An experimental drug for Crohn’s disease is showing encouraging results in an early trial, sending many patients into remission and keeping them there for 12 weeks or more. The compound, called mongersen, is a pill that shuts down inflammation in the gut.
Crohn’s is an inflammatory bowel disease that causes pain, severe diarrhea and fatigue and can lead to weight loss, malnutrition and ulceration of the intestines. Roughly 565,000 people in the United States have the condition, which has an unknown cause and no cure.
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Mongersen works by indirectly inhibiting inflammation caused by the immune protein TNF-alpha, researchers report in the March 19 New England Journal of Medicine. Some approved Crohn’s drugs such as adalimumab (Humira) and infliximab (Remicade) block TNF-alpha directly by binding to it. But many patients fail to achieve or maintain remission on these drugs. Mongersen works differently, starting a domino effect by inhibiting production of a compound called Smad7. That restores the activity of an immune-calming protein called transforming growth factor beta 1. The wide-ranging effects of this protein include suppressing TNF-alpha.
This chain reaction, by restoring a “physiologic mechanism of immunosuppression,” might give the experimental drug an advantage over those directly binding to TNF-alpha, says study coauthor Giovanni Monteleone, a gastroenterologist at the University of Rome Tor Vergata in Italy.
Monteleone and colleagues in 17 centers in Italy and Germany gave 160 Crohn’s patients a placebo or a small, medium or large dose of mongersen daily for two weeks. Two weeks after stopping these randomly assigned treatments, 22 of 40 patients who got the medium dose were in remission, as were 28 of 43 assigned the high dose. In contrast, only a handful of people getting the low-dose pills were in remission; the same was true for those getting the placebo.
Twelve weeks after the study onset, improvement remained steady in the medium- and high-dose groups, with roughly two-thirds of those patients in remission. In an earlier safety trial, some patients who got the higher doses remained in remission for at least six months, Monteleone says.
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These heady findings come with caveats. Mongersen pills are coated to delay their release until they reach the ileum — the end section of the small intestine — or the adjacent start of the large intestine, commonly called the right colon. Accordingly, the researchers excluded people from the study if they had Crohn’s disease afflicting other parts of the digestive tract such as the stomach, upper small intestine or the transverse and left colon.
Even so, the drug may have broad applicability among Crohn’s patients, says Monteleone. He notes that most Crohn’s lesions are found in the region that was afflicting patients in the study; less than 10 percent of Crohn’s patients have inflammatory ulcers in the upper areas of the digestive tract. Earlier research also suggested that mongersen could address Crohn’s inflammation in parts of the colon farther downstream, Monteleone says. The researchers are planning a clinical trial that will include such patients.
Another caveat concerns the patient pool used in the study. Patients were recruited for it using a composite scoring system based on abdominal pain severity and frequency, number of loose stools daily, detection of an abdominal mass and other symptoms. But although these patients were sick, a better test is a colonoscopy, in which a physician can use a scope to verify ulcers or other damage, writes Séverine Vermeire, a gastroenterologist at University Hospitals Leuven in Belgium in the New England Journal. A previous Crohn’s trial had found that more than one in six patients deemed to have Crohn’s disease based on the scoring system turned out not to have it when undergoing colonoscopy. As a result, Vermeire says, it is unclear how many people in this trial might not have had Crohn’s lesions.
Nevertheless, Vermeire calls the results “unprecedented” among Crohn’s drugs, noting that months of protection after a 14-day treatment contrasts with the recurrence of symptoms often seen after the withdrawal of other drugs. “The impressive clinical effects of mongersen beg for follow-up studies to confirm that we have indeed entered a new phase of Crohn’s disease treatment,” she writes.