Dominique; Grutters, Jan C.; Wiebe, Sabrina; Stansen, Wibke; Quaresma, Manuel; Stowasser, Susanne; Wuyts, Wim

doi:10.1164/rccm.201706-1301oc

Cited by 225 publications

(176 citation statements)

References 11 publications

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“…Overall, our observations support the inclusion of patients with more advanced lung function impairment in future IPF trials investigating novel therapies, as well as combination antifibrotic therapy [28,29]. Whether patients with even greater lung function impairment than those included in this analysis should be included in future clinical trials is open to speculation, but it is certainly a concept for further investigation.…”

Section: Discussionsupporting

confidence: 63%

Pirfenidone in patients with idiopathic pulmonary fibrosis and more advanced lung function impairment

Nathan

Costabel

Albera

et al. 2019

Respiratory Medicine

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A B S T R A C TBackground: Patients with idiopathic pulmonary fibrosis (IPF) demonstrate a range of lung function impairment. However, the efficacy of antifibrotics compared with placebo has not been assessed in patients with more advanced disease. This post-hoc analysis investigated the efficacy and safety of pirfenidone versus placebo in patients with IPF and more advanced lung function impairment, defined as percent predicted forced vital capacity (%FVC) < 50% and/or percent predicted carbon monoxide diffusing capacity < 35%. Methods: Patients randomised to pirfenidone 2,403 mg/day or placebo in the ASCEND (NCT01366209) and CAPACITY (NCT00287716; NCT00287729) trials with more advanced baseline lung function impairment (pirfenidone, n = 90; placebo, n = 80) were included. Mortality, lung function, hospitalisation, exercise capacity and dyspnoea were investigated over 52 weeks. Results: At Week 52 versus placebo, pirfenidone was associated with significantly lower risks of all-cause mortality (hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.09-0.86; p=0.0180), ≥10% absolute %FVC decline or allcause mortality (HR 0.40; 95% CI 0.23-0.69; p=0.0006) and ≥10% absolute %FVC decline or respiratory-related hospitalisation or all-cause mortality (HR 0.46; 95% CI 0.28-0.76; p=0.0018). At Week 52, median treatment differences favouring pirfenidone were 36.7 m for 6-min walk distance and −8.0 points for the University of California-San Diego Shortness of Breath Questionnaire total score. Treatment-emergent adverse events (TEAEs) led to discontinuation in 14.4% and 21.3% of patients with pirfenidone and placebo, respectively. Conclusion: Pirfenidone demonstrated clinically relevant benefits across multiple domains in patients with IPF and more advanced disease without an increased risk of discontinuation due to TEAEs.

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Section: Discussionsupporting

confidence: 63%

Pirfenidone in patients with idiopathic pulmonary fibrosis and more advanced lung function impairment

Nathan

Costabel

Albera

et al. 2019

Respiratory Medicine

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“…It is generally recognized that alveolar epithelial cell injury and inflammation lead to aberrant proliferation of fibroblasts, resulting in an exaggerated deposition of extracellular matrix (ECM) in the lung parenchyma and eventually leading to lung function damage (2). However, the molecular mechanism underlying IPF is not fully understood, and there is still lack of effective treatment for IPF aside from lung transplantation, even though a number of studies have reported the anti-fibrotic effects of nintedanib and pirfenidone on lung fibrosis (3)(4)(5). Therefore, it is of great value to reveal the pathogenesis of IPF and to explore more effective therapeutic strategies and drugs for the treatment of IPF.…”

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confidence: 99%

lncRNA PFAL promotes lung fibrosis through CTGF by competitively binding miR‐18a

Shan

et al. 2018

FASEB j.

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Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic parenchymal lung disease of unknown etiology and lacks an effective intervention. Long noncoding RNAs (lncRNAs) participate in organ fibrosis and various pulmonary diseases, but the role of lncRNAs in lung fibrosis is not fully understood. In the present study, we identified that lncRNA NONMMUT021928, designated as pulmonary fibrosis-associated lncRNA (PFAL), was up-regulated in the lungs of mice with experimental lung fibrosis, and in TGF-β1-induced fibrotic lung fibroblasts. Further study showed that overexpression of PFAL promoted cell proliferation, migration, and fibroblast-myofibroblast transition. Overexpression further resulted in extracellular matrix deposition and fibrogenesis in lung fibroblasts through regulation of microRNA-18a (miR-18a). Importantly, knockdown of PFAL alleviated lung fibrosis both in vitro and in vivo. Mechanistically, our study showed that PFAL promoted lung-fibroblast activation and fibrogenesis by acting as a competing endogenous RNA for miR-18a: forced expression of PFAL inhibited the expression and activity of miR-18a, whereas silencing of PFAL had the opposite effect. Furthermore, we found that miR-18a was decreased during lung fibrosis in vitro and in vivo, as well as in patients with IPF. Moreover, knockdown of miR-18a led to fibrogenesis in lung fibroblasts, whereas enhanced expression of miR-18a attenuated TGF-β1-induced lung fibrosis by directly targeting the regulation of connecting tissue growth factor. Taken together, these results revealed the effect and mechanism of lncRNA PFAL in pulmonary fibrosis and suggested that PFAL depletion may provide a novel strategy for the treatment of lung fibrosis.-Li, X., Yu, T., Shan, H., Jiang, H., Sun, J., Zhao, X., Su, W., Yang, L., Shan, H., Liang, H. lncRNA PFAL promotes lung fibrosis through CTGF by competitively binding miR-18a.

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“…Additionally, they note that, due to the similar adverse event profile of the two therapies, there was uncertainty in identifying the treatment responsible for some of the TEAEs. Vancheri et al 43 also reported on the safety of combination therapy, and found that gastrointestinal adverse events occurred in 69.8% of patients treated with nintedanib with add-on pirfenidone and 52.9% of patients treated with nintedanib. Crestani et al 44 examined the long-term safety of nintedanib.…”

Section: Discussionmentioning

confidence: 99%

Systematic review and network meta-analysis of approved medicines for the treatment of idiopathic pulmonary fibrosis

Skandamis

Kani

Markantonis

et al. 2019

Journal of Drug Assessment

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Background: Clinical practice guidelines for the treatment of idiopathic pulmonary fibrosis (IPF) currently recommend pirfenidone and nintedanib. However, there is a lack of evidence from head-tohead comparisons. Objectives: To perform a systematic review and network meta-analysis (NMA) to access the efficacy and tolerability of two new treatments for IPF, pirfenidone and nintedanib. Methods: Randomized controlled trials (RCTs) selection (CENTRAL, MEDLINE, Embase), data extraction, risk of bias analysis, and GRADE assessment were carried out by two authors separately. Direct estimates were calculated using standard pairwise meta-analysis. A Bayesian mixed treatment comparison approach for NMA estimates, with 95% confidence intervals (CI), was used to compare the treatments, calculating odds ratios (OR) and number needed to treat (NNTB) or harm (NNTH). Results: The NMA on 10 randomized controlled trials showed that each drug had a positive effect on percentage of forced vital capacity (FVC) decline 10% (pirfenidone OR ¼ 0.54 [95% CI ¼ 0.37-0.80], NNTB ¼ 9 [95% CI ¼ 7-22]; nintedanib OR ¼ 0.59 [95% CI ¼ 0.41-0.84], NNTB ¼ 9 [95% CI ¼ 6-23]), but no significant differences were noted when comparing pirfenidone and nintedanib with respect to acute exacerbations, mortality, and serious adverse events (FVC decline OR ¼ 0.91 [95% CI ¼ 0.45-2.03]) or dropouts (OR ¼ 0.75 [95% CI ¼ 0.33-1.27]). Nintedanib showed an effect on dropouts, OR ¼ 1.61 (1.13-2.28) and . Conclusions: Based on RCTs of 12 month duration in patients with IPF, a positive effect on FVC decline was noted for both treatments and on dropouts for nintedanib, but no significant differences were noted between treatments. ARTICLE HISTORY

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Nintedanib with Add-on Pirfenidone in Idiopathic Pulmonary Fibrosis. Results of the INJOURNEY Trial

Cited by 225 publications

References 11 publications

Pirfenidone in patients with idiopathic pulmonary fibrosis and more advanced lung function impairment

Pirfenidone in patients with idiopathic pulmonary fibrosis and more advanced lung function impairment

lncRNA PFAL promotes lung fibrosis through CTGF by competitively binding miR‐18a

Systematic review and network meta-analysis of approved medicines for the treatment of idiopathic pulmonary fibrosis

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