SAN ANTONIO – A proprietary oral fixed-dose, triple-antibiotic combination pill offers a promising new approach to the treatment of Crohn’s disease, , declared at the annual meeting of the American College of Gastroenterology.
In the phase 3 MAP US trial, patients with Crohn’s disease who were randomized to the fixed-dose combination of 45 mg rifabutin, 95 mg clarithromycin, and 10 mg clofazimine, known for now as RHB-104, experienced significantly higher rates of clinical remission and improvement in inflammation as assessed endoscopically and via biomarkers, compared with placebo-treated controls, reported Dr. Graham, professor of medicine at Baylor College of Medicine, Houston.
RHB-104 is effective against Mycobacterium avium paratuberculosis (MAP) – and therein hangs a tale.
“MAP has been considered as a possible cause of Crohn’s disease since the disease was described by Crohn in 1932,” the gastroenterologist noted. “These randomized trial data provide further evidence suggesting an important role for MAP or similar microorganisms in the pathogenesis of Crohn’s disease.”
For Dr. Graham, this is a case of deja vu all over again. More than a quarter century ago he was lead author of a highly influential randomized, controlled trial which established that treatment with antibiotics directed against Helicobacter pylori cured peptic ulcer disease. As such, he became internationally recognized as a key figure in the resultant revolution in peptic ulcer treatment. He hears an echo of that earlier transformative change in the MAP US results.
“This is either an additional therapy or it’s the beginning of a paradigm shift. I mean, I see this as we’re standing at the same place now as we were standing with Helicobacter pylori 30 years ago, when the question was: Have we found something that we can eradicate and change the natural history of the disease and cure it? You can say this [MAP-directed therapy] is going in that direction, but it certainly hasn’t gotten to the point of proof yet. The results have to be reproduced,” he said.
The MAP US trial included 331 patients with moderate to severely active Crohn’s disease at 92 sites who had failed to achieve an adequate response with conventional therapies. Participants were randomized double blind to twice-daily RHB-104 or placebo for 52 weeks. Those not in remission at 26 weeks could opt for open-label RHB-104. Background concomitant treatment with corticosteroids, tumor necrosis factor inhibitors, and immunosuppressives was permitted.
The primary outcome was clinical remission as defined by a Crohn’s Disease Activity Index (CDAI) score below 150 at week 26. This was achieved in 36.7% of the active treatment group and 23% of controls, a highly significant difference. The clinical remission rates at week 16 were 42.2% and 29.1%, respectively. At week 26, 44% of RHB-104-treated patients had achieved at least a 100-point reduction in CDAI score, compared with baseline, as did 30.9% of controls. The key symptom score provided by the sum of the abdominal pain and bowel movement components of the CDAI was significantly lower in the RHB-104 group than in controls from week 16 on.
The remission rate at week 26 in the group on RHB-104 was similarly favorable regardless of whether or not they were on anti–tumor necrosis factor therapy.
“This suggests that RHB-104 can be used effectively and safely as an adjunct treatment to other medications to enhance the response to medical therapy,” according to Dr. Graham, who was principal investigator for MAP US.
The composite endpoint of clinical remission plus at least a 50% reduction from baseline in fecal calprotectin or C-reactive protein was achieved in 21.1% of the RHB-104 group and 9.1% of controls at week 26, and by 16.9% on RHB-104 and 7.9% on placebo at week 52.
In the 35 patients who underwent endoscopy at week 26, a 50% or greater reduction in the Simple Endoscopic Score in Crohn’s Disease was documented in 28.6% of patients on RHB-104 versus 4.8% of controls.
Durable remission, defined as a CDAI score below 150 at all study visits from week 16 to week 52, was achieved in 18.7% of the RHB-104 group, compared with 8.5% of controls.
The side effect profiles of RHB-104 and placebo were similar, with no serious adverse events recorded in the 52-week study. An increase in the QT interval on ECG was noted in the RHB-104 group from week 4 on, but it wasn’t associated with any clinical findings. Further study of this ECG finding is underway.
Several audience members rose to urge caution in interpreting the MAP US data.
“We must adhere to Koch’s postulates before we make conclusions about causative agents of an infectious disease, and I didn’t see those data here. So I look forward to a future presentation that shares that,” one gastroenterologist commented.
“I haven’t seen any data here that shows Mycobacterium was present in these patients,” noted another.
Dr. Graham replied that MAP US was a hypothesis-driven clinical trial: Crohn’s disease has much in common with an inflammatory bowel disease occurring in ruminant animals, where RHB-104 has shown treatment efficacy.
“This is a Mycobacterium avium organism, so it’s not something you’re going to cure in 2 weeks or 2 months. But the question is, do you have an effect on the disease, and the answer in MAP US was unquestionably yes. It’s very positive data to further pursue the hypothesis, but the study doesn’t provide a definitive answer,” he said.
Dr. Graham reported serving as a consultant to RedHill Biopharma, the study sponsor.