Taking an approach with a long and checkered history, a new drug seems to alleviate the symptoms of Crohn’s disease, a condition that can devastate the intestines, according to clinical trial results released today. The drug, constructed with building blocks like those of RNA and DNA, is the subject of a bold bet by the biotechnology company Celgene, which last year paid $710 million to secure rights to it. Still, there are lingering questions about how successfully the drug beats back the inflammatory illness, and researchers are now looking to launch a much larger clinical trial to address them.
Crohn’s disease is marked by inflammation in the gut, especially in the large and small intestines. Many treatments attempt to modulate or suppress the immune system, but they don’t always work and can have serious side effects. Almost 10 years ago, a team led by gastroenterologist Giovanni Monteleone of the University of Rome Tor Vergata proposed another approach. In many people with Crohn’s disease and its cousin, ulcerative colitis, a protein called SMAD7 is overproduced in the inflamed gut. This SMAD7 in turn suppresses the activity of a protein called TGF-β, which regulates how immune cells function and keeps intact the barrier between the intestines and the rest of the body. Monteleone’s team hypothesized that if they could blunt the gene for SMAD7, then they would keep TGF-β functioning normally and control gut inflammation. And to thwart the gene, they aimed to tie up the RNA it makes, thus inhibiting the production of SMAD7.
Targeting the RNA that produce proteins is a strategy called antisense, and it’s one that has generated tremendous excitement over the years—and precious few approved treatments. Although the approach sounds great in theory, it’s been marred by side effects and also by challenges in targeting the right tissues. There is only a tiny handful on the U.S. market: Most recently, an antisense drug was approved in 2013 for a genetic disease that causes extremely high cholesterol. Nevertheless, in 2006 Monteleone and his team showed that the antisense approach to tamping down SMAD7 seemed to ease inflammation of the large intestine in mice.
Now, Monteleone and colleagues have shown that their SMAD7-blocking drug, known as mongersen, also appears to work in humans. For the so-called phase II clinical trial, the researchers recruited 166 patients with Crohn’s and divided them into four roughly equal groups. One received a placebo, and the rest got different doses of the drug. The researchers defined success based on symptoms and reported that in the two high-dose groups, 55% and 65% of patients reached clinical remission after 2 weeks of treatment and remained in remission for 2 weeks afterward. In a very small group of patients followed over time, remissions were more likely to persist in those who had a high drug dose than in those who had a placebo—six of nine patients, versus one of nine. Side effects were generally mild, the team wrote online today in The New England Journal of Medicine.
Monteleone hopes the promising results will pan out in a larger study and wonders if this trial will open up a new way of thinking about Crohn’s. Normally, scientists imagine that “the tissue damage was due to excess immune response against bacteria” in the gut, he says. But the new results suggest there’s also a problem with what he calls “counter-regulation,” in which the normal anti-inflammatory gears grind away in the cell.
The drug “looks promising,” says Charles Elson, a mucosal immunologist and gastroenterologist at the University of Alabama, Birmingham, who was not involved in the work. He notes, however, that antisense therapy has been “promising for 20 years.” And as often happens, the result “raises more questions than it answers,” he says.
In particular, it's not clear that how people reported feeling matches up with what’s happening inside their intestines—for example, whether ulcers were healing—Elson says. One particular puzzle is that blood levels of C-reactive protein, which often tracks with inflammation, didn’t reliably drift downward in patients who reported feeling better. Monteleone agrees that focusing on a patient’s symptoms isn’t enough: He wants to take biopsies of affected tissue to “understand what is going on” after treatment.