Idiopathic pulmonary fibrosis (IPF) is also known as usual interstitial pneumonitis (UIP). There are estimated to be 48,000 new diagnoses of IPF per year in the United States, with 40,000 deaths per year.

About two thirds of patients with IPF pass away within five years of diagnosis. For many years, combination therapy with prednisone and azathioprine had been used. However, the PANTHER trial revealed convincingly that combination therapy with prednisone and Imuran actually resulted in greater mortality, more hospitalizations, and more serious adverse events than placebo. Therefore, combination therapy with azathioprine and prednisone is no longer recommended. For a while, treatment of IPF had been essentially supportive including supplemental oxygen, pulmonary rehabilitation and vaccination against Streptococcus pneumoniae and influenza. Lung transplant can also be considered when appropriate.

A new therapy?

Pirfenidone (Esbriet) is an antifibrotic agent, which has now been shown in several clinical trials to reduce disease progression and improve progression free survival in patients with IPF. Pirfenidone inhibits the synthesis of transforming growth factor Beta, which plays a role in cell proliferation and differentiation.

There have been two previous phase III trials of Pirfenidone that seem to have conflicting results. One study (published in 2010) showed that Pirfenidone slows disease progression while another study (published in 2011) did not meet its end point.

However, this last study did have some trends that were in a positive direction; this resulted in the FDA requesting the “ Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis Study” (ASCEND). The result of this study was published in the New England Journal of Medicine. In the ASCEND study, 278 patients with IPF were randomized to receive Pirfenidone 2403 mg per day for 52 weeks. 277 patients were randomized to receive Placebo. The primary endpoint was forced vital capacity and secondary end points included 6-minute walk test distance, progression free survival, dyspnea, overall mortality and disease specific mortality.The proportion of patients who had an absolute reduction of at least 10% in predicted forced vital capacity (FVC) or who died was 47.9% less in the Pirfenidone group as compared to the Placebo group. In addition, the average decrease in FVC from baseline was lower in the Pirfenidone group versus the Placebo group (235 versus 428 mL).

Furthermore, the proportion of patients who had no decline in FVC was 132% higher in the Pirfenidone group than in the Placebo group and there was also less decline in the 6-minute walk distance in the Pirfenidone group compared to the Placebo group as well as better progression free survival. However, there was no significant difference in dyspnea score and all cause mortality or disease specific mortality between the two groups.

There has been a pooled analysis of data from all three Pirfenidone trials, which revealed that the overall risk for death at 5 2 weeks was lower in the Pirfenidone group versus the placebo group with a hazard ratio of 0.52. In this pooled analysis Pirfenidone improved both all cause mortality and disease specific mortality. The most common side effects included gastrointestinal and skin related adverse effects, but these rarely led to treatment discontinuation. Unfortunately, patients on Pirfenidone do not necessarily perceive improvement and Pirfenidone is certainly not a cure for this serious illness. Nevertheless, it appears to be a good option for slowing down the progression of this serious condition.

Nintedanib – a second option

Another new option for treating UIP/IPF is Nintedanib (OFEV®) This is a tyrosine kinase inhibitor that targets growth factors including the vascular endothelial growth factor receptor, fibroblast growth factor receptor and platelet derived growth factor receptor. In May 2014, Luca Richeldi et al published the results of two 52 week randomized, double blind phase 3 studies of nintedanib (150 mg twice/day) versus placebo in the New England Journal of Medicine. 1066 patients were enrolled in a 3:2 randomization. The adjusted annual rate of change in FVC was negative 115 ml with Nintedanib versus negative 240 ml with placebo. Diarrhea occurred in over 60 percent of patients on Nintedanib but led to discontinuation in less than five percent.

The most frequent serious adverse reactions reported in patients treated with OFEV® (more than placebo), were bronchitis (1.2% vs. 0.8%) and myocardial infarction (1.5% vs. 0.4%). However, in the predefined category of major adverse cardiovascular events (MACE) including myocardial infarction, fatal events were reported in 0.6% of OFEV® treated patients and 1.8% of placebo-treated patients. Therefore, the clinician must weigh the risk/benefit ratio of using this medication in a patient with known coronary artery disease (or cardiovascular risk factors) carefully.

In conclusion, IPF/UIP is a relatively common and progressive pulmonary disorder. Pirfenidone and Nintedanib are two new agents that appear to slow down the progression of this disease. Further research needs to be done to identify agents that can reverse pulmonary fibrosis. Since Nintedanib and Pirfenidone seem to have similar efficacy, most clinicians choose one over the other based on side effect profile and dosing considerations.