Antibiotic Add-On Active in Crohn's Disease
More evidence for a mycobacterial origin
Charles Bankhead,October 31, 2019
SAN ANTONIO -- Treatment with an oral antibiotic combination led to clinically and significantly meaningful improvement in clinical response and remission in patients with active Crohn's disease, a randomized placebo-controlled trial showed.
Patients treated with antibiotics targeting Mycobacterium avium paratuberculosis (MAP) had significantly higher rates of clinical remission and response at 26 weeks. Improvement occurred more often in patients taking concomitant anti-tumor necrosis factor (TNF) or immunosuppressive therapy.
A small subgroup analysis suggested the combination of rifabutin, clarithromycin, and clofazimine led to endoscopic healing, David Y. Graham, MD, of Baylor College of Medicine in Houston, reported here at the American College of Gastroenterology meeting.
"Antimicrobial therapy with RHB-104 demonstrated meaningful improvement in the efficacy and biomarkers of active inflammation and endoscopic recovery in patients with active Crohn's disease," said Graham. "The onset of symptomatic improvement was rapid and was seen by at least week 4. Clinical remission occurred as early as week 16 and was sustained through week 52. There was a trend toward corticosteroid-free remission at week 52."
"These data provide further evidence suggesting a role for Mycobacterium avium paratuberculosis, or a similar organism, in the pathogenesis of Crohn's disease," he added. "Remission data and safety data suggest this potentially may be a use of adjuvant therapy to other medications to enhance the response to medical therapy."
In the discussion that followed the presentation, an audience member inquired about
the frequency of bacterial infection in Crohn's disease and the potential role of antibiotic therapy in treatment.
"This is either an additional therapy, or it's the beginning of a paradigm shift," Graham responded. "I see this as we're standing at the same place we were standing with Helicobacter 30 years ago, when the question was, have we found something that if we eradicate, would it change the natural history of the disease and cure it. This is going in that direction, but it certainly hasn't gotten there at this point."
Infectious Link?
In response to a question about
the causative role of MAP in Crohn's disease and specificity of the antibiotic combination, Graham pointed out that a "tremendous number of other studies" of antibiotics for inflammatory bowel disease failed to demonstrate a clinically meaningful effect. The study is hypothesis generating, he added, and suggests "this is a potential cause and this is a potential treatment."
The bottom line is whether the treatment had an effect on the disease. "The answer unquestionably was yes. It's very positive data to pursue the hypothesis, but the answer is yet to come."
The association between Crohn's disease and infection with MAP dates back to the 1930s. MAP can be cultured from peripheral blood mononuclear cells of patients with Crohn's disease more often than in healthy controls, said Graham. The observations led to the hypothesis that treatment of Crohn's disease with anti-MAP therapy would support a causative role for MAP in Crohn's.
The hypothesis led to a global multicenter, randomized trial to evaluate the efficacy of RHB-104 in patients with moderately or severely active Crohn's disease. Eligibility criteria included diagnosed disease of the ileum and/or colon at least 6 months prior to randomization; active Crohn's disease confirmed by abnormal endoscopy, abnormal imaging, C-reactive protein level ≥1.0 mg/dL, or fecal calprotectin level ≥162.9 µg/g stool; and a Crohn's Disease Activity Index (CDAI) score of 220-450.
Eligible patients were already being treated with one or more medications for Crohn's disease: 5-ASA, corticosteroids, azathioprine, 6-mercaptopurine, methotrexate, infliximab (Remicade), or adalimumab (Humira).
The trial had a primary endpoint of clinical remission (CDAI <150) at week 26. Key secondary endpoints included clinical response (100-point decrease in CDAI) at week 26, clinical remission at weeks 16 and 52, durable remission, and corticosteroid-free remission.
Key Findings
Data analysis included 331 randomized patients who had a mean age of 39, and men accounted for 57% of the study population. Two thirds of the patients had the ileum as the primary disease site, and the time since diagnosis of Crohn's disease averaged 10.6 years. The mean baseline CDAI score was 296, and laboratory values included mean CRP of 1.36 mg/dL and calprotectin of 668 µg/g of stool. about
half the patients were on corticosteroids and immunosuppressives, and a fifth were being treated with TNF inhibitors.
After 26 weeks of treatment, 36.7% of patients in the RHB-104 group had attained clinical remission as compared with 23.0% of the placebo group (P=0.007), and 44.0% versus 30.9% had clinical response (P=0.916). Additionally, 42.2% of the RHB-104 group achieved early remission (week 16) versus 29.1% of the placebo group (P=0.015).
Patients on concomitant anti-TNF therapy tended toward a greater absolute benefit (26-week remission rate of 35.5% vs 18.8%, P=0.08), but a significantly greater proportion of patients not treated with TNF inhibitors met the primary endpoint (37% vs 24.8%, P=0.03). Patients in the RHB-104 arm had significantly greater improvement in the abdominal pain and loose bowel movement components of the CDAI at weeks 16 and 20 and at week 24.
In a subgroup of 35 patients assessed endoscopically at 26 weeks, 35.7% of the RHB-104 group had at least 25% improvement in the Simple Endoscopic Score versus 9.5% for the placebo group (P=0.048), and 50% improvement was seen in 28.6% versus 4.8% of patients (P=0.11).
Significantly more patients in the RHB-104 group attained remission plus at least a 50% decrease in fecal calprotectin or CRP at weeks 16 (25.9% vs 9.7%, P=0.0002), 26 (21.1% vs 9.1%, P=0.003), and 52 (16.9% vs 7.9%, P=0.02). The proportion of patients with a calprotectin level ≥162.9 µg/g, decreased significantly through 52 weeks in the RHB-104 group as compared with the placebo group.
Durable remissions occurred significantly more often with RHB-104, including only visits at weeks 16 and 52 (25.3% vs 12.4%, P=0.003) and all visits from week 16 through week 52 (18.7% vs 8.5%, P=0.008).
In general, the type and frequency of adverse events were similar, Graham reported.
The study was supported by RedHill Biopharma.
Graham and several coinvestigators disclosed relationships with RedHill Biopharma, including employment.
Primary Source
American College of Gastroenterology
Source Reference: Graham DY, et al "RHB-104, a fixed-dose, oral antibiotic combination against Mycobacterium avium paratuberculosis (MAP) infection, is effective in moderately to severely active Crohn's disease" ACG 2019; Abstract 58.
https://www.medpagetoday.com/meetingcoverage/acg/83055