Looking Ahead for Pulmonary Fibrosis Patients

Idiopathic pulmonary fibrosis may see more effective treatment options in 2014

/ Author:  / Reviewed by: Joseph V. Madia, MD Beth Bolt, RPh

(RxWiki News) Patients with idiopathic pulmonary fibrosis have not had many treatment options to improve their quality of life. Results of clinical trials due in 2014 may change that. A review of current treatment and the status of clinical trials for idiopathic pulmonary fibrosis (IPF) was recently published.

The research showed that the state of therapy for IPF is moving toward treatments that may slow the fibrosis progression. The results of important clinical trials are due in 2014.

"Ask your pulmonologist about advances in IPF treatment."

The review was conducted by a team led by Mark G. Jones from Academic Unit of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK.

Idiopathic pulmonary fibrosis is a chronic disease of the lungs where normal lung tissue becomes scarred and fibrous. The inability of scarred tissue to expand with breathing means that lung function gradually decreases and breathing becomes more difficult.

According to the review, the standard care for IPF patients has been a combination therapy of prednisolone, an anti-inflammatory drug; azathioprine, a drug that suppresses the immune system, and n-acetylcysteine, an drug that helps clear mucus from the lungs. The effectiveness of this treatment was carefully studied in a clinical trial called PANTHER-IPF. In this trial, some patients were given n-acetylcysteine alone, 77 patients were given the three drugs commonly used and 78 patients were given a fake drug, called a placebo.

All IPF patients were planned to receive drugs for 60 weeks. After 32 weeks, the triple therapy group was stopped because an 11 percent increase in death was seen. This group also had a 29 percent increased risk of hospitalization and a 31 percent increase in serious adverse events. The group receiving placebo had a one percent increased risk of death, an eight percent increase in hospitalization and a nine percent increase in serious adverse events. The groups receiving n-acetylcysteine and placebo were not halted and results are due in 2014.

Because a clotting defect may be part of the IPF, a clinical trial comparing warfarin, an anti-clotting drug with placebo was done. Warfarin significantly increased the death rate to 28.1 percent, compared to a death rate of 6.2 percent in placebo patients and the study was stopped early.

The BUILD-3 trial tested the effect of a drug called bosentan (brand name Tracleer). Bosentan helps to combat the blood vessel constriction and fibrosis seen in IPF. The drug was given to 407 patients and placebo was given to 209 patients. Bosentan did not cause serious side effects in the patients, but it also did not show a difference from placebo or an improvement in IPF.

Ambrisentan (brand name Letairis) blocks a cell receptor that is active in blood vessel constriction. Blood vessel constriction in IPF means that less blood circulates through the lungs for oxygenation. A study using ambrisentan was stopped early when patients who received the drug were more likely to have worse disease (27.4 percent, compared to 17.2 percent in placebo) and be hospitalized due to lung problems (13.4 percent, compared to 5.5 percent in placebo).

Another drug that blocks fibrosis, macitentan (brand name Opsumit)), was tested in a clinical trial named MUSIC. Macitentan was given to 119 IPF patients and placebo was given to 59 patients. The drug did not cause serious side effects, but the drug did not cause any disease improvement during the 12 months.

In a small study, everolimus (brand name Zortress), a drug that suppresses the immune system and slows development of fibrosis, was given to 44 patients and placebo was given to 45 patients. The patients given everolimus had faster disease progression than those given placebo. The disease in everolimus patients got worse in an average of 180 days and the disease in patients given placebo got worse in 450 days.

Results from a small pilot study using an antibiotic mixture of trimethoprim/sulfamethoxazole suggested a small improvement in lung function so a larger study was conducted where trimethoprim/sulfamethoxazole was given to 92 IPF patients and 86 patients were given placebo. At the end of 12 months, no improvement in lung function was seen and almost one third of the patients dropped out of the study because of side effects of the drug that included rash and nausea.

Sildenafil (brand name Viagra) opens blood vessels and has the potential to improve blood flow through the lungs. A clinical trial of IPF patients was conducted and 89 people were given sildenafil and 91 were given placebo. The research team had hoped to see a 20 percent improvement in a six minute walk distance done at 12 weeks, but did not see this improvement in the patients given sildenafil. The patients given sildenafil did show a small increase in their breathing function and they reported better quality of life.

A study called TOMORROW tested the effect of nintedanib (brand name Vargatef) on IPF. Nintedanib blocks factors that contribute to fibrosis development and it has been theorized that it might slow the progress of IPF. In the TOMORROW clinical trial, four different doses of nintedanib or placebo were given to a total of 432 IPF patients. The group that received the highest dose of nintedanib, 150 mg twice a day, had a 68 percent decrease in rate of decline in a lung function test over a year compared to placebo. This difference was not quite statistically significant, but was also associated with patients’ report of a higher health-related quality of life.

The groups treated with nintedanib reported more side effects of nausea, vomiting and diarrhea than the placebo group and they also had a slight increase in liver function enzymes, indicating small effects of the drug on the liver. Two clinical trials testing 150 mg nintedanib twice daily are currently underway in studies with a total patient enrollment of 1066. The results of that trial are due in 2014.

Pirfenidone is a drug with anti-oxidant, anti-fibrotic and anti-inflammatory actions. It has been approved in Europe under the brand name Esbriet for treatment of IPF. In a Japanese study, patients given 1,200 mg/day had a significant difference in a lung function measurement compared to the placebo group and had a longer time without disease worsening.

In two other studies testing pirfenidone, one study where patients were given a dose of 2,403 mg/day reported a slowing of the decline in lung function by 72 weeks compared to patients who received placebo. This slowing of disease was not seen in the second study. These studies were stopped early due to side effects of nausea, vomiting, lack of appetite, skin rash, sun sensitivity and dizziness in the patients receiving pirfenidone.

When data from three clinical trials using pirfenidone were grouped together and analyzed, the data showed that treatment with pirfenidone reduced the risk of disease progression by 30 percent compared to placebo. A new clinical trial using pirfenidone, named ASCEND is underway and is due to report results in 2014.

Chronic cough is seen in 80 percent of patients with IPF. Thalidomide has anti-inflammatory properties that have been shown in clinical trials to reduce the cough in IPF patients. In a small study where 12 IPF patients were given thalidomide and 12 were given placebo, the patients who received thalidomide saw a significant improvement in cough and they reported better breathing-related quality of life.  Side effects occurred in 74 percent of the thalidomide group compared to 22 percent of the placebo group and included dizziness, constipation and generally feeling ill.

Treatment of people with IPF is based on guidelines developed from recommendations from scientific groups who evaluate current therapies. The authors of the review article report that, “Pharmacologic therapy for IPF was considered to be without any definite, evidence-based benefit, and lung transplantation was the only intervention strongly recommended given its proven survival benefit in IPF . In appropriate patients, enrolment in a clinical trial and/or lung transplantation was therefore recommended.” Dr. Smith’s team concluded that there is no evidence of any treatment that can stop IPF, but some therapies may be able to stabilize it or slow the rate at which it gets worse.

The approval of pirfenidone in Europe has been encouraging and results of three other important clinical trials separately testing the triple therapy of prednisolone, azathioprine and n-acetylcysteine; nintedanib and pirfenidone are due in 2014. Preliminary results with these drugs have shown potential for some of these agents to help slow the progression of IPF and give patients a better quality of life.

The authors did not disclose any conflicts of interest.

This review article was published in the December issue of Respiration.

Review Date: 
December 30, 2013
Last Updated:
December 31, 2013