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In patients with a progressive interstitial lung disease, 62% of whom had a CT pattern of usual interstitial pneumonia, those who received nintedanib had a lower annual rate of decline in the forced vital capacity than those who received placebo at 52 weeks.

In this randomized, placebo-controlled trial, treatment with nintedanib, an intracellular inhibitor of multiple tyrosine kinases, led to a reduced rate of loss of forced vital capacity in patients with idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis is a fatal lung disease characterized by worsening dyspnea and progressive loss of lung function. 1 A decline in forced vital capacity (FVC) is consistent with disease progression and is predictive of reduced survival time. 1 – 6 Idiopathic pulmonary fibrosis is believed to arise from an aberrant proliferation of fibrous tissue and tissue remodeling due to the abnormal function and signaling of alveolar epithelial cells and interstitial fibroblasts. 7 The activation of cell-signaling pathways through tyrosine kinases such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) has been implicated in the pathogenesis of . . .

In this randomized, controlled trial, the use of pirfenidone in patients with idiopathic pulmonary fibrosis led to a slower rate of loss in forced vital capacity than the use of placebo. Idiopathic pulmonary fibrosis is a chronic, progressive, and fatal lung disease that is characterized by irreversible loss of lung function. 1 Although periods of transient clinical stability may be observed, continued progression of the disease is inevitable. 2 The prognosis is poor, with a 5-year survival rate that is similar to the rates for several cancers. 3 – 6 Pirfenidone is an oral antifibrotic therapy that has been evaluated for the treatment of idiopathic pulmonary fibrosis in three phase 3, randomized, controlled trials. One of these trials was conducted in Japan and involved 275 patients. It was followed by two multinational studies, Clinical Studies . . .

Nerandomilast (BI 1015550) is an orally administered preferential inhibitor of phosphodiesterase 4B with antifibrotic and immunomodulatory effects. In a phase 2 trial involving patients with idiopathic pulmonary fibrosis, treatment with nerandomilast stabilized lung function over a period of 12 weeks. In this phase 3, double-blind trial, we randomly assigned patients with idiopathic pulmonary fibrosis in a 1:1:1 ratio to receive nerandomilast at a dose of 18 mg twice daily, nerandomilast at a dose of 9 mg twice daily, or placebo, with stratification according to background antifibrotic therapy (nintedanib or pirfenidone vs. none). The primary end point was the absolute change from baseline in forced vital capacity (FVC), measured in milliliters, at week 52. A total of 1177 patients underwent randomization, of whom 77.7% were taking nintedanib or pirfenidone at enrollment. Adjusted mean changes in FVC at week 52 were -114.7 ml (95% confidence interval [CI], -141.8 to -87.5) in the nerandomilast 18-mg group, -138.6 ml (95% CI, -165.6 to -111.6) in the nerandomilast 9-mg group, and -183.5 ml (95% CI, -210.9 to -156.1) in the placebo group. The adjusted difference between the nerandomilast 18-mg group and the placebo group was 68.8 ml (95% CI, 30.3 to 107.4; P<0.001), and the adjusted difference between the nerandomilast 9-mg group and the placebo group was 44.9 ml (95% CI, 6.4 to 83.3; P = 0.02). The most frequent adverse event in the nerandomilast groups was diarrhea, reported in 41.3% of the 18-mg group and 31.1% of the 9-mg group, as compared with 16.0% in the placebo group. Serious adverse events were balanced across trial groups. In patients with idiopathic pulmonary fibrosis, treatment with nerandomilast resulted in a smaller decline in the FVC than placebo over a period of 52 weeks. (Funded by Boehringer Ingelheim; FIBRONEER-IPF ClinicalTrials.gov number, NCT05321069.).

Abstract Rationale Nintedanib and pirfenidone slow the progression of idiopathic pulmonary fibrosis (IPF), but the disease continues to progress. More data are needed on the safety and efficacy of combination therapy with nintedanib and add-on pirfenidone. Objectives To investigate safety, tolerability, and pharmacokinetic and exploratory efficacy endpoints in patients treated with nintedanib and add-on pirfenidone versus nintedanib alone. Methods Patients with IPF and FVC greater than or equal to 50% predicted at screening who completed a 4- to 5-week run-in with nintedanib 150 mg twice daily without dose reduction or treatment interruption were randomized to receive nintedanib 150 mg twice daily with add-on pirfenidone (titrated to 801 mg three times daily) or nintedanib 150 mg twice daily alone in an open-label manner for 12 weeks. The primary endpoint was the percentage of patients with on-treatment gastrointestinal adverse events from baseline to Week 12. Analyses were descriptive and exploratory. Measurements and Main Results On-treatment gastrointestinal adverse events were reported in 37 of 53 patients (69.8%) treated with nintedanib with add-on pirfenidone and 27 of 51 patients (52.9%) treated with nintedanib alone. Predose plasma trough concentrations of nintedanib were similar when it was administered alone or with add-on pirfenidone. Mean (SE) changes from baseline in FVC at Week 12 were −13.3 (17.4) ml and −40.9 (31.4) ml in patients treated with nintedanib with add-on pirfenidone (n = 48) and nintedanib alone (n = 44), respectively. Conclusions Nintedanib with add-on pirfenidone had a manageable safety and tolerability profile in patients with IPF, in line with the adverse event profiles of each drug. These data support further research into combination regimens in the treatment of IPF. Clinical trial registered with www.clinicaltrials.gov (NCT02579603).

Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterised by dyspnea and loss of lung function. Methods Using pooled data from the replicate, randomized, 52-week, placebo-controlled INPULSIS ® trials, we characterized the safety and tolerability of nintedanib 150 mg twice daily in patients with IPF and described how adverse events were managed during these trials. Results One thousand and sixty- one patients were treated (nintedanib 638; placebo 423). Higher proportions of patients in the nintedanib group than the placebo group had ≥1 dose reduction to 100 mg bid (27.9 % versus 3.8 %) or treatment interruption (23.7 % versus 9.9 %). Adverse events led to permanent treatment discontinuation in 19.3 % and 13.0 % of patients in the nintedanib and placebo groups, respectively. Diarrhea was the most frequent adverse event, reported in 62.4 % of patients in the nintedanib group versus 18.4 % in the placebo group; however, only 4.4 % of nintedanib-treated patients discontinued trial medication prematurely due to diarrhea. Monitoring of liver enzymes before and periodically during nintedanib treatment was recommended so that liver enzyme elevations could be managed through dose reduction or treatment interruption. Conclusion Nintedanib had a manageable safety and tolerability profile in patients with IPF. Recommendations for adverse event management minimized permanent treatment discontinuations in the INPULSIS ® trials. Trial registration clinicaltrials.gov NCT01335464 and NCT01335477

In a trial, patients with moderate to severely advanced idiopathic pulmonary fibrosis were treated with nintedanib plus sildenafil or nintedanib alone, with the goal of decreasing IPF symptoms. There were no between-group differences in any of three symptom measures.

Abstract Rationale Immunosuppression was associated with adverse events for patients with idiopathic pulmonary fibrosis (IPF) in the PANTHER-IPF (Evaluating the Effectiveness of Prednisone, Azathioprine and N-Acetylcysteine in Patients with IPF) clinical trial. The reason why some patients with IPF experience harm is unknown. Objectives To determine whether age-adjusted leukocyte telomere length (LTL) was associated with the harmful effect of immunosuppression in patients with IPF. Methods LTL was measured from available DNA samples from PANTHER-IPF (interim analysis, n = 79; final analysis, n = 118). Replication cohorts included ACE-IPF (Anticoagulant Effectiveness in Idiopathic Pulmonary Fibrosis) (n = 101) and an independent observational cohort (University of Texas Southwestern Medical Center-IPF, n = 170). LTL-stratified and medication-stratified survival analyses were performed using multivariable Cox regression models for composite endpoint-free survival. Measurements and Main Results Of the subjects enrolled in the PANTHER-IPF and ACE-IPF, 62% (49/79) and 56% (28/50) had an LTL less than the 10th percentile of normal, respectively. In PANTHER-IPF, exposure to prednisone/azathioprine/N-acetylcysteine was associated with a higher composite endpoint of death, lung transplantation, hospitalization, or FVC decline for those with an LTL less than the 10th percentile (hazard ratio, 2.84; 95% confidence interval, 1.02–7.87; P = 0.045). This finding was replicated in the placebo arm of ACE-IPF for those exposed to immunosuppression (hazard ratio, 7.18; 95% confidence interval, 1.52–33.84; P = 0.013). A propensity-matched University of Texas Southwestern Medical Center IPF cohort showed a similar association between immunosuppression and composite endpoints (death, lung transplantation, or FVC decline) for those with an LTL less than the 10th percentile (hazard ratio, 3.79; 95% confidence interval, 1.73–8.30; P = 0.00085). An interaction was found between immunosuppression and LTL for the combined PANTHER-IPF and ACE-IPF clinical trials (P  interaction = 0.048), and the University of Texas Southwestern Medical Center IPF cohort (P  interaction = 0.00049). Conclusions LTL is a biomarker that may identify patients with IPF at risk for poor outcomes when exposed to immunosuppression.

Acetylcysteine, which has been advocated as a treatment for patients with idiopathic pulmonary fibrosis, showed no benefit over placebo with respect to loss of lung function in such patients at 60 weeks. Idiopathic pulmonary fibrosis is a chronic, progressive lung disease of unknown cause that is characterized by the histopathological or radiologic patterns of usual interstitial pneumonia in a typical clinical setting. 1 , 2 To date, no pharmacologic therapies have been shown to improve survival. 1 In the IFIGENIA study (Idiopathic Pulmonary Fibrosis International Group Exploring N -Acetylcysteine I Annual), investigators found that a three-drug regimen (prednisone, azathioprine, and acetylcysteine) preserved pulmonary function better than a two-drug regimen consisting of azathioprine plus prednisone. 3 In PANTHER-IPF (Prednisone, Azathioprine, and N -Acetylcysteine: A Study That Evaluates Response in Idiopathic Pulmonary Fibrosis), patients with mild-to-moderate impairment in . . .

Background Idiopathic pulmonary fibrosis (IPF) predominantly affects individuals aged > 60 years who have several comorbidities. Nintedanib is an approved treatment for IPF, which reduces the rate of decline in forced vital capacity (FVC). We assessed the efficacy and safety of nintedanib in patients with IPF who were elderly and who had multiple comorbidities. Methods Data were pooled from five clinical trials in which patients were randomised to receive nintedanib 150 mg twice daily or placebo. We assessed outcomes in subgroups by age < 75 versus ≥ 75 years, by < 5 and ≥ 5 comorbidities, and by Charlson Comorbidity Index (CCI) ≤ 3 and > 3 at baseline. Results The data set comprised 1690 patients. Nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks versus placebo in patients aged ≥ 75 years (difference: 105.3 [95% CI 39.3, 171.2]) (n = 326) and < 75 years (difference 125.2 [90.1, 160.4]) (n = 1364) (p = 0.60 for treatment-by-time-by-subgroup interaction), in patients with < 5 comorbidities (difference: 107.9 [95% CI 65.0, 150.9]) (n = 843) and ≥ 5 comorbidities (difference 139.3 [93.8, 184.8]) (n = 847) (p = 0.41 for treatment-by-time-by-subgroup interaction) and in patients with CCI score ≤ 3 (difference: 106.4 [95% CI 70.4, 142.4]) (n = 1330) and CCI score > 3 (difference: 129.5 [57.6, 201.4]) (n = 360) (p = 0.57 for treatment-by-time-by-subgroup interaction). The adverse event profile of nintedanib was generally similar across subgroups. The proportion of patients with adverse events leading to treatment discontinuation was greater in patients aged ≥ 75 years than < 75 years in both the nintedanib (26.4% versus 16.0%) and placebo (12.2% versus 10.8%) groups. Similarly the proportion of patients with adverse events leading to treatment discontinuation was greater in patients with ≥ 5 than < 5 comorbidities (nintedanib: 20.5% versus 15.7%; placebo: 12.1% versus 10.0%). Conclusions Our findings suggest that the effect of nintedanib on reducing the rate of FVC decline is consistent across subgroups based on age and comorbidity burden. Proactive management of adverse events is important to reduce the impact of adverse events and help patients remain on therapy. Trial registration: ClinicalTrials.gov NCT00514683, NCT01335464, NCT01335477, NCT02788474, NCT01979952.