Fall 2005

Crohn's and Colitis Center Physicians Pioneer New Treatment for Crohn's Disease

Physicians in the Massachusetts General Hospital Crohn's and Colitis Center are pioneering an innovative approach to the treatment of Crohn's disease. Crohn's disease has been seen as a T-cell-driven process, and treatment has been targeted to suppressing the immune response and to relieve inflammation. New research suggests that a deficiency of the innate intestinal immune system, leading in turn to a secondary T-cell response, may contribute to the development of Crohn's disease, and that stimulation of the innate immune system has significant benefits for some patients.

Center co-director Joshua R. Korzenik, MD, was lead investigator for a multi-center, randomized, placebo-controlled study of 124 patients with moderate-to-severe Crohn's disease who were treated with sargramostim, or granulocytemacrophage colony-stimulating factor (GM-CSF). (Sargramostim for Active Crohn's Disease, New England Journal of Medicine, May 26, 2005.) GM-CSF is used to to treat chemotherapy related neutropenia.

Patients in the study received by daily self-injection 65g per kilogram of GM-CSF for a period of 6 weeks. At the end of the study period, responses were assessed using the Crohn's Disease Activity Index (CDAI), IBDQ scores, and endoscopic scores where available. Forty-eight percent of patients in the sargramostim group achieved reductions of 100 points or greater in the CDAI, as compared with 26 percent in the placebo group, and 40 percent of the sargramostim group went into remission, as compared with 19 percent in the placebo group. Typical duration of response was 8 to 10 weeks. The most common side effects were injection site reactions and bone pain. Both were generally mild and transient.

These results are quite promising, and physicians in the Crohn's and Colitis Center are currently investigating whether responders can be successfully re-treated. Patients with mild-to-severe Crohn's disease who are not responding to conventional treatment may be suitable candidates for this protocol. Enrolled patients will receive 8 weeks of open-label treatment. Responders will be followed, and if and when their disease flares, they will be eligible for re-treatment. At that point they will be randomized to receive either a placebo or active treatment for another 8 weeks. Following the re-treatment phase, patients will be eligible for a full year of open-label treatment.

The recently-published findings, as well as the current clinical trial, developed out of research Dr. Korzenik and his colleague Brian Dieckgraefe, MD, PhD, began in 1998. They studied 35 patients with glycogen storage disease type 1b, a rare immunodeficiency disease. Surprisingly, 10 of them had Crohn's disease, (many more had some evidence of chronic intestinal problems but had not been sufficiently investigated to diagnose Crohn's disease) - a counterintuitive finding in a population with a known immune deficiency. Drs. Korzenik and Dieckgraefe postulated that the T-cell activity seen in Crohn's is in fact the end of a cascade that begins with a deficiency of the innate intestinal immune system. Consequently, they designed and conducted studies to investigate the safety and efficacy of GM-CSF treatment for Crohn's disease.

Their hypothesis was bolstered by the identification in 2001 of a mutation in the CARD15/NOD2 gene, which is associated with a defect in the innate immune system and which occurs twice as frequently in Crohn's patients as in the general population.

Dr. Korzenik concludes, "This novel approach is based on a new insight into the development of Crohn's disease and represents an exciting opportunity for innovative treatment. The next steps will include bench research to better understand the mechanisms by which GM-CSF works, and continuing clinical development of optimum therapeutic strategy, and validation of our initial findings in larger, broader trials."

Crohn's and Colitis Center Clinical Trials

1. A six-week randomized, double-blind, controlled trial of high dose Asacol (6.0 g/day) versus low dose Asacol (2.4 or 3.6 g/day) for the treatment of mild to moderate Crohn's Disease.



2. A randomized, double-blind, placebo-controlled (sham-controlled) study to evaluate the safety and effectiveness of the Adacolumn Apheresis System for the treatment of moderate to severe Ulcerative Colitis.



3. A Phase III randomized, double-blind, placebo-controlled multicenter retreatment study of Sargramostim (Leukine) in patients with active Crohn's Disease and prior treatment responses to Sargramostim.



4. Open label trial of Leukine (Sargramostim), a recombinant Human Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), in active Crohn's Disease.



5. Prospective registry in IBD study at Massachusetts General Hospital (PRISM).



6. Double-blind, randomized, parallel arm, dose ranging study of IMURAN in subjects with active Crohn's Disease requiring treatment with Prednisone: A Crohns Disease Optimal Range Dose of IMURAN Study (ACORDIS).



7. A randomized, controlled trial of Rosiglitazone for Ulcerative Colitis.



8. A Phase I, multicenter, randomized, placebo-controlled, blinded study of Rituximab in subjects with active Ulcerative Colitis.



9. Probiotics and Intestinal Disease: The effect of Probiotics on fecal flora and symptoms of patients with Crohn's Disease.



10. A study of pouch outcomes among patients who have undergone Restorative Proctocolectomy with Ileal Pouch Anal Anastomosis.



11. Prospective development and evaluation of a Biomarker Index for monitoring Crohn's Disease clinical activity.



12. A prospective, randomized, double-blinded, placebo (Sham) controlled study to evaluate the safety and efectiveness of the Adacolumn Apheresis System for the treatment of moderate to severe Crohn's Disease.



13. A randomized, double-blind, placebo-controlled clinical study of the Oral IL-12/23 Inhibitor, STA-5326 Mesylate for the induction of clinical response in patients with Crohn's Disease.