Public Release: 

Breakthrough therapies treat Crohn's disease

Trials investigating pharmacologic agents, gut worms may benefit patients in need of new therapeutic options

American Gastroenterological Association

New Orleans, LA - Crohn's disease, which currently affects up to one million people in the U.S., causes inflammation in the lining of the small intestine that can lead to pain and discomfort. Though the condition usually occurs in the lower part of the small intestine, it can affect any part of the digestive tract. New studies presented today at Digestive Disease Week show the commitment of gastroenterology researchers to this population that is in need of new treatment options. Digestive Disease Week (DDW) is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.

"These studies present confirming evidence that we are getting closer to finding an absolute cause for Crohn's disease," said Jim Lewis, M.D., of the University of Pennsylvania. "We hope that until we can find a cure for Crohn's, these new options will improve the quality of life for sufferers."

All of the studies below analyzed patient response based on the Crohn's Disease Activity Index (CDAI), which measures the severity of a patient's disease.

A Phase III, Double-blind, Placebo-controlled Study of the Efficacy, Safety and Tolerability of AntegrenTM (natalizumab) in Maintaining Clinical Response and Remission in Crohn's Disease (ENACT-2) (Abstract 900030*)
AntegrenTM (natalizumab) has undergone a successful phase III induction of response/remission study (ENACT-1). In this multi-center, international trial, researchers conducted a randomized, controlled study (ENACT-2) to determine whether a six-month regimen of the drug could maintain the clinical response/remission achieved by the previous study.

ENACT-2 studied 339 adult subjects with Crohn's disease (CD) from ENACT-1 who had achieved a response on the drug (* 70-point reduction in CDAI) and/or remission (CDAI score of less than 150) and had a CDAI score of less than 220 after receiving three infusions of natalizumab. These patients were re-randomized to natalizumab (300 mg, 168 pts) or placebo (171 pts) for up to 12 additional monthly infusions. Researchers observed the proportion of subjects who maintained the response they had achieved in ENACT-1 for an additional six months, as well as remission rates.

At six months, 61 percent of natalizumab-treated subjects (103/168) continued to meet the criteria for clinical response versus 29 percent in the placebo group. Also, 44 percent of patients maintained clinical remission, compared with 26 percent on placebo. In addition, 55 percent (37/67) of natalizumab-treated patients who received steroids in ENACT-1 were re-randomized to natalizumab in ENACT-2 and were withdrawn from steroids. "We are pleased to report that natalizumab has demonstrated clinical superiority over placebo in sustaining response and remission over a six-month period," said Brian Feagan, M.D., lead author of the study. "These results are the next step to offering a novel treatment option for patients suffering from Crohn's disease."

A Randomized, Double-blind, Placebo-controlled Trial of the Human Anti-TNF-alpha Monoclonal Antibody Adalimumab for the Induction of Remission in Patients with Moderate to Severely Acute Crohn's Disease (Abstract 900085)
Adalimumab, a monoclonal antibody, is currently approved for the treatment of patients suffering from rheumatoid arthritis, which causes severe inflammation in the lining of the joints. As the mechanism of rheumatoid arthritis is similar to that of Crohn's disease, researchers evaluated the efficacy and tolerability of adalimumab for patients suffering from Crohn's.

Adalimumab is a fully human monoclonal antibody that targets tumor necrosis factor-alpha (TFN-*). A total of 299 patients without previous exposure to TNF-antagonists and with active Crohn's Disease were randomized to one of four treatments administered at week zero and week two (week 0/week 2): 160mg/80mg adalimumab, 80mg/40mg adalimumab, 40mg/20mg adalimumab, or placebo/placebo. Researchers observed for clinical remission (CDAI less than 150) and clinical response (CDAI decrease compared to baseline of *70 or *100) at week four in the two higher doses of adalimumab compared to placebo.

Adalimumab at doses of 80mg/40 mg and 160mg/80 mg was found safe and effective in the treatment of patients with moderate to severe Crohn's disease. Thirty percent of patients who received adalimumab 80mg/40mg or 160mg/80mg achieved clinical remission compared to 12 percent of the placebo group. The overall incidence of adverse events was low, with the most common event being mild injection site reactions.

"These results are unique, when compared to results seen with other anti-TFN biologic therapies," said Steven Hanauer, M.D., lead author of the study. "Further studies should demonstrate the benefit offered by this drug for the Crohn's patient population."

Trial of Helminth Ova in Active Crohn's Disease (Abstract 100712)
Crohn's disease (CD) appears to result from an inappropriate immune response to normal gut flora. Research has shown that CD is more prevalent in industrialized countries, where intestinal worms, or helminths, are rare. Helminths down-regulate immune responses, a property that could benefit CD. Researchers from the University of Iowa confirmed the benefit in a clinical trial to evaluate the efficacy and safety of the helminth T. suis as ova therapy in patients with CD.

The 24-week open label study enrolled 29 patients with a CDAI of 220-450. Most patients had long-standing disease (mean seven years) resistant to standard therapy before enrollment. The patients ingested 2500 T. suis ova every three weeks. At week 12, 75.9 percent (22 pts) showed clinical response, while 72.4 percent (21 pts) were in remission. The mean initial CDAI of responders was 286.3 +/- 10.7, and decreased to 96.2 +/- 10.8 at week 12 and 99.9 +/- 7.8 at week 24. The treatment caused no side effects or complications.

"We found that this unique therapy was well tolerated and produced a substantial improvement in CD patients," said Joel Weinstock, M.D., lead author of the study. "These results strengthen the notion that the de-worming of the population is related to the increased frequency of CD in industrialized countries. It now may be possible not only to safely treat, but also prevent inflammatory bowel disease by exposing children to natural biological agents lost from their environment."

Fontolizumab (HuZAFTM), a Humanized Anti-Interferon-Gamma Antibody, Has Clinical Activity and Excellent Tolerability in Moderate to Severe Crohn's Disease (Abstract 900139)
Until recently, there has not been a variety of therapeutic options for patients with Crohn's disease (CD), particularly with regard to tolerable side effects. A humanized antibody aimed at a novel target, interferon gamma, has shown excellent tolerability and activity in this patient population.

Researchers compared the results of one or two intravenous doses of fontolizumab in patients with moderate to severe CD. A total of 133 patients with CDAI scores between 250 and 450 were randomized to receive placebo, 4 mg/kg or 10 mg/kg of fontolizumab. The first 42 patients received a single treatment while the other 91 received two infusions.

Researchers observed the patients for clinical response (a decrease in CDAI score of greater than or equal to 100 points) or remission (CDAI score of less than or equal to 150), as well as the safety profile, and analyzed results for the patients who received two infusions of treatment until three months after the last dose of study drug. For patients receiving one or two doses, there was significant improvement in the rate of remission compared with placebo at day 28 for the 4mg/kg cohort. For patients receiving two doses, there was a significant increase in remission on day 42, response on day 56, and improvement in mean CDAI scores at days 28, 42, 56 and 84 for both active treatment groups. Additionally, concentrations of C reactive protein (CRP) decreased significantly compared to placebo on day 42 for the 4mg/kg cohort and on days 28, 42, 56 and 84 for the 10mg/kg cohort.

Fontolizumab was well tolerated, without infusion reactions or significant (grade three or four) adverse effects considered related to study treatment. In only 5.5% of patients were anti-fontolizumab antibodies detected; none were neutralizing and they were transient, of low magnitude and without clinical consequences.

"This compound demonstrated a significant beneficial effect on disease activity in patients who received two infusions of the treatment," said Daniel Hommes, M.D., the lead author of the study from the Amsterdam Medical Center. "But we were particularly pleased to see that the safety and tolerability profiles of fontolizumab were strong, and improved the value of this new investigational agent to suffering patients."

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Digestive Disease Week (DDW) is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. Jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and the Society for Surgery of the Alimentary Tract (SSAT), DDW takes place May 15-20, 2004 in New Orleans, Louisiana. The meeting showcases approximately 5,000 abstracts and hundreds of lectures on the latest advances in GI research, medicine and technology.

*Abstract numbers listed above correlate to abstract ID numbers listed on the DDW Web site, www.ddw.org.

They do not coincide with program numbers as found in the printed DDW Program Guide.

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