Pirfenidone and Nintedanib for Treatment of Idiopathic Pulmonary Fibrosis

Gayathri Sathiyamoorthy, MD; Sameep Sehgal, MD; Rendell W. Ashton, MD

Disclosures

South Med J. 2017;110(6):393-398. 

In This Article

Nintedanib

Nintedanib is an oral tyrosine kinase inhibitor that was approved by the FDA in October 2014 for the treatment of IPF. It has an antifibrotic effect in the lung by inhibiting vascular endothelial growth factor receptors, fibroblast growth factor receptor, and platelet-derived growth factor receptors.[15] The drug was initially designed as an antineoplastic drug and has been studied for treatment of various cancers.[15]

Important Clinical Trials

After initial animal studies showed antifibrotic effects of nintedanib, the To Improve Pulmonary Fibrosis with BIBF 1120 trial was published in 2011.[16] This phase II trial assessed the efficacy of nintedanib at varying doses compared with placebo in 432 patients with IPF in a 12-month period. A dose of 150 mg twice daily decreased the annual decline in FVC by 68%. This finding missed statistical significance by a small margin. Secondary endpoints of acute exacerbations and dyspnea scores showed a statistically significant decrease. This trial suggested that the dose of 150 mg twice daily had the highest efficacy and was studied further.[16]

The INPULSIS-1 and -2 trials were two multinational replicate 52-week, phase III randomized controlled trials conducted in 24 countries that included 1066 patients with IPF.[16] These studies compared nintedanib with placebo and found a statistically significant difference in the annual rate of decline in FVC (-114.7 mL/year in the nintedanib group compared with -239.9 mL/year in the placebo group, P < 0.001). INPULSIS 1 did not show a significant difference in the time to first exacerbation (P = 0.67) or a reduction in the number of patients with acute exacerbations. INPULSIS 2 showed a significant increase in time to first exacerbation (P = 0.005) and the number of patients with exacerbation was lower than that in the placebo group. Prespecified pooled analysis also did not show a significant difference in the time to first exacerbation or a reduction in the proportion of patients with an exacerbation between the groups. There also was no difference in death from any cause or respiratory cause between the groups.[17]

In a subsequent analysis of the IMPULSIS trials, nintedanib showed efficacy in reducing FVC decline across all subgroups. The greatest treatment effect was seen in patients with low FVC (<70% predicted) who had lower rates of acute exacerbations and had greater improvement in dyspnea scores, however. Nintedanib also had a greater treatment impact in female patients and patients taking bronchodilators.[18]

Based on these studies it appears that nintedanib decreases the progression of IPF as measured by the decline in FVC. It does not improve mortality, nor does it improve the time to first acute exacerbation or dyspnea scores, except in certain subgroups.

Adverse Reactions

Nintedanib was fairly well tolerated in the two IMPULSIS studies; 27% of patients required at least one dose reduction during the study period. Diarrhea was seen in 62.4% of patients, which was mild to moderate in most cases. Most patients did not require a dose reduction as a result of diarrhea and their symptoms were controlled with antidiarrheal medications.[19] Only 4.4% of these patients were forced to discontinue the medication because of diarrhea.[19] Nausea and vomiting also were common adverse effects but were most often limited to one episode.[19] Elevation of liver enzymes greater than three times the upper limit of normal was seen in 4.9% of patients receiving nintedanib.[16]

Of note, adverse reactions related to ischemic heart disease were similar in both the nintedanib group (4.2%) and the control group (4%). Within the category, however, a subcategory of myocardial infarct was reported to be higher in the nintedanib group (2.7%) than in the placebo group (1.2%).[18] The clinical significance of this result remains unclear.

Drug Interactions/Special Considerations

Nintedanib is excreted mainly through the liver by CYP3A4 and as such, it is not recommended for patients with moderate to severe liver disease. As with pirfenidone, smoking may reduce the availability of nintedanib. The Risk Evaluation and Mitigation Strategy program requires that LFT monitoring be conducted monthly for 3 months and then every 3 months thereafter.

Dosing

Nintedanib is administered as a twice-daily 150-mg capsule.

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