Idiopathic pulmonary fibrosis (IPF) is without doubt a devastating disease. Imre Noth, MD, professor of medicine and director of the interstitial lung disease program at the University of Chicago, once described it for a Chicago Tribune reporter this way: “Imagine the lungs are two balloons,” he said, “and they’re shriveling. They get rumply and cobble-stony and eventually they look like solid cement bricks. You can imagine it’s a lot harder to breathe as your lungs turn into bricks. In its advanced stages, IPF makes simple movements—walking, sitting up, lying down—feel like wind sprints, or like drowning.”
“If you can’t breathe,” he added, “nothing else matters.”
For a long time, Noth has begun his research publications on a somber note. The first sentence or two sets a tone.
- Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease of unknown cause characterized by the histopathologic pattern of usual interstitial pneumonia. The median survival of patients with IPF after the onset of symptoms is 2 to 5 years.
- Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease that affects over 128,000 people in the U.S., has a yearly mortality of 48,000, and has no effective treatment.
- Idiopathic pulmonary fibrosis (IPF) has a low incidence, but is a devastating disease of unknown aetiology that is characterized by an interstitial fibrotic process and high mortality.
His most recent study, published online September 2, 2015, by the American Journal of Respiratory and Critical Care Medicine, seems, at first, to follow this dour pattern. “Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease,” it begins, “with high mortality and no known cure.”
But the paper provides some rare good news, the first evidence of a beneficial drug-gene interaction. For about 25 percent of IPF patients, those with two copies of a particular variation in a gene called TOLLIP, there is an inexpensive, readily available therapy called N-acetyl cysteine that significantly—in this small sample—reduced the risk of hospitalization and death.
But there’s a downside. For 75 percent of patients, those without the lucky variation, NAC makes the disease worse.
“This needs to be confirmed,” Noth insisted. “It may not sound like a big step, at first, but in IPF, it’s a foot in the door. I’m hugely excited. If this gets replicated, it is a poster child for what we now call precision medicine. It involves a simple genetic test and, for one out of four people, it points to an available, inexpensive beneficial drug.”
In late 2014, the Food and Drug Administration approved the first two drugs for treatment of IPF, perfenidone and nintedanib. They make a difference, but have only a “limited effect,” Noth said. They slow the rate of decline in lung function by as much as 40 to 50 percent, but they come with multiple side effects, including nausea and vomiting, diarrhea, fatigue and headaches.
Plus, one year’s supply of either drug costs more than $90,000. A year’s supply of the anti-oxidant N-acetyl cysteine (NAC), on the other hand, is available over the counter for about $30 a month, or $360 for a year, significantly less than one percent the cost of the prescription drugs. In the right patients, this pill, taken twice a day, is about six times as effective at preventing adverse events.
When he presented the data at a conference, the first question from the audience was “How can I get my patients tested?” Noth is working with his laboratory colleagues to establish a federally certified program.
For Noth and colleagues, the road to their discovery was long. They began by searching for genes that could be involved in IPF. A genome-wide association study of more than 1,500 patients, published in 2013, revealed 20 genetic loci that may be associated with this disease. A more focused investigation showed that four of these play a crucial role. One of those four was the variant in TOLLIP.
A clinical trial known as PANTHER, testing the effects of NAC on IPF, almost threw the search off course. The study suggested that NAC had no real impact. Patients taking the medication did no better or worse, on average, than those taking a placebo.
But Noth and colleagues gave the results a second look. They re-analyzed the trial data after segregating the participants based on their gene tests. Again, this tiny variation in TOLLIP stood out. Patients who had two copies of the gene with one particular variation—about 1 out of 4—did much better on NAC than those taking the placebo. NAC had little impact on patients with one copy of each version. Patients with two copies of the other variation did potentially worse.
To confirm this result, Noth’s team analyzed genetic test results from about 90 University of Chicago IPF patients who had participated in another trial, INSPIRE. They found nearly identical results.
The study has several limitations, Noth admits. It was a small sample, examined in retrospect. Patients were not randomized by genotype.
On the other hand, they were able to replicate the finding in another group of patients. The biology made sense. The TOLLIP protein is involved in regulating inflammation and plays a role in protecting the lungs and airway. And the benefit associated with NAC therapy for those with the preferred genotype was “qualitatively similar across both cohorts.”
The nature of the analysis, however, means there is still work to be done. “What we have so far is persuasive, and appealing, but not yet absolutely convincing,” Noth said. He and collaborators are organizing a larger, randomized, multi-center prospective trial in which 500 IPF patients will be stratified according to their genetic risks and carefully monitored.
“Right now I’m feeling pretty good about it,” he said, “good enough that I’m focused on how to organize the next trial ethically. Is it permissible to expose patients with what appears to be a risk-associated genotype to NAC? We think we know how to do this.”
“If this study confirms our initial finding,” he added, “it could be the most important thing I’ve ever done.”
He’s received encouragement from the arbiters of scientific progress. The American Journal of Respiratory and Critical Care Medicine quickly accepted the current paper.
Noth and co-author Justin Oldham, MD, a critical care fellow at the University of Chicago, originally submitted the study to the New England Journal of Medicine. “They took it seriously,” Noth said. “The reviewers went through it carefully.” Ultimately they turned it down, “but it was the nicest rejection from NEJM that I have ever seen,” he said. “They want first look at our paper on the next trial.”