Efficacy of Nintedanib in Idiopathic Pulmonary Fibrosis across Prespecified Subgroups in INPULSIS.
Costabel Ulrich,Inoue Yoshikazu,Richeldi Luca,Collard Harold R,Tschoepe Inga,Stowasser Susanne,Azuma Arata
American journal of respiratory and critical care medicine
RATIONALE:In the two replicate, placebo-controlled, 52-week, phase III INPULSIS trials, nintedanib 150 mg twice daily significantly reduced the annual rate of decline in FVC, the primary endpoint, in subjects with idiopathic pulmonary fibrosis (IPF). It is unknown if this effect was uniform across all subjects treated with nintedanib. OBJECTIVES:To investigate the potential association of demographic and clinical variables with the effect of nintedanib in subjects with IPF. METHODS:Subgroup analyses of pooled data from the INPULSIS trials were prespecified. Subgroups were analyzed by sex, age (<65, ≥65 yr), race (white, Asian), baseline FVC percentage predicted (≤70%, >70%), baseline St. George's Respiratory Questionnaire (SGRQ) total score (≤40, >40), smoking status (never, ex/current), systemic corticosteroid use (yes/no), and bronchodilator use (yes/no). MEASUREMENTS AND MAIN RESULTS:A total of 1,061 subjects were treated (nintedanib n = 638, placebo n = 423). There was no statistically significant difference in the effect of nintedanib for the primary endpoint or the key secondary endpoints of change from baseline in SGRQ total score or time to first acute exacerbation in any subgroup. Treatment effects for the key secondary endpoints seemed more pronounced in subjects with baseline FVC ≤70% predicted, because the majority of acute exacerbations and a greater deterioration in SGRQ total score occurred in placebo-treated subjects in this subgroup. CONCLUSIONS:Pooled data from the INPULSIS trials support a consistent effect of nintedanib across a range of IPF phenotypes by slowing disease progression across a number of prespecified subgroups.
Acute exacerbations in the INPULSIS trials of nintedanib in idiopathic pulmonary fibrosis.
Collard Harold R,Richeldi Luca,Kim Dong Soon,Taniguchi Hiroyuki,Tschoepe Inga,Luisetti Maurizio,Roman Jesse,Tino Gregory,Schlenker-Herceg Rozsa,Hallmann Christoph,du Bois Roland M
The European respiratory journal
Time to first investigator-reported acute exacerbation was a key secondary end-point in the INPULSIS trials of nintedanib in patients with idiopathic pulmonary fibrosis (IPF).We used the INPULSIS trial data to investigate risk factors for acute exacerbation of IPF and to explore the impact of nintedanib on risk and outcome of investigator-reported and adjudicated confirmed/suspected acute exacerbations. Mortality following these events and events adjudicated as not acute exacerbations was analysed using the log rank test.Risk of acute exacerbations was most strongly associated with the following variables: baseline forced vital capacity (higher risk with lower value), baseline supplemental oxygen (higher risk with use), baseline antacid medication (higher risk with use), treatment (higher risk with placebo), and for confirmed/suspected acute exacerbations, cigarette smoking. Mortality was similar following investigator-reported and adjudicated confirmed/suspected acute exacerbations. Nintedanib had no significant effect on risk of mortality post-exacerbation.Investigator-reported acute exacerbations of IPF are associated with similar risk factors and outcomes as adjudicated confirmed/suspected acute exacerbations.
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 A,
American journal of respiratory and critical care medicine
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).
Safety of nintedanib added to pirfenidone treatment for idiopathic pulmonary fibrosis.
Flaherty Kevin R,Fell Charlene D,Huggins J Terrill,Nunes Hilario,Sussman Robert,Valenzuela Claudia,Petzinger Ute,Stauffer John L,Gilberg Frank,Bengus Monica,Wijsenbeek Marlies
The European respiratory journal
We assessed safety and tolerability of treatment with pirfenidone (1602-2403 mg·day) and nintedanib (200-300 mg·day) in patients with idiopathic pulmonary fibrosis (IPF).This 24-week, single-arm, open-label, phase IV study (ClinicalTrials.gov identifier NCT02598193) enrolled patients with IPF with forced vital capacity % pred ≥50% and diffusing capacity of the lung for carbon monoxide % pred ≥30%. Before initiating nintedanib, patients had received pirfenidone for ≥16 weeks and tolerated a stable dose of ≥1602 mg·day for ≥28 days. The primary end-point was the proportion of patients who completed 24 weeks of combination treatment on pirfenidone (1602-2403 mg·day) and nintedanib (200-300 mg·day). Investigators recorded treatment-emergent adverse events (TEAEs), attributing them to pirfenidone, nintedanib, both or neither.89 patients were enrolled; 73 completed 24 weeks of treatment (69 meeting the primary end-point) and 16 discontinued treatment prematurely (13 due to TEAEs). 74 patients had 418 treatment-related TEAEs, of which diarrhoea, nausea and vomiting were the most common. Two patients had serious treatment-related TEAEs.Combined pirfenidone and nintedanib use for 24 weeks was tolerated by the majority of patients with IPF and associated with a similar pattern of TEAEs expected for either treatment alone. These results encourage further study of combination treatment with pirfenidone and nintedanib in patients with IPF.
Stability or improvement in forced vital capacity with nintedanib in patients with idiopathic pulmonary fibrosis.
Flaherty Kevin R,Kolb Martin,Vancheri Carlo,Tang Wenbo,Conoscenti Craig S,Richeldi Luca
The European respiratory journal
In the Phase III INPULSIS® trials, nintedanib reduced the annual rate of decline in forced vital capacity (FVC) placebo in patients with idiopathic pulmonary fibrosis (IPF).We conducted 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.
An open-label feasibility study of nintedanib combined with docetaxel in Japanese patients with locally advanced or metastatic lung adenocarcinoma after failure of first-line chemotherapy.
Yamamoto Noboru,Kenmotsu Hirotsugu,Goto Koichi,Takeda Koji,Kato Terufumi,Takeda Masayuki,Horinouchi Hidehito,Saito Isao,Sarashina Akiko,Tanaka Tetsuya,Morsli Nassim,Nakagawa Kazuhiko
Cancer chemotherapy and pharmacology
PURPOSE:This open-label feasibility study assessed the tolerability of nintedanib 200 mg in combination with docetaxel 75 mg/m as a starting dose in Japanese patients with a body surface area (BSA) < 1.5 m and locally advanced or metastatic lung adenocarcinoma. METHODS:Eligible patients received docetaxel 75 mg/m every 21 days and nintedanib administered at 200 mg twice daily (bid), starting on day 2 of each cycle. Treatment was continued until disease progression or undue toxicity. The primary endpoint was the number of patients experiencing dose-limiting toxicities (DLTs) in cycle 1 (days 1-21). RESULTS:Of 10 treated patients, 2 patients (20%) experienced DLTs during cycle 1. These DLTs were grade 3 liver enzyme elevations [alanine aminotransferase (2 patients) and aspartate aminotransferase (2 patients)], and grade 2 hyperbilirubinemia (1 patient). Nine patients met the predefined criteria for nintedanib 200 mg bid plus docetaxel 75 mg/m to be considered a tolerable starting dose. All patients experienced ≥ 1 adverse event (AE) during the treatment period (all drug-related), but no patients experienced AEs that led to discontinuation of nintedanib. Of the five serious AEs reported during treatment, none were drug-related. There was no apparent effect of nintedanib on the pharmacokinetics of docetaxel. The objective response and disease control rates were 40 and 70%, respectively. CONCLUSION:Nintedanib 200 mg bid plus docetaxel 75 mg/m is a tolerable starting dose in Japanese patients with a BSA < 1.5 m with locally advanced or metastatic lung adenocarcinoma. CLINICALTRIALS. GOV NUMBER:NCT02300298.
Effects of Ketoconazole and Rifampicin on the Pharmacokinetics of Nintedanib in Healthy Subjects.
Luedtke Doreen,Marzin Kristell,Jungnik Arvid,von Wangenheim Ute,Dallinger Claudia
European journal of drug metabolism and pharmacokinetics
BACKGROUND:Nintedanib is a substrate for p-glycoprotein which can impact bioavailability. We investigated the effects of ketoconazole, a p-glycoprotein inhibitor, and rifampicin, a p-glycoprotein inducer, on the pharmacokinetics of nintedanib. METHODS:In the ketoconazole study, 34 healthy subjects received nintedanib 50 mg orally alone and 1 h after the last dose of ketoconazole given orally at a dose of 400 mg once daily for 3 days in 1 of 2 randomized sequences. In the rifampicin study, 26 subjects received nintedanib 150 mg orally alone and the morning after the last dose of rifampicin given orally at a dose of 600 mg once daily for 7 days. The primary objective was to determine the relative bioavailability of nintedanib administered following multiple doses of ketoconazole or rifampicin versus alone, based on AUC from time 0 extrapolated to infinity (AUC) and maximum concentration (C) calculated using an analysis of variance. Geometric mean ratios and 2-sided 90% CIs were calculated. RESULTS:Exposure to nintedanib increased when it was administered following ketoconazole versus alone (AUC: geometric mean ratio, 160.5% [90% CI, 148.2-173.7]; C: geometric mean ratio, 179.6% [90% CI, 157.6-204.8]) and decreased when it was administered following rifampicin versus alone (AUC: geometric mean ratio, 50.1% [90% CI, 47.2-53.3]; C: geometric mean ratio, 59.8% [90% CI, 53.8-66.4]). The time to reach C (t) and half-life (t) of nintedanib were unaffected by co-administration of ketoconazole or rifampicin. CONCLUSIONS:Exposure to nintedanib is increased by co-administration of ketoconazole and decreased by co-administration of rifampicin, likely due to effects on bioavailability of the absorbed fraction. ClinicalTrials.govidentifiers:NCT01679613, NCT01770392.
Nintedanib plus Sildenafil in Patients with Idiopathic Pulmonary Fibrosis.
Kolb Martin,Raghu Ganesh,Wells Athol U,Behr Jürgen,Richeldi Luca,Schinzel Birgit,Quaresma Manuel,Stowasser Susanne,Martinez Fernando J,
The New England journal of medicine
BACKGROUND:Nintedanib is an approved treatment for idiopathic pulmonary fibrosis (IPF). A subgroup analysis of a previously published trial suggested that sildenafil may provide benefits regarding oxygenation, gas exchange as measured by the diffusion capacity of the lungs for carbon monoxide (Dl), symptoms, and quality of life in patients with IPF and severely decreased Dl. That idea was tested in this trial. METHODS:We randomly assigned, in a 1:1 ratio, patients with IPF and a Dl of 35% or less of the predicted value to receive nintedanib at a dose of 150 mg twice daily plus sildenafil at a dose of 20 mg three times daily (nintedanib-plus-sildenafil group) or nintedanib at a dose of 150 mg twice daily plus placebo three times daily (nintedanib group) for 24 weeks. The primary end point was the change from baseline in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 12 (the total score ranges from 0 to 100, with higher scores indicating worse health-related quality of life). Secondary end points included measures of dyspnea and safety. RESULTS:A total of 274 patients underwent randomization. There was no significant difference in the adjusted mean change from baseline in the SGRQ total score at week 12 between the nintedanib-plus-sildenafil group and the nintedanib group (-1.28 points and -0.77 points, respectively; P=0.72). A benefit from sildenafil treatment was not observed with regard to dyspnea as measured with the use of the University of California, San Diego, Shortness of Breath Questionnaire. No new safety signals were observed, as compared with previous trials. CONCLUSIONS:In patients with IPF and a Dl of 35% or less of the predicted value, nintedanib plus sildenafil did not provide a significant benefit as compared with nintedanib alone. No new safety signals were identified with either treatment regimen in this population of patients. (Funded by Boehringer Ingelheim; INSTAGE ClinicalTrials.gov number, NCT02802345 .).
Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial.
du Bois Andreas,Kristensen Gunnar,Ray-Coquard Isabelle,Reuss Alexander,Pignata Sandro,Colombo Nicoletta,Denison Ursula,Vergote Ignace,Del Campo Jose M,Ottevanger Petronella,Heubner Martin,Minarik Thomas,Sevin Emmanuel,de Gregorio Nikolaus,Bidziński Mariusz,Pfisterer Jacobus,Malander Susanne,Hilpert Felix,Mirza Mansoor R,Scambia Giovanni,Meier Werner,Nicoletto Maria O,Bjørge Line,Lortholary Alain,Sailer Martin Oliver,Merger Michael,Harter Philipp,
The Lancet. Oncology
BACKGROUND:Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer. METHODS:In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB-IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m(2)) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2-21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01015118. FINDINGS:Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17·2 months [95% CI 16·6-19·9] vs 16·6 months [13·9-19·1]; hazard ratio 0·84 [95% CI 0·72-0·98]; p=0·024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [<1%] grade 4 vs placebo group nine [2%] of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 [20%] grade 3 and 200 (22%) grade 4 vs placebo group 90 [20%] grade 3 and 72 [16%] grade 4; thrombocytopenia: 105 [12%] and 55 [6%] vs 21 [5%] and eight [2%]; anaemia: 108 [12%] and 13 [1%] vs 26 [6%] and five [1%]). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non-drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown). INTERPRETATION:Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability. FUNDING:Boehringer Ingelheim.
Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume.
Kolb Martin,Richeldi Luca,Behr Jürgen,Maher Toby M,Tang Wenbo,Stowasser Susanne,Hallmann Christoph,du Bois Roland M
RATIONALE:There is no consensus as to when treatment for idiopathic pulmonary fibrosis (IPF) should be initiated. Some physicians prefer not to treat patients with preserved lung volume. OBJECTIVE:To investigate whether patients with IPF and preserved lung volume receive the same benefit from nintedanib as patients with more impaired lung volume. METHODS:Post hoc subgroup analyses of pooled data from the two replicate phase III INPULSIS trials by baseline FVC % predicted (≤90%, >90%). RESULTS:At baseline, 274 patients had FVC >90% predicted and 787 patients had FVC ≤90% predicted. In patients treated with placebo, the adjusted annual rate of decline in FVC was consistent between patients with FVC >90% predicted and FVC ≤90% predicted (-224.6 mL/year and -223.6 mL/year, respectively). There was no statistically significant difference between these subgroups in the effect of nintedanib on annual rate of decline in FVC, change from baseline in St George's Respiratory Questionnaire total score or time to first acute exacerbation. In patients with baseline FVC >90% predicted and ≤90% predicted, respectively, the adjusted annual rate of decline in FVC with nintedanib was -91.5 mL/year (difference vs placebo: 133.1 mL/year (95% CI 68.0 to 198.2)) and -121.5 mL/year (difference vs placebo: 102.1 mL/year (95% CI 61.9 to 142.3)). Adverse events associated with nintedanib were similar in both subgroups. CONCLUSIONS:Patients with IPF and preserved lung volume (FVC >90% predicted) have the same rate of FVC decline and receive the same benefit from nintedanib as patients with more impaired lung volume. TRIAL REGISTRATION NUMBER:NCT01335464 and NCT01335477.
Nintedanib in Japanese patients with idiopathic pulmonary fibrosis: A subgroup analysis of the INPULSIS® randomized trials.
Azuma Arata,Taniguchi Hiroyuki,Inoue Yoshikazu,Kondoh Yasuhiro,Ogura Takashi,Homma Sakae,Fujimoto Tsuyoshi,Sakamoto Wataru,Sugiyama Yukihiko,Nukiwa Toshihiro
Respirology (Carlton, Vic.)
BACKGROUND AND OBJECTIVE:Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial pneumonia. Nintedanib significantly reduced the annual rate of decline in forced vital capacity (FVC) compared with placebo in patients with IPF in two replicate trials (INPULSIS®). We examined the efficacy and safety of nintedanib in Japanese patients. METHODS:We conducted pre-specified subgroup analyses of the annual rate of decline in FVC, time to first acute exacerbation (AE), change from baseline in St George's Respiratory Questionnaire (SGRQ) total score and safety using pooled data from the INPULSIS® trials for Japanese patients. RESULTS:In the overall population, 76 of 638 and 50 of 423 patients in the nintedanib and placebo groups, respectively, were Japanese. Results in Japanese patients were consistent with those in the overall population. In Japanese patients, the adjusted annual rate of decline in FVC was -135.9 mL/year in the nintedanib group and -267.7 mL/year in the placebo group (difference (95% CI): 131.9 (50.7, 213.1) mL/year); the hazard ratio for the time to first AE was 0.25 (0.06, 1.02); and the adjusted mean change from baseline in SGRQ total score at week 52 was 5.81 in the nintedanib group and 9.68 in the placebo group (difference: -3.87 (-8.51, 0.76)). Diarrhoea and liver-related adverse events were the most common events in the nintedanib group, but were reversible following dose reduction, drug interruption or symptomatic therapy. CONCLUSION:The present results indicate that the efficacy and safety of nintedanib in Japanese patients are comparable with those in the overall population.
Treatment Rationale and Design for J-SONIC: A Randomized Study of Carboplatin Plus Nab-paclitaxel With or Without Nintedanib for Advanced Non-Small-cell Lung Cancer With Idiopathic Pulmonary Fibrosis.
Otsubo Kohei,Kishimoto Junji,Kenmotsu Hirotsugu,Minegishi Yuji,Ichihara Eiki,Shiraki Akira,Kato Terufumi,Atagi Shinji,Horinouchi Hidehito,Ando Masahiko,Kondoh Yasuhiro,Kusumoto Masahiko,Ichikado Kazuya,Yamamoto Nobuyuki,Nakanishi Yoichi,Okamoto Isamu
Clinical lung cancer
We describe the treatment rationale and procedure for a randomized study (J-SONIC; University Hospital Medical Information Network Clinical Trials Registry identification no., UMIN000026799) of carboplatin plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with or without nintedanib for patients with advanced non-small cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis (IPF). The study was designed to examine the efficacy and safety of nintedanib administered with carboplatin plus nab-paclitaxel versus carboplatin plus nab-paclitaxel alone in chemotherapy-naive patients with advanced NSCLC associated with IPF. Eligible patients (enrollment target, n = 170) will be randomized at a 1:1 ratio to receive 4 cycles of carboplatin (area under the curve, 6 on day 1) plus nab-paclitaxel (100 mg/m on days 1, 8, and 15) administered every 3 weeks either without (arm A) or with (arm B) nintedanib (150 mg twice daily), to be followed in arm B by single-agent administration of nintedanib (150 mg twice daily). The present trial is the first randomized controlled study for the treatment of NSCLC associated with IPF. The goal of the study is to demonstrate that nintedanib combined with carboplatin plus nab-paclitaxel prolongs the interval to acute exacerbation of IPF compared with carboplatin plus nab-paclitaxel alone.
Long-term treatment of patients with idiopathic pulmonary fibrosis with nintedanib: results from the TOMORROW trial and its open-label extension.
Richeldi Luca,Kreuter Michael,Selman Moisés,Crestani Bruno,Kirsten Anne-Marie,Wuyts Wim A,Xu Zuojun,Bernois Katell,Stowasser Susanne,Quaresma Manuel,Costabel Ulrich
The TOMORROW trial of nintedanib comprised a randomised, placebo-controlled, 52-week period followed by a further blinded treatment period and an open-label extension. We assessed outcomes across these periods in patients randomised to nintedanib 150 mg twice daily or placebo at the start of TOMORROW. The annual rate of decline in FVC was -125.4 mL/year (95% CI -168.1 to -82.7) in the nintedanib group and -189.7 mL/year (95% CI -229.8 to -149.6) in the comparator group. The adverse event profile of nintedanib remained consistent throughout the studies. These results support a benefit of nintedanib on slowing progression of idiopathic pulmonary fibrosis beyond 52 weeks.
Idiopathic pulmonary fibrosis: current treatment options and critical appraisal of nintedanib.
Bonella Francesco,Stowasser Susanne,Wollin Lutz
Drug design, development and therapy
Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia and is characterized by a poor prognosis, with an estimated 5-year survival of approximately 20%. Progressive and irreversible lung functional impairment leads to chronic respiratory insufficiency with a severely impaired quality of life. In the last 2 decades, novel treatments for IPF have been developed as a consequence of an increasing understanding of disease pathogenesis and pathobiology. In IPF, injured dysfunctional alveolar epithelial cells promote fibroblast recruitment and proliferation, resulting in scarring of the lung tissue. Recently, pirfenidone and nintedanib have been approved for the treatment of IPF, having shown efficacy to slow functional decline and disease progression. This article focuses on the pharmacologic characteristics and clinical evidence supporting the use of nintedanib, a potent small-molecule tyrosine kinase inhibitor, as therapy for IPF. After introducing the mechanism of action and pharmacokinetics, an overview of the safety and efficacy results from the most recent clinical trials of nintedanib in IPF is presented.
Safety, tolerability and appropriate use of nintedanib in idiopathic pulmonary fibrosis.
Corte Tamera,Bonella Francesco,Crestani Bruno,Demedts Maurits G,Richeldi Luca,Coeck Carl,Pelling Katy,Quaresma Manuel,Lasky Joseph A
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.
Nintedanib (OFEV) in the treatment of idiopathic pulmonary fibrosis.
Fukihara Jun,Kondoh Yasuhiro
Expert review of respiratory medicine
INTRODUCTION:Nintedanib is a new anti-fibrosis agent that is an intracellular tyrosine kinase inhibitor targeting platelet derived growth factor receptor, fibroblast growth factor receptor and vascular endothelial growth factor receptor. Although nintedanib is attracting much attention as a new treatment option for patients with idiopathic pulmonary fibrosis (IPF), the clinical evidence is limited mainly to the results from the dose-deciding phase II TOMORROW trial and phase III INPULSIS trials, which evaluated efficacy and safety of nintedanib for patients with IPF, prespecified subgroup analyses, pooled analyses and meta-analyses derived from those trials. Areas covered: In this document, we mainly reviewed reports on working mechanisms of nintedanib, and efficacy and safety of nintedanib for patients with IPF. The literature search was undertaken using Pub Med. Expert commentary: It is unknown whether the efficacy of nintedanib in patients enrolled in the clinical trials will be the same for the entire spectrum of patients, including patients unfit for the clinical trials due to age, severity, timing of IPF diagnosis or diagnosis of interstitial pneumonias other than IPF. Sufficient consideration should be given when selecting candidates for nintedanib in the real world.
The safety and tolerability of nintedanib in the treatment of idiopathic pulmonary fibrosis.
Expert opinion on drug safety
INTRODUCTION:Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease that primarily affects older individuals. Nintedanib, a tyrosine kinase inhibitor, has been approved for the treatment of IPF in several countries. The safety and tolerability of nintedanib have been investigated in clinical trials and in real-world studies (compassionate use programs and post-marketing surveillance). Areas covered: Most frequent adverse events reported in patients treated with nintedanib (gastrointestinal); additional adverse events of special interest (elevations in liver enzymes, bleeding, cardiovascular adverse events); recommendations for managing adverse events. Expert opinion: Experience with nintedanib in real-world clinical practice suggests that it has a safety and tolerability profile consistent with that observed in clinical trials. Upon initiation of nintedanib, patient education, regular monitoring and proactive management of adverse events such as diarrhea are needed to minimize the risk of permanent treatment discontinuation. Algorithms are available to help manage diarrhea and liver enzyme elevations. Further investigation of the safety and tolerability profile of nintedanib when used in combination with pirfenidone is warranted.
Clinical use of nintedanib in patients with idiopathic pulmonary fibrosis.
Hajari Case Amy,Johnson Peace
BMJ open respiratory research
Idiopathic pulmonary fibrosis (IPF) is a rare lung disease characterised by progressive loss of lung function, dyspnoea and cough. IPF has a variable clinical course but a poor prognosis. Nintedanib, a tyrosine kinase inhibitor, is one of two drugs approved for the treatment of IPF. In clinical trials, nintedanib slowed disease progression by reducing the rate of decline in forced vital capacity (FVC) in patients with IPF and mild or moderate lung function impairment. The effect of nintedanib was consistent across patient subgroups defined by baseline characteristics including FVC % predicted, diffusion capacity of the lung for carbon monoxide % predicted and the presence of emphysema. Recently, it has been shown that the rate of decline in FVC and the treatment effect of nintedanib are the same in patients with preserved lung volume (FVC >90% predicted) as in patients with greater impairment in FVC, supporting the value of early treatment of IPF. The adverse events most commonly associated with nintedanib, both in clinical trials and real-world clinical practice, are mild gastrointestinal events, particularly diarrhoea. Side effects are manageable in a majority of patients through symptomatic treatment, dose reductions and treatment interruptions, enabling most patients to stay on treatment in the long term.
A Cost-Effectiveness Analysis of Nintedanib in Idiopathic Pulmonary Fibrosis in the UK.
Rinciog C,Watkins M,Chang S,Maher T M,LeReun C,Esser D,Diamantopoulos A
BACKGROUND:International guidelines recommend nintedanib (OFEV) as an option for the treatment of idiopathic pulmonary fibrosis (IPF). OBJECTIVE:The objective of this study was to assess the cost effectiveness of nintedanib versus pirfenidone, N-acetylcysteine and best supportive care (BSC) for the treatment of IPF from a UK payer's perspective. METHODS:A Markov model was designed to capture the changes in the condition of adults with IPF. Efficacy outcomes included mortality, lung function decline and acute exacerbations. Treatment safety (serious adverse events) and tolerability (overall discontinuation) were also considered. The baseline risk of these events was derived from patient-level data from the placebo arms of nintedanib clinical trials (TOMORROW, INPULSIS-1, INPULSIS-2). A network meta-analysis (NMA) was conducted to estimate the relative effectiveness of the comparator treatments. Quality of life and healthcare resource use data from the clinical trials were also incorporated in the economic model. RESULTS:Nintedanib showed statistically significant differences against placebo on acute exacerbation events avoided and lung function decline. In the cost-effectiveness analysis, the results were split between two treatments with relative low costs and modest effectiveness (BSC and N-acetylcysteine) and two that showed improved effectiveness (lung function) and higher costs (nintedanib and pirfenidone). All comparators were assumed to have similar projected survival and the difference in quality-adjusted life-years (QALYs) was driven by the acute exacerbations and lung function estimates. In the base-case deterministic pairwise comparison with pirfenidone, nintedanib was found to have fewer acute exacerbations and resulted in less costs and more QALYs gained. CONCLUSIONS:Compared with BSC (placebo), nintedanib and pirfenidone were the only treatments to show statistical significance in the efficacy parameters. We found substantial uncertainty in the overall cost-effectiveness results between nintedanib and pirfenidone. N-Acetylcysteine was largely similar to BSC but with a worse survival profile. INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.
Pirfenidone, nintedanib and N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis: A systematic review and meta-analysis.
Rogliani Paola,Calzetta Luigino,Cavalli Francesco,Matera Maria Gabriella,Cazzola Mario
Pulmonary pharmacology & therapeutics
BACKGROUND:The prevalence of idiopathic pulmonary fibrosis (IPF) is increasing every year. Pirfenidone and nintedanib were approved for treatment of IPF in 2014, but they received only a conditional recommendation for use and, thus, to date no drugs are strongly recommended for IPF. The aim of this study was to assess the effectiveness and safety of the currently approved drugs for IPF and N-acetylcysteine (NAC), the most debated drug in the last update of guidelines for IPF treatment. METHODS:RCTs in IPF were identified searching from databases of published and unpublished studies. The influence of pirfenidone, nintedanib and NAC on clinical outcomes, safety, and mortality was assessed via pair-wise meta-analysis. RESULTS:Ten papers (3847 IPF patients; 2254 treated; 1593 placebo) were included in this study. Our results showed that both pirfenidone and nintedanib, but not NAC, were significantly effective in reducing FVC decline and the risk of FVC ≥10% decline in percent predicted over 12 months. Nintenadib significantly protected against the risk of acute exacerbation and mortality. Pirfenidone and nintedanib showed a similar and good safety profile, whereas NAC provided a signal for increased adverse events. CONCLUSIONS:The rank of effectiveness emerging from this meta-analysis represents an indirect indicator of potential differences between currently approved doses of pirfenidone and nintedanib. Direct comparisons are necessary to assess this matter, and well designed bench-to-bedside studies would permit to understand the potential of combined, sequential, or adjunctive treatment regimens in which perhaps NAC may have a role for specific clusters of IPF patients.
Nintedanib plus docetaxel as second-line therapy in patients with non-small-cell lung cancer of adenocarcinoma histology: a network meta-analysis vs new therapeutic options.
Popat Sanjay,Mellemgaard Anders,Reck Martin,Hastedt Claudia,Griebsch Ingolf
Future oncology (London, England)
PATIENTS & METHODS:We provide an update to a network meta-analysis evaluating the relative efficacy of nintedanib + docetaxel versus other second-line agents in adenocarcinoma histology non-small-cell lung cancer. RESULTS:Overall similarity of nintedanib + docetaxel versus ramucirumab + docetaxel, and versus nivolumab. Comparing nintedanib + docetaxel with nivolumab, hazards ratio (HR) of overall survival and progression-free survival (PFS) pointed in opposite directions (overall survival: HR: 1.20 [95% credible interval: 0.92-1.58]; PFS: HR: 0.91 [0.68-1.21]). Exploratory subgroup analysis indicated superiority of nivolumab in high PD-L1 expression level subgroups; results were more favorable for nintedanib in all subgroups with low (<1%, <5%, <10%) PD-L1 expression levels - in particular, with regard to PFS. CONCLUSION:Results demonstrated similar efficacy of nintedanib + docetaxel compared with the new therapeutic options ramucirumab + docetaxel and nivolumab, with potential differences in subgroups according to PD-L1 expression level.
Nintedanib in the management of idiopathic pulmonary fibrosis: clinical trial evidence and real-world experience.
Rivera-Ortega Pilar,Hayton Conal,Blaikley John,Leonard Colm,Chaudhuri Nazia
Therapeutic advances in respiratory disease
Idiopathic pulmonary fibrosis (IPF) is a fibrotic interstitial lung disease associated with significant morbidity and mortality. Previously, IPF has been managed using immunosuppressive therapy; however, it has been shown that this is associated with increased mortality. In the last 5 years, two disease-modifying agents have been licensed for use in IPF, namely pirfenidone and nintedanib. Nintedanib is a tyrosine kinase inhibitor with antifibrotic properties that has also been shown to significantly reduce the progression of the disease. The scientific evidence shows that nintedanib is effective and well tolerated for the treatment of IPF in mild, moderate and severe stages of the disease. Real-world experiences also support the findings of previously conducted clinical trials and show that nintedanib is effective for the management of IPF and is associated with reducing disease progression. Gastrointestinal events, mainly diarrhoea, are the main adverse events caused by the treatment. Recent real-word studies also suggest that nintedanib stabilizes lung function till lung transplantation, with no increased surgical complications or postoperative mortality after lung transplantation. In this review, we will discuss the clinical trial evidence and real-world experience for nintedanib in the management of IPF.
Safety and efficacy of nintedanib for the treatment of metastatic colorectal cancer.
Riesco-Martinez Maria Carmen,Sanchez-Torre Ana,Garcia-Carbonero Rocio
Expert opinion on investigational drugs
INTRODUCTION:Nintedanib (BIBF 1200) is an oral tyrosine kinase inhibitor that targets the vascular endothelial growth factor (VEGFR), platelet-derived growth factor (PDGFR) and fibroblast growth factor (FGFR) receptors. It is approved in Europe in combination with docetaxel for patients with advanced lung adenocarcinoma who have progressed to first-line chemotherapy. However, its role in the treatment of metastatic colorectal cancer (mCRC) is uncertain. Recent results from the LUME-Colon 1 pivotal phase III trial showed only a marginal increase in progression free survival over placebo in refractory mCRC patients, with a toxicity profile similar to other antiangiogenic agents, and no benefit in overall survival. Areas covered: The aim of this review is to summarize the pharmacology, efficacy and safety profile of nintedanib in the context of mCRC, and to provide some perspective regarding the role of this drug in clinical practice. Expert commentary: Nintedanib provides limited clinical benefit in refractory CRC and its use in this clinical setting is not warranted. Efforts shall continue to pursue the identification of predictive biomarkers that allow the selection of subpopulations with a greater likelihood to benefit from this therapeutic approach, in order to improve the benefit-risk and cost-benefit ratios of this and other antiangiogenic agents.
Nintedanib for the treatment of idiopathic pulmonary fibrosis.
Varone Francesco,Sgalla Giacomo,Iovene Bruno,Bruni Teresa,Richeldi Luca
Expert opinion on pharmacotherapy
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.
Efficacy and Safety of Nintedanib for the Treatment of Idiopathic Pulmonary Fibrosis: An Update.
Rodríguez-Portal José Antonio
Drugs in R&D
Idiopathic pulmonary fibrosis is a fatal form of progressive fibrosing interstitial pneumonia with limited treatment options. In recent years, its management has been transformed with the approval of two new antifibrotic drugs: nintedanib and pirfenidone. Nintedanib is a tyrosine kinase inhibitor that efficiently slows idiopathic pulmonary fibrosis progression and has an acceptable tolerability profile. This article reviews new available evidence on the long-term efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis. Data from extension trials indicate that nintedanib continues to slow disease progression for up to 3 years and is similarly effective in patients with mild and severe impairment of lung function. Treatment with nintedanib reduces the risk of acute exacerbations, and a combined analysis of data from clinical trials of nintedanib shows a trend towards a reduction in mortality. Nintedanib is well tolerated and has been shown to be safe for up to 51 months. Gastrointestinal events, mainly diarrhoea, are the main adverse events caused by the treatment. Currently available data confirm its safety profile in real-life clinical settings, with no new safety concerns identified in patients with comorbidities.
Anti-fibrotic nintedanib-a new opportunity for systemic sclerosis patients?
Duarte Ana Catarina,Santos Maria José,Cordeiro Ana
Systemic sclerosis is a connective tissue disease characterized by progressive skin thickening and a wide spectrum of internal organ involvement. Pathogenesis includes vasculopathy, inflammation, and fibrosis. Although immunosuppressants such as cyclophosphamide and mycophenolate mofetil have shown some benefit in interstitial lung disease management, it is still a major cause of morbi-mortality in these patients. Therefore, there is a current need for new therapies. Here, we report a 65-year-old female patient with limited cutaneous systemic sclerosis, anti-topoisomerase-positive and extensive lung disease. The patient developed progressive lung fibrosis under several immunosuppressants and was started on nintedanib, with clinical and functional stabilization. Nintedanib is a tyrosine-kinase inhibitor that blocks several profibrotic pathways, inhibiting proliferation and migration of fibroblasts and decreasing the synthesis of extracellular matrix proteins. It is approved for idiopathic lung fibrosis and has demonstrated good results in inhibiting migration and proliferation of systemic sclerosis dermal fibroblasts, constituting a promising agent for systemic sclerosis-associated lung fibrosis.
Population pharmacokinetics of nintedanib in patients with idiopathic pulmonary fibrosis.
Schmid Ulrike,Doege Christiane,Dallinger Claudia,Freiwald Matthias
Pulmonary pharmacology & therapeutics
BACKGROUND:Nintedanib is a potent intracellular inhibitor of tyrosine kinases, including the receptor kinases vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor. A previous model assessed the population pharmacokinetics of nintedanib and its main metabolite BIBF 1202 in patients with non-small cell lung cancer and idiopathic pulmonary fibrosis (IPF). The objective of this analysis was to further characterise the population pharmacokinetics of nintedanib in patients with IPF by including data from the Phase III trials. METHODS:We pooled data from 933 patients with IPF participating in the Phase II TOMORROW trial and the two Phase III INPULSIS trials. Plasma concentrations of nintedanib (n = 3501) were analysed using nonlinear mixed-effects modelling. RESULTS:Pharmacokinetics of nintedanib was described by a one-compartment model with linear elimination, first-order absorption and an absorption lag time. The population estimates of absorption rate, lag time, apparent total clearance and apparent volume of distribution at steady state for a typical IPF patient were 0.0814 h, 0.689 h, 994 L/h, and 265 L. The model confirmed age, body weight, smoking and Asian race (with different effect sizes in different Asian subpopulations) as statistically significant covariates influencing nintedanib exposure. Serum lactate dehydrogenase levels were identified as another factor significantly influencing nintedanib plasma concentrations. No individual covariate at extreme values (5th and 95th percentiles of baseline for continuous covariates) resulted in changes in exposure of more than 50% relative to a typical patient. CONCLUSIONS:The developed model provides further details about the pharmacokinetics of nintedanib in patients with IPF and can be used for simulations exploring covariate effects and exposure-response analyses in this patient population.