Phase 3 Trials of Inhaled Treprostinil for Idiopathic Pulmonary Fibrosis.

Preclinical data indicate that inhaled treprostinil may be useful for the treatment of idiopathic pulmonary fibrosis (IPF) through an antifibrotic mechanism, a premise that is supported by clinical observation. In this phase 3, double-blind trial, we randomly assigned patients with IPF to receive inhaled treprostinil or placebo (12 breaths four times daily) over a period of 52 weeks. The primary end point was the change from baseline in the absolute forced vital capacity (FVC) at week 52. Secondary end points, which were analyzed in a prespecified order to control for multiplicity, were clinical worsening and acute exacerbation of IPF (each assessed in a time-to-event analysis), death by week 52, and the change from baseline in the percentage of predicted FVC, quality of life, and the diffusing capacity of the lungs for carbon monoxide by week 52. Safety was also assessed. A total of 593 patients underwent randomization and received at least one dose of treprostinil (298 patients) or placebo (295 patients). Of these, 463 patients (224 in the treprostinil group and 239 in the placebo group) completed the trial assessments through week 52. The mean age of the patients was 71.7 years, 80.1% were men, the mean FVC at baseline was 76.8%, and 75.4% of the patients were receiving background antifibrotic therapy. The median change in FVC at week 52 was -49.9 ml (95% confidence interval [CI], -79.2 to -19.5) in the treprostinil group and -136.4 ml (95% CI, -172.5 to -104.0) in the placebo group; the between-group difference in the change in FVC was 95.6 ml (95% CI, 52.2 to 139.0; P<0.001). Clinical worsening occurred in 81 patients (27.2%) in the treprostinil group and 115 patients (39.0%) in the placebo group (hazard ratio, 0.71; 95% CI, 0.53 to 0.95; P = 0.02). No substantial between-group difference in the time to IPF exacerbation was observed, and so no further inferences with regard to subsequent secondary end points were made. The most common adverse event was cough, reported in 48.3% of the patients in the treprostinil group and 24.1% of those in the placebo group. Discontinuation of treprostinil or placebo occurred in 33.6% and 24.7%, respectively, with approximately half these patients citing adverse events as the primary reason for discontinuation. In patients with IPF, inhaled treprostinil was associated with a smaller decline in FVC and fewer clinical-worsening events than placebo over a period of 52 weeks. (Funded by United Therapeutics; TETON-2 ClinicalTrials.gov number, NCT05255991.).

Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials

POSITIVE ENVISIA GENOMIC CLASSIFIER RESULT PREDICTS CLINICAL PROGRESSION IN FIBROTIC INTERSTITIAL LUNG DISEASE

BackgroundDecline in forced vital capacity (FVC) over time reliably predicts mortality in patients with idiopathic pulmonary fibrosis. The use of this measure in clinical practice is recommended by current evidence-based...

In treatment trials in idiopathic pulmonary fibrosis (IPF), there is an unmet need for an accurate primary end point. A European-wide consensus exists that mortality is not a practicable primary...

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease characterized by decline in lung function. Nerandomilast is an orally administered preferential inhibitor of phosphodiesterase 4B that has antifibrotic and immunomodulatory effects in preclinical studies. The FIBRONEER-IPF trial investigated the efficacy and safety of nerandomilast in patients with IPF. Study design including participants: FIBRONEER-IPF was a Phase III randomized, double-blind, placebo-controlled trial of nerandomilast. Patients with IPF who were taking nintedanib or pirfenidone (for ≥12 weeks) or not taking nintedanib or pirfenidone (for ≥8 weeks) were eligible to participate. Patients were randomized 1:1:1 to receive nerandomilast 9 mg twice daily (bid), nerandomilast 18 mg bid, or placebo, stratified by use of background therapy (nintedanib/pirfenidone versus neither). The primary endpoint was absolute change from baseline in forced vital capacity (FVC) (mL) at week 52. The key secondary endpoint was the time to first acute exacerbation, hospitalization for respiratory cause, or death, over the duration of the trial. Key existing data and/or data trends: Nintedanib and pirfenidone have become standard of care for IPF, but have limitations in their efficacy and tolerability. New therapies that can be used as monotherapy or with existing therapies are needed to preserve lung function and improve patient outcomes. In a Phase II trial in 147 patients with IPF, nerandomilast 18 mg bid stabilized lung function over 12 weeks, with acceptable safety and tolerability [N Engl J Med 2022;386:2178-87]. Anticipated main outcomes and timeline: In the FIBRONEER-IPF trial, 1177 patients received trial medication, of whom 77.7% were taking nintedanib/pirfenidone. Analyses based on the first database lock (which took place after the last patient had completed the week 52 visit) are available. Analyses of data from the whole trial will be available for presentation at ATS 2025. Adjusted mean changes in FVC (mL) at week 52 were −183.5 (95% confidence interval [CI]: −210.9, −156.1) in the placebo group, −138.6 (−165.6, −111.6) in the nerandomilast 9 mg bid group (difference vs placebo: 44.9 [95% CI: 6.4, 83.3]; p=0.02), and −114.7 (−141.8, −87.5) in the nerandomilast 18 mg bid group (difference vs placebo: 68.8 [30.3, 107.4]; p&amp;lt;0.001). Plasma concentrations of nerandomilast were reduced by approximately 50% in patients taking pirfenidone compared to nintedanib or no background therapy. Among patients not taking nintedanib/pirfenidone, adjusted mean changes in FVC (mL) at week 52 were −148.7, −70.4 and −79.2 in the placebo, nerandomilast 9 mg bid and nerandomilast 18 mg bid groups; among patients taking nintedanib, changes were −191.6, −130.7 and −118.5; among patients taking pirfenidone, changes were −197.0, −201.8 and −133.7, respectively. Up to first database lock, nerandomilast had no effect on time to first acute exacerbation, hospitalization for respiratory cause, or death. Over 52 weeks, adverse events led to treatment discontinuation in 10.7%, 11.7% and 14.0% of patients in the placebo, nerandomilast 9 mg bid and nerandomilast 18 mg bid groups, respectively. The most frequent adverse event in patients treated with nerandomilast was diarrhea. Significance of study: These results show that treatment with nerandomilast slows disease progression in patients with IPF. Boehringer Ingelheim has submitted a new drug application for nerandomilast for the treatment of IPF to the US FDA. Results from high-profile Phase II and Phase III clinical trials: Since the positive Phase III trials of nintedanib (N Engl J Med 2014;370:2071-2082) and pirfenidone (N Engl J Med 2014;370:2083-92) were published in 2014, several Phase II and III trials in patients with IPF (including Phase III trials of ziritaxestat [JAMA 2023;329:1567-1578], pamrevlumab [JAMA 2024;332:380-389], and zinpentraxin alfa [Am J Respir Crit Care Med 2024;209:1132-1140]) did not meet their primary endpoint or were terminated early.

The traditional Chinese medicine compound preparation known as Jinbei Oral Liquid (JBOL) consists of 12 herbs, including Astragalus membranaceus (Fisch.) Bge, Codonopsis pilosula (Franch.) Nannf, et al. Having been used for over 30 years in the treatment of pulmonary diseases, JBOL was evaluated in this study in order to assess its effect on idiopathic pulmonary fibrosis as well as its safety (ChiCTR2000035351, Chictr.org.cn.09/08/2020). A double-blind, multicenter, randomized, proof-of-concept trial was conducted to assess the efficacy of oral JBOL 40 ml and Corbrin Capsules 1 g compared to a placebo and Corbrin Capsules in patients with idiopathic pulmonary fibrosis (IPF). Over a 26-week period, patients received the active treatment or placebo three times daily, in a 1:1 ratio. This clinical study uses a randomized method, with a cycle of every 4 patients. TCM doctors at or above the deputy director level of the research center conduct TCM dialectics on IPF patients. To assess efficacy, over the duration of the trial, we measured serial changes in a composite indicator encompassing time to first acute exacerbation of IPF (first hospitalization or death due to respiratory cause), total lung capacity (TLC) (mL), predicted forced vital capacity (FVC%), forced vital capacity (FVC) (mL), predicted diffusing capacity of the lungs for carbon monoxide (predicted DLco%), 6-minute walk distance (6MWD), St. George’s Respiratory Questionnaire (SGRQ) total score, and arterial oxygen partial pressure (PaO2) from baseline to week 26 versus placebo. A total of 103 patients were screened, and 72 received the study medication. Of these, 68 patients were included in the analysis set, with 34 receiving JBOL and 34 receiving a placebo. After 26 weeks, a statistically significant reduction in total lung capacity (TLC) was observed for the JBOL group, with a change of 136 mL compared to -523 mL for the placebo group (difference 659 mL, 95% CI -1215 to -104 mL, p = 0.02). The study found that the change in FVC% predicted was − 1.48% and − 3.58% for the JBOL and placebo groups, respectively (difference of 2.10%, 95% CI -7.13 to 2.93, p = 0.41). Additionally the differences between the two groups in changes in FVC (mL), DLCO % predicted, PaO2 (mmHg) measures were − 67 mL (95% CI -238 to 104), -7.74% (95% CI -17.26 to 1.79), and − 3.57 mmHg (95% CI -10.02 to 2.87), respectively. Treatment with JBOL compared to placebo resulted in sequential changes in acute exacerbation, with no significant difference in SGRQ scores. It was not found that there was a statistically significant difference between the JBOL and placebo groups in TEAE reporting and serious TEAE reporting. Compared to the placebo group, there was a statistically significant reduction (p < 0.021) in TLC (mL) after 26 weeks for JBOL. The rates of FVC % predicted, FVC, DLCO % predicted, and PaO2 in the group treatment with JBOL were numerically lower than those in the placebo treatment group, although these differences did not reach statistical significance. JBOL exhibited comparable safety to placebo. This study has preliminarily shown the efficacy and safety of JBOL for IPF, but this is an exploratory clinical trial, more patient-involved studies should be needed in the near future.Trial registration: Chictr.org.cn ChiCTR2000035351; the trial was prospective clinical studies registered on August 9, 2020.

In the Phase III INPULSIS® trials, nintedanib reduced the annual rate of decline in forced vital capacity (FVC) versus placebo in patients with idiopathic pulmonary fibrosis (IPF).We conducted post hoc analyses of the distribution of changes in FVC in the INPULSIS® trials and FVC changes in the open-label extension trial INPULSIS®-ON in subgroups of patients based on whether patients had shown an improvement or no decline in FVC in INPULSIS®. Analyses were descriptive.Based on the annual rate of change in FVC, 158 of 638 patients (24.8%) treated with nintedanib and 38 of 423 patients (9.0%) treated with placebo had an improvement/no decline in FVC in the INPULSIS® trials. In patients whose FVC improved/did not decline, median (interquartile range) improvements in FVC at week 52 were 76.5(31-152) mL and 57.5(31-103) mL in the nintedanib and placebo groups, respectively. Changes in FVC from baseline to week 48 of INPULSIS®-ON were similar in patients whose FVC improved or declined in the preceding INPULSIS® trial.In the INPULSIS® trials, treatment with nintedanib resulted in a greater proportion of patients with IPF showing an improvement/no decline in FVC compared to taking placebo. Mechanisms underlying improvement in FVC in patients with IPF are unknown.

Biomarkers of extracellular matrix turnover in patients with idiopathic pulmonary fibrosis given nintedanib (INMARK study): a randomised, placebo-controlled study

&lt;sec&gt;&lt;st&gt;Background&lt;/st&gt; Nintedanib, an intracellular inhibitor of tyrosine kinases, is in development for the treatment of idiopathic pulmonary fibrosis (IPF). The INPULSIS™ trials were two replicate 52-week, randomised, double-blind, placebo-controlled Phase III trials that investigated the efficacy and safety of nintedanib 150 mg twice daily in 1066 patients with IPF. Declines in forced vital capacity (FVC)% predicted of &gt;5% and &gt;10% in patients with IPF have been proposed as indicators of disease progression and have been associated with reduced survival. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Aim&lt;/st&gt; To determine the effect of nintedanib on changes in FVC% predicted in the INPULSIS™ trials. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Methods&lt;/st&gt; The proportions of patients with absolute and relative declines in FVC% predicted of &gt;5% and &gt;10% at week 52 in each INPULSIS™ trial were determined in a post-hoc analysis. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Results&lt;/st&gt; In each trial, a significantly greater proportion of patients in the placebo group had an absolute decline in FVC% predicted of &gt;5% compared with the nintedanib group. In INPULSIS™-1, a significantly greater proportion of patients in the placebo group had an absolute decline in FVC% predicted of &gt;10% compared with the nintedanib group; the difference between groups in INPULSIS™-2 was numerically in favour of nintedanib but did not reach statistical significance. In each trial, significantly greater proportions of patients in the placebo group had relative declines in FVC% predicted of &gt;5% and &gt;10% compared with the nintedanib group. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Conclusion&lt;/st&gt; In the INPULSIS™ trials, nintedanib reduced the proportion of patients with IPF who experienced disease progression as measured by categorical FVC decline. &lt;/sec&gt;

In patients with IPF, this study aimed (i) to examine the relationship between serial change in CT parameters of lung volume and lung function, (ii) to identify the prognostic value of serial change in CT parameters of lung volume, and (iii) to define a threshold for serial change in CT markers of lung volume that optimally captures disease progression. Serial CTs were analysed for progressive volume loss or fibrosis progression in 81 IPF patients (66 males, median age = 67years) with concurrent forced vital capacity (FVC) (median follow-up 12months, range 6-23months). Serial CT measurements of volume loss comprised oblique fissure posterior retraction distance (OFPRD), aortosternal distance (ASD), lung height corrected for body habitus (LH), and automated CT-derived total lung volumes (ALV) (measured using commercially available software). Fibrosis progression was scored visually. Serial changes in CT markers and FVC were compared using regression analysis, and evaluated against mortality using Cox proportional hazards. There were 58 deaths (72%, median survival = 17months). Annual % change in ALV was most significantly related to annual % change in FVC (R2 = 0.26, p < 0.0001). On multivariate analysis, annual % change in ASD predicted mortality (HR = 0.97, p < 0.001), whereas change in FVC did not. A 25% decline in annual % change in ASD best predicted mortality, superior to 10% decline in FVC and fibrosis progression. In IPF, serial decline in CT markers of lung volume and, specifically, annualised 25% reduction in aortosternal distance provides evidence of disease progression, not always identified by FVC trends or changes in fibrosis extent. • Serial decline in automated and surrogate markers of lung volume on CT corresponds to changes in FVC. • Annualised reductions in the distance between ascending aorta and posterior border of the sternum on CT predict mortality beyond annualised percentage change in FVC.

BackgroundNintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis.MethodsWe conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire, both assessed over a 52-week period.ResultsA total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was −114.7 ml with nintedanib versus −239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and −113.6 ml with nintedanib versus −207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2.ConclusionsIn patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. (Funded by Boehringer Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.)

Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): a double-blind, randomised, placebo-controlled, phase 2b trial

BackgroundIdiopathic pulmonary fibrosis (IPF) is a rare and serious disease characterized by progressive lung-function loss. Limited evidence has been published on the impact of lung-function loss on subsequent patient outcomes. This study examined change in forced vital capacity (FVC) across IPF patients in the 6 months after diagnosis and its association with clinical and healthcare resource utilization (HRU) outcomes in a real-world setting in the U.S.MethodsA retrospective chart review was conducted of patients diagnosed with IPF by U.S. pulmonologists. Patient eligibility criteria included: 1) 40 years or older with a confirmed date of first IPF diagnosis with high-resolution computed tomography and/or lung biopsy between 01/2011 and 06/2013; 2) FVC results recorded at first diagnosis (±1 month) and at 6 months (±3 months) following diagnosis. Based on relative change in FVC percent predicted (FVC%), patients were categorized as stable (decline <5 %), marginal decline (decline ≥5 % and <10 %), or significant decline (decline ≥10 %). Physician-reported clinical and HRU outcomes were assessed from ~6 months post-diagnosis until the last contact date with the physician and compared between FVC% change groups. Multivariable Cox proportional-hazards models were constructed to assess risk of mortality, suspected acute exacerbation (AEx), and hospitalization post-FVC% change. Generalized estimating equations were used to account for multiple patients contributed by individual physicians.ResultsThe sample included 490 IPF patients contributed by 168 pulmonologists. The mean (SD) age was 61 (11) years, 68 % were male, and the mean (SD) baseline FVC% was 60 % (26 %). 250 (51 %) patients were categorized as stable, 98 (20 %) as marginal decline, and 142 (29 %) as significant decline. The mean (SD) observation time was 583 (287) days. In both unadjusted analysis and multivariable models, significantly worse clinical outcomes and increased HRU were observed with greater lung-function decline.ConclusionsThese findings suggest that nearly half of IPF patients experienced decline in FVC% within ~6 months following IPF diagnosis. Greater FVC% decline was associated with an increased risk of further IPF progression, suspected AEx, mortality, and higher rate of HRU. Management options that slow FVC decline may help improve future health outcomes in IPF.

Background : Chronic hypersensitivity pneumonia (CHP) is characterized by varying degrees of inflammation and progressing fibrosis of the lung caused by persistent exposure to a variety of inhaled antigens. The prognosis of patients with CHP who show fibrosing change in their lung tissue have been reported to be as poor as that of the patients with idiopathic pulmonary fibrosis (IPF). Annual changes in forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DL CO ) have been reported to predict the outcome of patients with IPF. Aim : We conducted this study to clarify whether annual changes in FVC and/or DL CO can predict the prognosis of the patients with CHP. Methods : We retrospectively recruited 45 patients with CHP. Spirometry and DL CO measurements were made by one specialized technician, and annual declines in both FVC and DL CO were calculated as the slope of the regression line. Results : Median overall survival time of 45 patients with CHP was 1891±203.5 days. The mean annual declines in FVC and DL CO were 165.4±46.1 ml/year and 0.92±0.41 ml/year, respectively. The Cox proportional-hazards regression analyses revealed that more than 10% of annual decline in FVC and more than 15% of annual decline in DL CO were significant predictors of poor overall survival ( P =0.001 and P =0.001, respectively). Furthermore, multivariate analyses revealed that annual changes in both FVC and DL CO are independent prognostic factor for the patients with CHP even after adjusted by other covariates. Conclusion : In the present study, we demonstrated that the annual changes in pulmonary function could independently predict the prognosis of the patients with CHP.