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Trial implicates MAP as treatable cause of Crohn’s disease


Treatment with an oral antibiotic targeting Mycobacterium avium paratuberculosis (MAP) led to significant improvement in patients with Crohn’s disease

The drug, a fixed-dose combination of clarithromycin, rifabutin and clofazimine (RHB-104, RedHill Biopharma) is yet to be approved for Crohn’s. However, the findings strengthen the case that MAP infection may be the cause of at least some cases of the disease.

Infection with MAP has been a suspected, if controversial, cause of Crohn’s since the disease was first described in 1932, said David Y. Graham, MD, a professor of gastroenterology at Baylor College of Medicine, in Houston.

“This triple antimicrobial therapy, RHB-104, is a promising new approach to the treatment of Crohn’s disease, and these data provide further evidence suggesting a role for MAP or a similar organism in the pathogenesis of Crohn’s disease,” Dr. Graham said.

The trial, called MAP US, randomly assigned 331 patients with active Crohn’s to receive RHB-104 or a placebo. Patients recruited for the trial remained on their baseline treatments, including biologics, throughout the study.

The primary end point was clinical remission, defined as a score on the Crohn’s Disease Activity Index (CDAI) of less than 150 at week 26. Patients were followed to week 52. The data were presented at the 2019 annual meeting of the American College of Gastroenterology (abstract 58).

At 26 weeks, the rate of clinical remission was 36.7% and 23% for patients receiving RHB-104 and placebo, respectively (P=0.007). Clinical response at week 26, defined as a decrease in the CDAI score of at least 100 points, was achieved in 44% and 30.9% of patients in each group, respectively (P=0.017).

Other outcomes also supported a therapeutic effect of the combination antibiotic. For example, more patients in the RHB-104 group achieved remission by 16 weeks (42.2% vs. 29.1%; P=0.015), according to the researchers. The share of patients in durable remission, defined as that across all visits from week 16 through 52, also was significantly higher in the group receiving the antibiotic (18.7% vs. 8.5%; P=0.008), they reported.

The greater rate of remission with RHB-104 was similar among the 67 patients who took TNF-alpha inhibitors during the trial (35.5% vs. 16.7%; P=0.08) when compared with the 264 who did not (37% vs. 24.8%; P=0.03).

In the trial, 35 patients underwent endoscopic evaluation at 26 weeks. In this relatively small group, the proportion who achieved a 50% or greater improvement in the Simple Endoscopic Score for Crohn’s Disease (SES-CD) was greater on RHB-104 than on placebo (28.6% vs. 4.8%; P=0.11) but fell short of statistical significance. The proportion did reach significance when response was defined as a SES-CD25, signifying a 25% reduction in surface involvement.

The combination antibiotic significantly outperformed placebo in relative reductions in fecal calprotectin and C-reactive protein, according to Dr. Graham. The relative reductions in these biomarkers of inflammatory activity consistently favored RHB-104 over time. For fecal calprotectin, the relative reduction was 16.2% (P=0.0002) at 16 weeks and 9% (P=0.02) at 52 weeks.

The antibiotic was not associated with an increased risk for adverse events, although Dr. Graham’s team did observe an increase in QT intervals beginning at week 4 of the trial, which is consistent with earlier reports of the effects of the clarithromycin and clofazimine components of RHB-104. The electrocardiogram changes were not associated with any clinical consequences in this trial, he added.

Dr. Graham stressed that the study does not prove MAP causes Crohn’s, but it does strengthen the hypothesis that bacterial infection is at least a contributing factor to the activity of the disease. The specific antibiotics in this combination might be critical, he added.

“There has been a tremendous number of studies with antibiotics but they have not produced the same type of response,” Dr. Graham said. The key question was, “Do you have an effect on the disease [with this combination], and the answer was unquestionably yes.”

David T. Rubin, MD, the section chief of Gastroenterology, Hepatology and Nutrition at the University of Chicago, called the data potentially “important,” but he emphasized that “we must adhere to Koch’s postulates” before drawing conclusions about the role of specific bacteria as causative agents in Crohn’s disease.

These postulates include proving the presence of the bacterium in every case of the disease and reproducing the disease when a culture of the bacteria is inoculated in a healthy host. No data of this kind—or even findings demonstrating MAP infection among enrolled patients—were presented, Dr. Rubin said.

Previous studies found MAP to be more common in patients with Crohn’s disease, but this bacterium is also cultured from healthy hosts, Dr. Graham said. He agreed that more work is needed to prove the hypothesis that MAP or another bacterium is the causative agent in Crohn’s.

 

Read Trial implicates MAP as treatable cause of Crohn’s disease by Ted Bosworth.

Posted on: March 13 2020

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