Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis

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. 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. 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. The present results indicate that the efficacy and safety of nintedanib in Japanese patients are comparable with those in the overall population.

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Efficacy and safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease treated with mycophenolate: a subgroup analysis of the SENSCIS trial

BackgroundInterstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis–related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD.MethodsWe conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis. Patients who had systemic sclerosis with an onset of the first non-Raynaud’s symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo. The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George’s Respiratory Questionnaire (SGRQ) at week 52.ResultsA total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous systemic sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was −52.4 ml per year in the nintedanib group and −93.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P=0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of −0.21 (95% CI, −0.94 to 0.53; P=0.58) and 1.69 (95% CI, −0.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group.ConclusionsAmong patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo. (Funded by Boehringer Ingelheim; SENSCIS ClinicalTrials.gov number, NCT02597933.)

In the two-replicate randomized Phase III INPULSIS® trials in patients with idiopathic pulmonary fibrosis (IPF), nintedanib 150 mg bd significantly reduced the annual rate of decline in forced vital capacity (FVC) compared with placebo. The key secondary endpoints were time to first investigator-reported acute exacerbation and change from baseline in St George's Respiratory Questionnaire total score, both over 52 weeks. Here, we assessed the effect of nintedanib in Asian patients. Pre-specified subgroup analyses of the effect of nintedanib on the primary and key secondary endpoints in Asian versus White patients were undertaken based on pooled data from the two INPULSIS® trials. Safety data were analyzed descriptively. Of the treated patients, 322 were Asian (nintedanib n = 194; placebo n = 128) and 608 were White (nintedanib n = 360; placebo n = 248). In Asian patients, the nintedanib versus placebo difference in the adjusted annual rate of decline in FVC was 94.1 mL/year (95% CI: 33.7, 154.6). The treatment effect of nintedanib on the annual rate of decline in FVC in Asian and White patients was similar (treatment-by-subgroup interaction P = 0.72) and consistent with the overall population. No significant treatment-by-subgroup interaction was observed for the key secondary endpoints between Asian and White patients. In Asian patients, the most common adverse event in the nintedanib group was diarrhoea (56.2% of patients vs 15.6% for placebo). In pre-specified subgroup analyses of Asian versus White patients with IPF in the INPULSIS® trials, race did not influence the effect of nintedanib on disease progression.

OP0124 EFFECTS OF NINTEDANIB IN PATIENTS WITH PROGRESSIVE FIBROSING INTERSTITIAL LUNG DISEASE ASSOCIATED WITH RHEUMATOID ARTHRITIS (RA-ILD) IN THE INBUILD TRIAL

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

BackgroundThe forced vital capacity (FVC) of healthy individuals depends on their age, sex, ethnicity and height. Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is characterised by loss of FVC. We compared FVC values in the subjects with SSc-ILD in the SENSCIS trial of nintedanib versus placebo with values from hypothetical matched healthy references.MethodsThe SENSCIS trial enrolled subjects with SSc with first non-Raynaud symptom in the prior ≤ 7 years, extent of fibrotic ILD on HRCT ≥ 10%, and FVC ≥ 40% predicted. FVC at baseline and decline in FVC over 52 weeks were compared with FVC values in hypothetical healthy reference subjects matched 1:1 to the subjects in the trial for age, sex, ethnicity and height, determined using equations published by the European Respiratory Society Global Lung Function Initiative.ResultsAt baseline, mean (SD) FVC was 2460 (737) mL in the nintedanib group (n = 287) compared with 3403 (787) mL in the hypothetical matched healthy references. Mean (SD) FVC was 2544 (817) mL in the placebo group (n = 286) compared with 3516 (887) mL in the hypothetical matched healthy references. Mean (SE) changes in FVC at week 52, i.e., age-related loss of lung function, in the hypothetical healthy references matched to the nintedanib and placebo groups, respectively, were − 26.3 (0.5) mL and − 25.8 (0.5) mL. The difference in the change in FVC at week 52 between the nintedanib group and the hypothetical healthy references was 26.6 mL (95% CI: 1.2, 52.0; p = 0.04). The difference in the change in FVC at week 52 between the placebo group and the hypothetical healthy references was 77.5 mL (95% CI: 51.4, 103.7; p < 0.0001).ConclusionsSubjects with SSc-ILD in the SENSCIS trial had impaired lung function at baseline and experienced further deterioration over 52 weeks. The decline in FVC in the placebo group was four-fold greater than in a hypothetical group of matched healthy references, whereas the decline in FVC in patients who received nintedanib was two-fold greater than in hypothetical healthy references. These data highlight the clinical relevance of the slowing of FVC decline provided by nintedanib.Trial registration Registered 5 November 2015, https://clinicaltrials.gov/ct2/show/NCT02597933.

&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;

THU0330 EFFECTS OF NINTEDANIB IN PATIENTS WITH SYSTEMIC SCLEROSIS-ASSOCIATED ILD (SSC-ILD) AND DIFFERING EXTENTS OF SKIN FIBROSIS: FURTHER ANALYSES OF THE SENSCIS TRIAL

Baseline Lung Function Had No Effect on Long-Term Reduction in FVC Decline With Nintedanib in Patients With Idiopathic Pulmonary Fibrosis (IPF)

Rationale: Nintedanib demonstrated efficacy in slowing the annual rate of decline in forced vital capacity (FVC) in patients with progressive fibrosing interstitial lung diseases (PF-ILDs) in the Phase III INBUILD trial (NCT02999178). The aim of this study was to generate additional data on the efficacy of nintedanib versus placebo over 52 weeks in Chinese patients with PF-ILDs. Methods: In the randomized, double-blind, Phase IIIb study, Chinese patients with chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype were randomized 2:1 to receive nintedanib 150 mg twice daily or placebo for 52 weeks, with randomization stratified by high-resolution computed tomography (HRCT) pattern (usual interstitial pneumonia [UIP] -like fibrotic pattern or other fibrotic patterns). The primary endpoint was the annual rate of decline in FVC over 52 weeks. Results: A total of 81 patients were randomized to nintedanib (n=54) or placebo (n=27). At baseline, patients in the placebo and nintedanib groups had a mean age of 65.8 and 63.8 years, 59.3% and 51.9% were female, and 85.2% and 83.3% had UIP-like fibrotic pattern on HRCT. Nintedanib reduced the annual rate of decline in FVC over 52 weeks compared with placebo (adjusted rate of decline −85.32 mL/year vs −191.89 mL/year in the placebo group; between-group difference 106.57 mL; 95% CI −47.13, 260.28) (Figure). Living with pulmonary fibrosis (L-PF) total score increased (worsened) from baseline to a smaller extent with nintedanib than placebo (adjusted mean change 2.92 vs 14.18; between-group difference −11.27; 95% CI −20.05, −2.49]) at week 52, and fewer patients in the nintedanib group than in the placebo group had an acute ILD exacerbation (11.1% vs 25.9%) over 52 weeks. Treatment-emergent AEs occurred in all patients receiving nintedanib and 92.6% of patients receiving placebo, and resulted in treatment discontinuation in 10 and one patient(s), respectively. Serious adverse events occurred in 37.0% of patients in the nintedanib group and 44.4% of patients in the placebo group. Three patients in the nintedanib group and no patient in the placebo group had adverse events of special interest (AESIs). No new safety concerns were identified with nintedanib. Conclusions: In Chinese patients with PF-ILDs, the annual rate of decline in FVC was lower in patients treated with nintedanib than with placebo. Nintedanib had an acceptable safety profile in these patients, with no new safety concerns identified. These findings are consistent with those from the INBUILD study, supporting the efficacy of nintedanib in Chinese patients with PF-ILDs.

SAT0329 IS THE RATE OF LUNG FUNCTION DECLINE THE SAME IN PATIENTS WITH SYSTEMIC SCLEROSIS-ASSOCIATED ILD (SSC-ILD) WHO EXPERIENCE WEIGHT LOSS? DATA FROM THE SENSCIS TRIAL

To investigate the efficacy and safety of nintedanib versus placebo in Chinese patients with idiopathic pulmonary fibrosis (IPF). The INPULSIS® trials consisted of two replicate, randomized, placebo-controlled, double-blind trials comparing nintedanib 150mg bid with placebo over a 52-week treatment period. The primary endpoint was annual rate of decline in forced vital capacity (FVC); key secondary endpoints were change from baseline in Saint George's Respiratory Questionnaire's total score and time to first investigator-reported acute exacerbation. Data from both trials were pooled for the Chinese subgroup analyses. A total of 101 Chinese patients (nintedanib/placebo: 61/40) were treated. The demographic characteristics were generally balanced between treatment arms. Over 52weeks, the rate of decline in FVC was lower in nintedanib-treated patients compared with placebo-treated patients in the Chinese subgroup [- 126.43 vs. - 229.82mL/year; ∆ = 103.39mL/year (95% confidence interval, CI: - 19.40 to 226.18)]. The proportion of patients with adverse events (AEs) over 52weeks was similar between treatment arms. The most commonly reported AEs with nintedanib treatment were gastrointestinal symptoms (diarrhoea, nausea, and vomiting). Nintedanib is clinically efficacious in Chinese patients with IPF with approximately 50% reductions in the rate of decline in FVC, demonstrating slowed disease progression. Similar to the overall INPULSIS® population, nintedanib has a favourable benefit/risk profile in Chinese patients with IPF. CLINICALTRIALS. NCT01335464, NCT01335477. Boehringer Ingelheim. Plain language summary available for this article.

No Effect of Dose Adjustments on Long-Term Reduction in FVC Decline With Nintedanib in Patients With Idiopathic Pulmonary Fibrosis (IPF)