Carrie Bergmans and Peter Higgins, M.D., Ph.D., investigated three aspects of IBD treatment.
Ongoing trials test immune suppression drugs for IBD
issue 17 | fall/winter 2012
It's not unusual for patients diagnosed with Crohn's disease and ulcerative colitis to get little benefit from current medical therapies. Most of the current therapies only work in slightly more than half of patients. The University of Michigan Inflammatory Bowel Disease Center is participating in clinical trials to find new ways to halt the inflammatory response that contributes to 1.4 million Americans suffering from Crohn's and UC.
"The good news is that many of the medications being tested in current clinical trials are either already on the market or known to control an inflammatory response," says Carrie Bergmans, senior clinical research coordinator in U-M's Division of Gastroenterology.
"Medications used for rheumatoid arthritis and psoriasis are now being investigated for IBD. The link between all of these diseases is an overactive autoimmune system," she says.
NEW PATHWAYS FOR RELIEF
Patients who are not responsive to current medications may benefit from a new direction in IBD treatment. The study of ustekinumab in Crohn's disease examines the safety and effectiveness of Stelara (ustekinumab), a drug from the family of immune suppression drugs with a target that is different from most current therapies.
Most existing biologics for IBD work by blocking an inflammation-causing protein called tumor necrosis factor (TNF). Stelara, marketed to treat psoriasis, blocks interleukin-12 and interleukin-23, two other immune-system proteins linked to inflammation. Interleukin-23 is an immune-system signaling molecule that is overactive in those with Crohn's disease.
The UNITI study is enrolling patients with moderate to severe Crohn's disease who have failed conventional therapy. Patients will be assigned to three treatment groups, with two-thirds receiving active drug and one-third receiving placebo. If they complete the initial eight-week phase, they will be eligible to enter a maintenance phase, and people who benefit from ustekinumab can continue to receive the drug for free for up to three years.
While many medications studied for IBD are readily available, the use of immune–suppressive drugs originally designed for other conditions is not one-size-fits-all.
"The dosing for IBD is often much higher," says U-M gastroenterologist Peter Higgins, M.D., Ph.D., a principal investigator of dozens of IBD-related clinical trials at the University of Michigan Health System. "And the kind of doses needed to be effective are often only available through clinical trials."
RAISING THE STAKES FOR BLOCKING INFLAMMATION
Researchers worldwide are enrolling patients in the OCTAVE Trials, which are studying the benefit of tofacitinib for the treatment of ulcerative colitis. U-M is currently enrolling patients with UC.
Drugs are not universally effective in treating UC, a chronic inflammatory disease of the colon. A recent report in the New England Journal of Medicine illustrated the potential for tofacitinib in successfully controlling the inflammatory response in rheumatoid arthritis. Tofacitinib was actually a bit better than Humira (adalimumab) for patients with rheumatoid arthritis.
''The link between all of these diseases is an overactive autoimmune system.''
In the Phase II studies, tofacitinib produced an 80 percent clinical response rate. Tofacitinib, an oral medication, is now being tested in a Phase III clinical trial at the University of Michigan and is part of the trend of finding new therapeutic targets. Tofacitinib suppresses the Janus kinase (JAK) enzyme, another known trigger of inflammation, and may be especially helpful for patients who did not benefit from anti-TNF therapy.
A SAFE BREAK FROM MEDICATION
Eventually, most IBD patients find a medicine that helps them achieve remission, but an estimated 50 percent of patients stop taking their medicines within two years of achieving remission, which doctors consider a bad idea, because this can eventually result in severe flares of IBD. Even if patients are not experiencing symptoms, management of IBD is considered a lifelong effort to keep the immune system under control.
However, recent studies have suggested that the return of inflammation can be detected with stool tests before symptoms occur. This might allow patients to stop their medications, and with careful monitoring, identify the return of inflammation and re-start therapy before symptoms start. The Calprotection-Directed Humira Therapy study (CADHUM) will look at whether patients in remission can safely stop taking adalimumab (Humira) with close monitoring and re-dosing if inflammation returns.
"The key is consistent monitoring," says Higgins. "Patients get into trouble when they stop taking medications and also stop seeing their physician."
Those enrolled in the trial will have periodic lab tests –taking blood and stool samples – to identify biomarkers of inflammation. Higgins says inflammation can be identified three to six months before patients experience symptoms of pain, diarrhea and tiredness. If and when lab tests show elevated biologic markers, Humira therapy will resume.