The US Food and Drug Administration has approved only two agents for idiopathic pulmonary fibrosis (IPF)— nintedanib and pirfenidone. Both are effective, but both carry adverse events that discourage some patients from even attempting therapy.
“The data are pretty compelling that most patients should at least have a trial of antifibrotic therapy,” said Mary E. Strek, MD, FCCP, a professor of medicine and director of the pulmonary medicine service at the University of Chicago. “There are clear benefits in the slowing of progression, and the separation of the progression curves starts very early.”
The two agents also show clear benefits in time to the first acute exacerbation. That is a particularly important point, Dr. Strek said, because acute exacerbations in IPF can be fatal. And at least one trial, INJOURNEY, shows benefit from combination therapy vs nintedanib alone.
The two agents also have potentially difficult side effects. Nintedanib is associated with diarrhea, elevated liver function tests, bleeding, and cardiovascular events. Pirfenidone adverse effects include GI intolerance, elevated LFTs, rash, and agranulocytosis.
These effects can be managed in most patients, Dr. Strek said, and dose interruption or reduction may help.
But if a patient develops agranulocytosis, pirfenidone should be stopped immediately, she added.
Gastroesophageal reflux disease, GERD, is another problem in IPF.
“GERD happens to all of us, more so in IPF,” said Mary Beth Scholand, MD, FCCP, associate professor of internal medicine at the University of Utah. “Up to 90% of IPF patients have GERD. And GERD may play a role in progression from micro aspiration.”
Antacid therapy works, she added, and some trials have shown a survival advantage and reductions in exacerbations with antacid use.
Trials with Nissen fundoplication, a surgical treatment for GERD, show promising results for IPF patients, but the numbers are small, Dr. Scholand cautioned. Current European guidelines for IPF recommend symptomatic treatment of GERD rather than all comers.
Lung transplantation remains the only option for patients who fail treatment. Both bilateral and single lung transplants can be effective, noted Hilary Robbins, MD, assistant professor of clinical medicine at New York Presbyterian Hospital.
“We refer thousands of IPF patients for lung transplantation, but we can only do a few hundred lungs ever year,” she said. “And patients with IPF have the highest risk of death on the waiting list.”
That raises a conundrum. Bilateral transplants provide better survival than single-lobe grafts, at least on unadjusted analysis, but IPF patients waiting for bilateral transplants have a higher risk of death while waitlisted than single-lung candidates.
The hope is for development and approval of new therapeutic agents that may lessen the need for transplantation. Multiple phase 1, 2, and 3 clinical trials are under way.
“Most emerging therapies target specific steps in the pathogenesis of IPF,” said Nina Patel, MD, FCCP, an associate professor of medicine and clinical director of the ILD program at Columbia University Medical Center.
IPF begins with injury to alveolar epithelial cells (AECs) from the environment, genetics, intrinsic factors, epigenetic changes, aging and other causes, she continued.
The next step is abnormal wound healing response and the initiation of fibrosis, which transitions into unimpeded fibrosis.
Agents in development target different pathways in the evolution of IPF. Some aim to reduce the burden of injury to AECs while others attempt to modulate the AEC response to injury or TGF-beta activation, both crucial steps in initiating the fibrotic process. Other candidates target fibroblast, myofibroblast activities and pathways mediating fibrosis.
There are also programs under way in stem cell therapy as well as to improve palliative care and management of symptoms such as cough.
“We only have two FDA-approved therapies now,” Dr. Patel said. “If we repeat this talk in 10 years, I would hope we have a lot more to work with.”