Nintedanib Slows Idiopathic Pulmonary Fibrosis Progression

Jim Kling

May 27, 2014

SAN DIEGO — Nintedanib slows the progression of idiopathic pulmonary fibrosis by reducing the rate of decline in forced vital capacity, according to 2 replicate phase 3 trials.

"We know that tyrosine kinases, in particular fibroblast growth factor and vascular endothelial growth factor [which nintedanib inhibits], are involved in the mechanism of disease. It has been a logical step to target tyrosine kinases to see if this leads to a reduction in the progression of disease," said Luca Richeldi, MD, professor of respiratory medicine at the University of Southampton in the United Kingdom.

It is estimated that 5000 patients in the United Kingdom are diagnosed with idiopathic pulmonary fibrosis each year, and the prognosis is poor. With about a 30% 5-year survival, it is likely to kill more people than breast cancer, Dr. Richeldi told Medscape Medical News.

The results of both trials were presented here at the American Thoracic Society 2014 International Conference and published online simultaneously in the New England Journal of Medicine.

INPULSIS-1 and INPULSIS-2

Dr. Richeldi and colleagues conducted 2 randomized, double-blind, placebo-controlled, parallel-group phase 3 trials of nintedanib at 205 sites in 24 countries (INPULSIS-1 and INPULSIS-2).

The primary outcome was the annual rate of change in forced vital capacity over 52 weeks. Secondary outcomes included time to the first acute exacerbation and change in St. George's Respiratory Questionnaire (SGRQ) score over 52 weeks.

The 513 INPULSIS-1 and 513 INPULSIS-2 patients with idiopathic pulmonary fibrosis were randomized to nintedanib 150 mg twice daily or placebo.

The reduction in forced vital capacity was lower in the nintedanib group than in the placebo group in INPULSIS-1 (114.7 vs 239.9 mL; P < .001) and INPULSIS-2 (113.6 vs 207.3 mL; P < .001).

The difference between nintedanib and placebo in time to first acute exacerbation was significant only in INPULSIS-2 (hazard ratio, 0.38; 95% confidence interval, 0.19 - 0.77; P = .005).

This discrepancy is likely related to the fact that exacerbations are rare in idiopathic pulmonary fibrosis, so the trials were underpowered to detect it, say the researchers.

Similarly, the difference between nintedanib and placebo in mean change in SGRQ score from baseline, suggesting less deterioration in quality of life, was significant only in INPULSIS-2 (2.80 vs 5.48 points; P = .02).

With the positive results recently reported for the antifibrotic pirfenidone, "we are entering an era when we might have more than 1 option for the disease, which is quite good," said Dr. Richeldi.

Nintedanib and pirfenidone have different safety profiles and have been tested in somewhat different patient populations. "I think it will be for the companies and the community to try to find the best of use of each drug," he said.

The next challenge is to find patients earlier in the course of their disease. This can be tricky because idiopathic pulmonary fibrosis can be difficult to distinguish from chronic obstructive pulmonary disease. Generally, high-resolution CT scans are required to diagnose the disease, Dr. Richeldi explained.

INPULSIS-1 and INPULSIS-2 hit their primary end points, but were a little inconsistent in their secondary end points. "That's not unusual in studies of idiopathic pulmonary fibrosis," said Fernando Martinez, MD, executive vice chair of medicine at the Weill Cornell Medical College in New York City.

He noted that the trials showed some tolerability issues. "There's clearly good and there's clearly caution, but I think it is a really good step forward. This was a good meeting for idiopathic pulmonary fibrosis patients," Dr. Fernandez told Medscape Medical News.

The fact that patients didn't necessarily perceive an improvement in quality of life, as evidenced by the SGRQ scores, could be a drawback to a drug that can have significant adverse effects, he added.

"Patients will have to provide the most important insight," said Dr. Fernandez. They will need to express "exactly what they want and how they want to achieve it. But having options with at least some beneficial effect is a major advantage."

The study was funded by Boehringer-Ingelheim. Dr. Richeldi is part of the steering committee for the drug development program. Dr. Fernandez has consulted with Boehringer-Ingelheim for its COPD program.

American Thoracic Society (ATS) 2014 International Conference. Presented May 20, 2014.

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