Idiopathic Pulmonary Fibrosis: Hope, At Last

There have been stunning “firsts” in research on idiopathic pulmonary fibrosis (IPF), a mysterious disease that stiffens and stills the lungs, killing half its victims in three years.

In May, results of Phase 3 clinical trials on the first two effective drugs for IPF were published in the New England Journal of Medicine (NEJM).

And in June, the first paper explaining IPF in any kind of depth was published in Science Translational Medicine. The paper identified IPF’s relationship to a potent protein evolutionarily conserved for eons, from bacteria to man, atherosclerosis to IPF. The work behind the paper was so compelling the National Institutes of Health (NIH) last month awarded the authors a grant to start developing a drug neutralizing the protein. An antibody has already been chosen.

“Exciting,” Harvard University pulmonologist Gary Hunninghake told Bioscience Technology by email, of the Science pre-clinical work. He was uninvolved with the studies. “Very exciting indeed,” echoed Jack Elias, co-senior author of the Science paper, in a Bioscience interview. The IPF-associated protein that Elias’s team found—CHI3L1—“has been retained over species and time…We knew Mother Nature doesn’t do this unless it is very important.” When his team looked into it, they found CHI3L1 helps “stop cell death, while stimulating fibrosis and repair. It is a primordial, and fundamental, defense mechanism.”

Hunninghake wrote in the NEJM a revolution may be afoot. The new IPF drug trial results alone are “a major breakthrough….We may soon have choices in the medical management of pulmonary fibrosis.” It is even “reasonable to shift our understanding of the pathogenesis of this disease. It is now clear that (IPF) is a disease perpetuated by aberrant wound healing, rather than primarily by chronic inflammation.”

Agreed Elias: “The paradigm now, I think, is that there is an injury response and an overwhelming repair response; disorganized injury and over-exuberant repair.”

Wrote Hunninghake: “The force is finally with us.”

The IPF Mystery

IPF has long been a death sentence—a mysterious one. The disease prompts severe fibrotic lung scarring, rendering its victims less and less able to breathe over a frighteningly short period of time. At least 80,000 Americans have it. Half die in three years; 70 percent die in five. The cause has been elusive. There was “a debate between the inflammation people, and the disordered repair people,” Elias noted. But there has been no understanding, and no effective drugs.

Then, this summer: a comparative bonanza. In May, the results of three trials were published in NEJM showing that two anti-fibrotic drugs slowed scar formation. In two INPULSIS Phase III, randomized, double-blind, placebo-controlled trials, nintedanib was shown to prompt significant reductions in decline of forced vital capacity (FVC) in IPF patients at one year. (FVC is the maximum air a person can expel from the lungs after maximum inhalation.) This was the primary endpoint of the two studies. There was no improvement in respiratory symptoms. But while the trials were not designed to look for statistically significant differences in mortality, nintedanib did produce a reduced rate of death paralleling the reduced decline in lung function.

Also published in May: results of the ASCEND trial—or the fourth in a series of randomized, placebo-controlled, Phase III trials looking at pirfenidone in IPF patients. The first three trial results were inconclusive. This led to approval internationally, but not by the US Food and Drug Administration (FDA). But in this trial, the drug did meet the primary endpoint. It showed significant reductions in rate of FVC decline after one year. There was also a reduced decline in distance on a six-minute walk test.

And in a review of mortality combining the above results with those from earlier trials (CAPACITY), there was indication that pirfenidone may also reduce mortality.

On Medscape, pulmonologist Andy Schorr warned nintedanib came with a high dropout rate, apparently due to side effects. He also noted it appeared to fail to improve quality of life. “Distinction without a difference?” he asked. Regarding ASCEND, he questioned the way its results were pooled with CAPACITY for the mortality conclusions. He also took note of perfenidone tolerability issues.

Yet even Schorr said the three trials represented “exciting work that should be taken seriously.”

Said Elias: “I’ve been in the fibrosis game for a decade. To finally have something that works even a little bit for patients is wonderful.”

The First Compelling Clues?

But, as Elias added, the drugs are “no magic bullet. Even with perfenidone, the clinical experience is not a cure. It’s better than nothing, but people still progress, and still die.” 

Elias’ paper offering at least a partial answer to the mystery—and a promising new drug target--began as an asthma study in his lab at Yale, long before he moved to Brown to become dean of Medicine and Biological Sciences last year. “Ten to 15 years ago we developed an asthma model where we took a molecule called IL13 and expressed it in a mouse lung,” he said. “In those mice we found to our surprise: fibrosis. That led to a whole series of studies in our lab and others that nailed down IL13 as a very important mediator of tissue fibrosis.”

Many fields were interested, from liver to lung. Elias’ crew evaluated which genes in the fibrotic mice “were remarkably altered in expression. Two of the top ten were of the very poorly understood glycoside hydrolase family 18. When we looked, we found they had been evolutionarily retained over species and time.” As this meant they served a key function, “we focused on one of the molecules: CHI3L1. We knocked it out, overexpressed it, and developed techniques to look at its expression in human biopsies and serum.” They found it unbiquitous in injury. “When injured, you respond by trying to shut off the injury—and at the same time, to heal it. CHI3L1 does both. It stops cell death, while stimulating fibrosis and repair. If I cut myself shaving tomorrow, it will kick in. The pathway is remarkably regulate-able--and remarkably abnormal in diseases including atherosclerosis, obesity, asthma—and IPF.”

Via further experiments, Elias’ team found IPF is, in part, caused by fibrotic healing run amuck, trying to keep up with IPF’s ceaseless lung injury.  Why is it ceaseless? “The injury process is still enigmatic.” But it is real. Doctors find, in autopsy, IPF patients’ lungs possess old scarring over old injuries—and fresh scarring over new ones.

Elias, and the team of Yale Translational Lung Research Director Erica Herzog, are further investigating IPF mechanisms. They are also screening for drugs. They have identified an antibody they will turn into a drug via the above (CADET) grant for lung drug design.

“We are very excited about this whole area. We plan to stay in it for a while.”