A New Hope for Idiopathic Pulmonary Fibrosis

Published - Written by Daniela Lamas

It seemed benign at first. But the dry cough didn’t go away, despite a course of antibiotics and a prescription for an inhaler.

Then your 55-year-old patient started to get winded while walking up the stairs at his home, and a work-up – chest x-ray, CT scan and pulmonary function testing – led to a pulmonary appointment and ultimately to a diagnosis of idiopathic pulmonary fibrosis (IPF). The progressive and ultimately fatal lung disease carries a devastating prognosis: half are dead within three years, and there are no proven therapies to slow progression of the disease. This leaves those with IPF, like your patient, facing a grim future in which lung transplantation holds the only hope for extending survival.

That landscape might now be shifting, with three papers in this week’s issue of NEJM that offer new promise for medical treatments and clarify which therapies aren’t effective.

Just a few years ago, the goal behind medical treatments for IPF had been to decrease inflammation, in order to reverse or slow the lung scarring that characterizes the fibrotic disease. This premise led to a trial that compared a three-drug combination of immune suppression – prednisone, azathioprine and an antioxidant, acetylcysteine – to placebo, and to acetylcysteine alone. The study was stopped early as the group of IPF patients in the three-drug trial arm were more likely to die than those receiving either acetylcysteine or placebo.

In the intervening years, the question of whether acetylcysteine alone could yield a benefit remained open. After stopping the three-drug study arm, investigators had continued to enroll patients in the acetylcysteine versus placebo trial. While awaiting the results of this part of the trial, many doctors continued to prescribe this med for their IPF patients. However, this week’s issue of NEJM puts that practice to rest. Ultimately, researchers found that those patients randomly assigned to receive acetylcysteine did no better – by lung function, rate of exacerbation or death – than those assigned to receive placebo.

Now what? The two other IPF papers in this week’s NEJM offer exciting new directions. Luci Richeldi and the IMPULSIS trial investigators publish the results of two trials of a medication called Nintedanib, a tyrosine kinase receptor antagonist thought to have a benefit in IPF by acting against various pro-fibrotic growth factors. The investigators randomly assigned 1066 patients to receive either nintedanib or placebo. They tracked the rate of decline in lung function (measured by forced vital capacity, or FVC) and change in a symptom assessment score. They also monitored whether patients developed an exacerbation of IPF, which is important as these events can lead to life-threatening respiratory failure.

What they found? In both their trials of this drug, patients receiving nintedanib had slower decline in FVC over time, consistent with a slower disease progression. In one of the studies of this drug, there was a longer time to first IPF exacerbation – this wasn’t replicated in the other. In both studies, there was no significant difference in the self-reported scores for respiratory symptoms. And while mortality was not an endpoint for either study, there was a trend toward a reduced mortality among the patients taking nintedanib.

In another paper, researchers for the ASCEND trial announce their results for a drug called pirfenidone, an antifibrotic agent that’s been approved for use in patients with IPF abroad, but not yet by the FDA here. In their study, patients who received pirfenidone had a slower decline in FVC than those with placebo, and more of them had no decline at all over one year. There was no change in respiratory symptom scores, nor in rates of death in this study alone – however, when these results were pooled with prior studies of pirfenidone in IPF – the investigators did note a significant decrease in mortality among patients taking the drug. The authors of both studies point out that their drugs carry their own side effect profiles, which rarely led to discontinuing treatment – GI and skin-related problems in pirfenidone, and diarrhea in nintedanib.

In an accompanying editorial, Gary M. Hunninghake, a pulmonologist who studies IPF at Brigham and Women’s Hospital in Boston, notes that while these results represent “a major breakthrough for patients with idiopathic pulmonary fibrosis,” we should be “cautious” in extrapolating the findings to all patients. For instance, neither study enrolled patients with severe disease at the start, and neither study tracked patients for longer than one year. Furthermore, he comments, we don’t know how the drugs would work together or whether they might benefit patients with other kinds of fibrotic lung disease, or pre-clinical stages of IPF.

These are the kinds of studies that will inform care moving forward, which is a far cry from the recent past where IPF was a disease with no potential medical therapy. “The game has now changed,” Hunninghake commented. “We may soon have choices in the medical management of idiopathic pulmonary fibrosis.”