First Data on Efficacy and Safety of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis and Forced Vital Capacity of ≤50 % of Predicted Value

In the Phase III INPULSIS® trials, 52 weeks’ treatment with nintedanib reduced decline in forced vital capacity (FVC) versus placebo in patients with idiopathic pulmonary fibrosis (IPF). Patients who completed the INPULSIS® trials could receive nintedanib in an open-label extension trial (INPULSIS®-ON). Patients with FVC <50 % predicted were excluded from INPULSIS®, but could participate in INPULSIS®-ON. In patients with baseline FVC ≤50 % and >50 % predicted at the start of INPULSIS®-ON, the absolute mean change in FVC from baseline to week 48 of INPULSIS®-ON was −62.3 and −87.9 mL, respectively (n = 24 and n = 558, respectively). No new safety signals were identified in INPULSIS®-ON compared with INPULSIS®. The decline in FVC in INPULSIS®-ON in both subgroups by baseline FVC % predicted was similar to that in INPULSIS®, suggesting that nintedanib may have a similar effect on disease progression in patients with advanced disease as in less advanced disease.


Introduction
Idiopathic pulmonary fibrosis (IPF) is a chronic form of interstitial pneumonia associated with worsening dyspnoea and progressive decline in lung function [1]. Measuring decline in forced vital capacity (FVC) is an established method for assessing disease progression in patients with IPF and is a predictor of mortality [2,3].
Nintedanib, an intracellular inhibitor of tyrosine kinases [4,5], is approved for the treatment of IPF in several countries and regions, including the US, Europe [6,7] and Japan. In the most recent international clinical practice guideline, nintedanib received a conditional recommendation for use in the treatment of IPF, taking into account individual patients' preferences [8].
The INPULSIS Ò trials were two replicate, randomised, placebo-controlled trials that assessed the efficacy and safety of 52 weeks' treatment with nintedanib 150 mg twice daily (bid) in patients with IPF [9]. To be eligible to enter the INPULSIS Ò trials, patients had to be C40 years old and to have an FVC of C50 % predicted, diffusing capacity of the lung for carbon monoxide of 30-79 % predicted and forced expiratory volume in 1 s/FVC ratio of C0.7. In both trials, nintedanib slowed disease progression by reducing the annual rate of decline in FVC by approximately 50 % [9]. Diarrhoea was the most frequent adverse event in the nintedanib group, reported in 62.4 % of patients treated with nintedanib and 18.4 % on placebo [9].
Patients  These results suggest that first, the effect of nintedanib on slowing disease progression is maintained beyond 52 weeks and, second, that patients with severely impaired FVC may receive the same benefit from nintedanib on reduction in FVC decline as patients with less severe impairment. In general, the adverse event profile was similar in both subgroups, with no new safety signals identified in INPULSIS Ò -ON compared to INPULSIS Ò , but as might be expected, serious adverse events and fatal adverse events were more common in patients with more advanced disease, as were adverse events of dyspnoea and disease progression.
These are the first data to be published on the effects of antifibrotic therapy in patients with FVC \50 % predicted. Patients with FVC \50 % predicted are usually excluded from clinical trials in IPF [9][10][11][12][13] as it is thought that it is too difficult to retain patients with severe lung function impairment in trials. However, studying this patient population is important, as patients with IPF and severely  impaired FVC represent a patient group that require care in clinical practice [14]. Some physicians are already using antifibrotic drugs in patients with FVC \50 % predicted, based on regulatory authorities approving these drugs without restriction based on FVC [6,7], but many physicians believe that the benefits of antifibrotic treatment would likely be reduced, and the side-effects worse, in patients with more advanced disease.  [15][16][17], suggesting that nintedanib is effective in reducing progression of IPF irrespective of the stage of disease at which it is initiated. The latest international clinical practice guideline for IPF highlights that there is no evidence to suggest an optimal duration of therapy or a point at which therapy would no longer be efficacious [8].
As with all data from open-label extension trials, these results have limitations, including bias in the population who completed the randomised placebo-controlled trials and elected to continue in the open-label extension and the lack of a placebo comparator in the extension phase. Findings from this subgroup analysis should be interpreted with caution as the number of patients with FVC B50 % predicted at the start of INPULSIS Ò -ON was small.
In conclusion, in an interim analysis of data from the INPULSIS Ò -ON open-label extension trial, the decline in FVC in patients with baseline FVC B50 % and [50 % predicted was similar to that in patients treated with nintedanib in INPULSIS Ò , suggesting a similar benefit on disease progression, and no new safety signals were identified.  c Events that were incapacitating or that caused an inability to work or to perform usual activities d Events that resulted in death, were immediately life threatening, resulted in persistent or clinically significant disability or incapacity, required or prolonged hospitalisation, were related to a congenital anomaly or birth defect, or were deemed serious for any other reason e Adverse events that led to permanent treatment discontinuation in C1 % of patients in the nintedanib or placebo group in INPULSIS Ò and/or in the overall patient population in INPULSIS Ò -ON