Biologic therapies for bowel disease show promise in clinical trials

05/11/05

CHICAGO, IL (May 16, 2005) – Research presented today at Digestive Disease Week® 2005 (DDW) highlights three promising biologic therapies that may provide new treatment options for millions of people suffering with inflammatory bowel diseases (IBD) worldwide. Clinical trial results show that AlequelTM, adalimumab (Humira®) and infliximab (Remicade®) are effective in decreasing the severity of IBD symptoms and increasing rates of clinical remission and response in patients. DDW is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.

IBD currently affects more than a million Americans and leads to many millions of dollars in lost productivity and missed days of work every year. IBD is an umbrella term referring to several chronic diseases that cause inflammation of the intestines, including ulcerative colitis and Crohn's disease. Symptoms for both conditions are very similar and it is often difficult for physicians to differentiate between the two. The most common symptoms of both ulcerative colitis and Crohn's disease are diarrhea, abdominal pain, fever, fatigue and weight loss.

"Crohn's and ulcerative colitis are serious and complex diseases with varied treatment options. Unfortunately, the available therapies are not effective in many patients.," said John Johanson, M.D., of the University of Illinois. "These findings deliver promising news for patients who do not respond to currently available therapies and is a much needed step in improving the lives of people suffering from IBD."

The studies below analyzed patient response based on the Inflammatory Bowel Disease Questionnaire (IBDQ), the Crohn's Disease Activity Index (CDAI), which measures the severity of a patient's disease and the Mayo score for ulcerative colitis.

A Double Blind Clinical Trial for Treatment of Crohn's Disease by Oral Administration of AlequelTM, A Mixture of Autologous Colon Extracted Proteins: A Patient-Tailored Approach (Abstract W1042)

The concept of personalized treatment options, such as gene therapy for cancer, has increasingly become a reality. This study from Hadassah Hebrew University Medical Center and Enzo Therapeutics applies that principle to gastroenterology and explores the safety and efficacy of a personalized treatment for Crohn's disease by oral administration of AlequelTM, a protein-containing extract manufactured from tissue removed from a patient's own colon.

Thirty-one patients with moderate to severe Crohn's disease were enrolled in the 27-week randomized, placebo-controlled, double blind trial and received either placebo or the study drug, which was prepared from extracted colon proteins. Trial participants were monitored for response based on the Crohn's Disease Activity Index (CDAI) and Inflammatory Bowel Disease Questionnaire (IBDQ).

Clinical remission rates observed during the trial were 58 percent for patients receiving Alequel, compared to 29 percent for patients on placebo. A clinical response was seen in 67 percent of the participants receiving the drug compared to 29 percent of those that took placebo. Of the patients taking Alequel, 43 percent experienced an improvement in their overall quality of life compared to 12 percent of the placebo patients.

Three biomarkers were identified that may be used to generate an immune profile to predict clinical response to the treatment. These biomarkers, an antigen-specific T cell immune response, C reactive protein (CRP) levels and peripheral blood T cell subpopulations, may also be applicable as surrogate markers for the clinical effect of the drug.

"The notion of personalized therapy is an exciting new model for treating patients and is especially applicable in Crohn's disease, where a misfiring of the body's immune system is believed to be related to the inflammation observed with this condition," said Dean Engelhardt, Ph.D., study investigator from Enzo Therapeutics. "The results shown with Alequel tell us that we may now have a well-tolerated, personalized treatment alternative for patients with active Crohn's disease. Based on the promising nature of these results, larger confirmatory trials are being pursued."

Induction Maintenance of Clinical Remission and Response in Subjects with Crohn's Disease Treated During a Six-Month, Open-Label Period with Fully Human Anti-TFN-Alpha Monoclonal Antibody Adalimumab (Humira®) -- (Abstract 723)

In a study presented today, researchers from the Mayo Clinic assessed the long-term efficacy and safety of adalimumab in an open-label study of patients with active Crohn's disease. Results show that adalimumab's efficacy increased over time, while maintaining a strong safety profile. Adalimumab, which is currently approved to treat rheumatoid arthritis, has also shown positive results for Crohn's disease in previous clinical trials.

Study findings show that the rate of clinical remission increased from 5.5 percent at baseline to 33.2 percent after six months of treatment and the rate of clinical response improved from 40.5 percent at baseline to 78.2 percent after six months of therapy. Adverse events were mild to moderate in severity. Overall, a progressive increase in clinical response and clinical remission was seen in patients receiving adalimumab, as one-third of study participants were in clinical remission at the end of six months.

Adalimumab is a fully human monoclonal antibody that targets tumor necrosis factor-alpha (TFN-a), a protein produced by the body's immune system that is thought to contribute to the inflammation in Crohn's disease and ulcerative colitis. A total of 220 patients participated in the study, receiving 40mg of adalimumab every other week for one year. This study only includes data from the first six months of the study. Trial participants were assessed for clinical remission (defined as a CDAI<150) and clinical response (defined as a decrease in CDAI score, as compared to baseline, of =70 or =100) and received an increased dosage if they experienced flare ups or were not responsive to the treatment.

"The results from this trial illustrate the importance of follow-on studies to clarify long-term effects of potential new therapies," said William Sandborn, M.D., of the Mayo Clinic and lead investigator of the study. "The positive results found in this study reinforce previous adalimumab findings and are highly encouraging because they bring one step closer to identifying a new treatment option for people with Crohn's disease."

A Randomized Placebo-Controlled Trial of Infliximab Therapy for Active Ulcerative Colitis: ACT 1 Trial (Abstract 689) and Infliximab Induction and Maintenance Therapy for Ulcerative Colitis: the ACT 2 Trial (Abstract 688)

Results presented today from the ACT I and ACT II Trials show infliximab may be a promising treatment for active ulcerative colitis. Treatment options are limited for people with ulcerative colitis, a disease that causes inflammation and ulcers in the superficial layers of the large intestine. The standard first- and second-line therapies, 5-ASA agents and corticosteroids, are not effective in all patients and are often associated with severe side effects. While the use of anti-tumor necrosis factor (TNF) agents like infliximab have recently shown promise in Crohn's disease and rheumatoid arthritis, its use for ulcerative colitis has been less defined. Anti-TNF agents work by blocking the action of the reaction that causes abnormal joint inflammation.

Results from these two phase three, randomized, placebo-controlled studies show that infliximab appears effective in reducing signs and symptoms of the disease, inducing remission, attaining mucosal healing and allowing for reduced corticosteroid therapy, while maintaining remission. In the ACT I trial, 38.8 percent of the patients taking 5mg/kg and 32.0 percent of patients taking 10mg/kg of infliximab, respectively, were in clinical remission at week eight compared to 14.9 percent of those on placebo. In the ACT II trial, 33.9 percent of the patients taking 5mg/kg and 27.5 percent of patients taking 10mg/kg of infliximab, respectively, were in clinical remission at week eight compared to 5.7 percent of those receiving placebo. Infliximab was generally well tolerated with a safety profile similar to that previously reported.

In both studies, 364 patients suffering from active ulcerative colitis were randomized to receive infliximab at 5mg/kg and 10 mg/kg or placebo at weeks zero, two and six, then every eight weeks for 46 weeks (ACT I) or 22 weeks (ACT II). Patients in both studies were assessed for clinical response (defined as a decrease in Mayo score of =30 and =3 points, accompanied by a rectal bleeding score of 0 or 1 at week eight), clinical remission (defined as a Mayo score of =2, with no individual sub-scores >1) and mucosal healing (defined as an Endoscopy sub-score of 0 or 1).

"Given that anti-TNF agents like infliximab appear to be effective in treating Crohn's disease, it made sense to explore its use in ulcerative colitis as well," said Dr. William Sandborn of the Mayo Clinic and lead investigator of the ACT II trial. "I am pleased to say that the ACT I and ACT II results suggest that infliximab is an effective and well-tolerated treatment for ulcerative colitis. This is very encouraging news for a patient population that has few treatment options."

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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