Treatment of Crohn’s Disease using Anti-MAP (AMAT) Therapy
What is Atypical Mycobacteria Antibiotic Therapy (AMAT)?
For Crohn’s disease patients who have tested positive for human paratuberculosis, Atypical Mycobacteria Antibiotic Therapy (AMAT) may be beneficial. This therapy combines antibiotics that specifically target human paratuberculosis (MAP). It is sometimes sustained for years in an attempt to eradicate the pathogen and avoid bacterial resistance. Different combinations of antibiotics in differing strengths and duration have been tested, with generally positive results. Some of these antibiotics include clarithromycin, Rifabutin, rifampin, clofazimine, Ciprofloxacin, metronidazole and levofloxacin. For a meta-analysis of the published AMAT studies, see Primary treatment of Crohn’s disease: combined antibiotics taking center stage. The below table summarizes the results of the AMAT studies detailed in this analysis.
Comparing remission rates for AMAT therapy to the Anti-TNF medications, which are currently the costly gold standard of care for Crohn’s disease patients around the world, yields surprising results. The below chart shows the results of the 2007 Selby study, the only large, randomized AMAT study, along with the data for the major Humira and Remicade studies. While the Selby study concluded that AMAT showed no benefit over a placebo, the results were flawed due to sub-optimal doses of antibiotics and capsules that failed to rupture. In fact, when the results were viewed in an intention-to-treat (ITT) analysis, the remission rates for AMAT were significatly better than those of the Anti-TNF therapies.
An ITT analysis includes every subject who is randomized according to randomized treatment assignment. It ignores non-compliance, protocol deviations, withdrawal, and anything that happens after randomization. ITT analysis avoids over optimistic estimates of the efficacy of a treatment resulting from the removal of non-compliers by accepting that non-compliance and protocol deviations are likely to occur in actual clinical practice. For example, in the Accent I trial which looked at the effectiveness of Remicade, there were initially 573 people who were given the first dose of Remicade. However, only the 335 people who responded favorably to that initial dose after two weeks continued in the study. An ITT analysis would include all 573, randomly assigned to three groups for a total of 191 in each arm. Looking at the results for the highest dosage arm, a total of 50 people were in remission at 30 weeks, so the final remission rate was 26% (50/191) using an ITT analysis. In the end, even a sub-par dose of AMAT was more effective than the highest doses of the Anti-TNF medications.
Bear in mind, the remission rates in these abstracts will be different than the remission rates in the table above due to an alternate analysis. Additionally, drug trials are not generally compared side by side. One of the commonly prescribed AMAT drugs, clofazimine, is no longer available in some Western countries, including the United States. This medication is primarily used to treat leprosy, uncommon in developed countries. While not banned, supply was discontinued due to non-use.
One small study with 10 pediatric patients (age 8 to 17) from 2013 reported an 80% remission rate when treatment with RHB-104 was given for at least 6 months. AMAT was particularly effective in patients who had not previously taken immunosuppressive medications. A new study presented at the 2016 American College of Gastroenterology Meeting reported that 8 patients who were given AMAT as a first-line therapy achieved remission and experienced histological deep mucosal healing.
On July 26, 2016, the United States Food and Drug Administration (FDA) issued a warning regarding the use of antibiotics in the fluoroquinolone class. These include levofloxacin (Levaquin) and ciprofloxacin (Cipro) which are occasionally used in AMAT protocols. The FDA warns that fluroquinolones are associated with disabling side effects involving tendons, muscles, joints, nerves and the central nervous system. These side effects can occur hours to weeks after exposure to fluoroquinolones and may potentially be permanent. Therefore, the FDA has determined that fluoroquinolones should be reserved for use in patients with serious conditions who have no alternative treatment options. Due to this warning, mindful consideration should be given when including fluoroquinolones in any AMAT protocol. For more information, please see the full FDA News Release and Dr. William Chamberlin’s recent article on this topic.
From patients who have provided this information publicly, the most commonly used daily AMAT protocol utilizing clofazimine is: 1000 mg. of clarithromycin, 600 mg. of Rifabutin, 2 mg. per kg. of clofazimine. These doses are split in half and taken throughout the day. Some doctors prefer to ramp up this therapy to minimize initial side effects, starting with lower doses and gradually increasing the strength to the full dose over time. See below for more details on the RedHill Biopharma trial utilizing a version of this protocol. In countries where clofazimine is not available or must be obtained with governmental application, a commonly used daily protocol is: 1000 mg. of clarithromycin, 600 mg. of rifampin, 500 mg. of levofloxacin.
Dr. Thomas Borody, who runs the Centre for Digestive Diseases in Sydney, Australia has achieved an 85% remission rate (the highest in the world) prescribing antibiotic therapy for Crohn’s disease. The article Medical Pioneer from Down Under leads the World in Crohn’s Treatment by Warren Perley describes his approach and why this therapy has had continued success. See this site for a compilation of Anti-MAP resources, and The Crohn’s Disease Initiative, which has a broader focus of studying the etiology of Crohn’s disease rather than the symptoms.
Large Scale Clinical Trial Underway
RedHill Biopharma is conducting a large scale, Phase III clinical trial in multiple locations in the United States and Canada to test the effectiveness of triple antibiotic in Crohn’s disease. RHB-104 is a proprietary and potentially groundbreaking antibiotic combination therapy, in oral capsule formulation, with potential intracellular, antimycobacertial and anti-inflammatory properties. Developed by Dr. Thomas Borody, it’s based on increasing evidence supporting the hypothesis that Crohn’s disease is caused by a human MAP infection in certain susceptible patients. Symposium presenter, Patrick McLean, is the Product Manager at RedHill Biopharma. The study end date is projected to be April, 2018, with interim results to be released in August, 2017, which will hopefully shed some light on the questions surrounding the use of Anti-MAP therapy.
To learn more about the RHB-104 study or to find a RedHill trial site, please see ClinicalTrials.gov. Per the ClinicalTrials.gov site, the RedHill Biopharma medication RHB-104 contains clofazimine, Rifabutin and clarithromycin. RedHill gradually increases the dosage, with each capsule containing 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine. Eventually, the patient will take 5 capsules, twice a day for a total dosage of 950 mg. of clarithromycin, 450 mg. of rifabutin, and 100 mg. of clofazimine.
Why isn’t this treatment widely available?
Currently, AMAT is not an FDA approved treatment pathway for use in Crohn’s disease. While each individual antibiotic utilized in AMAT is approved by the FDA, they are approved for conditions other than Crohn’s disease. Their use in Crohn’s disease, or other MAP driven conditions, is therefore considered “off-label.” A medication is used “off-label” when the use is not specified on the FDA approved package label. Per the FDA regulations, doctors are allowed to prescribe a medication for an “off-label” usage “when they judge that it is medically appropriate for their patient.” For patients who have tried all available approved treatments with no benefit, doctors are allowed to consider using off-label medications. The combination of Cipro (ciprofloxacin) and Flagyl (metronidazole) is commonly prescribed off-label in Crohn’s disease for abcesses and fistulas.
Despite years of published studies, most doctors are reluctant or unwilling to treat Crohn’s disease with the AMAT protocol. One reason may be that although these individual studies give a large amount of data regarding the AMAT protocol, there is no consensus as to which combination, strength or duration of antibiotics, is most effective. Additional reasons may be:
- Funding to do the studies and research necessary has been lacking.
- Difficulty in the accurate detection of human paratuberculosis (MAP) and underestimation of the sophistication of mycobacterial disease is another treatment barrier.
- Doctors may not want to treat patients without laboratory confirmation of the bacteria.
- Potential liability of prescribing a therapy that is not an officially approved treatment pathway for Crohn’s disease.
Some well meaning, but busy gastroenterologists may find it impossible to keep up on all of the latest research, and are unaware of AMAT and it’s success. In any given year, there are about 3,000 research articles published in the field of Inflammatory Bowel Disease. This does not include the cross-field articles discussing IBD concerns related to microbiology, immunology, genetics, veterinary medicine and epidemiology; all of which have significance to the field of gastroenterology. It’s impossible to keep up on them all, so reading may be directed by opinion leaders, who may have leanings toward the political arena rather than those who understand the science best. At the end of the day, it’s hard to accept any new idea as truth.
“All truth passes through three stages. First, it is ridiculed. Second, it is violently opposed. Third, it is accepted as self-evident.”
Human Paratuberculosis Foundation is striving to achieve healing and a cure for human MAP related diseases, including Crohn’s disease. We eagerly await future research studies that examine the benefit of AMAT in Crohn’s disease and search for alternative Anti-MAP therapeutic options.