Phase II Data for Celgene’s Investigational Oral GED-0301 for Patients with Active Crohn’s Disease Published in New England Journal of Medicine
“GED-0301 offers a unique approach to treating Crohn’s, using antisense technology to target a key intracellular signaling protein thought to be involved in intestinal inflammation and the pathogenesis of the disease,” said Professor Giovanni Monteleone, University of Rome Tor Vergata. “This orally administered therapy is designed to act locally with its novel mechanism of action. The results from the phase II trial suggest that GED-0301 should be studied further in phase III trials for Crohn’s disease.”
This phase II trial enrolled 166 adult patients with moderate-to-severe Crohn’s disease, defined as Crohn’s Disease Activity Index (CDAI) ranging from 220 to 400 at least one week prior to enrollment, with documented inflammatory lesions in the terminal ileum and/or right colon.
The newly published findings from this phase II study showed that a significantly greater proportion of patients with active Crohn’s disease achieved the primary endpoint of clinical remission at both day 15 and day 28 with once daily GED-0301 40 mg (55 percent) or 160 mg (65 percent) than with GED-0301 10 mg (12 percent) or placebo (10 percent; P<0.001). Additionally, 67 (6/9 patients) percent of patients reached glucocorticoid-free remission at day 84 with 160 mg GED-0301 once daily, versus 11 (1/9 patients) percent with placebo (P=0.04).
For patients treated with GED-0301 160 mg once daily, 67 percent, 72 percent and 67 percent were in clinical remission (had a CDAI score less than 150) on day 15, day 28 and day 84, respectively, compared with 21 percent, 14 percent and 21 percent on placebo (P<0.0001 vs. placebo, for each time point). Similar results were seen in the GED-0301 40 mg once daily group (58 percent, 70 percent and 63 percent, respectively). For patients treated with GED-0301 10 mg once daily, clinical remission was achieved by 15 percent, 29 percent and 29 percent on day 15, day 28 and day 84, respectively (P=n.s. vs. placebo).
On day 28, 37 percent, 58 percent and 72 percent of patients treated with once daily GED-0301 10 mg, 40 mg or 160 mg once daily, respectively, achieved a clinical response (a 100-point reduction in CDAI score; a secondary endpoint), compared with 17 percent with placebo (P=0.04, P<0.001 and P<0.001, respectively).
The rates of patients with at least one adverse event (AE) in the GED-0301 groups were 49 percent, 62 percent and 49 percent for 10 mg, 40 mg and 160 mg once daily, respectively, compared with 67 percent for the placebo group. The most commonly reported AEs in the GED-0301 treatment groups were abdominal pain (10-12 percent), Crohn’s disease worsening (10-15 percent), urinary tract infection (5-15 percent) and C-reactive protein increase (5-9 percent). The rates of serious adverse events in the GED-0301 dose groups were 7 percent, 2 percent and 2 percent for 10 mg, 40 mg and 160 mg once daily, respectively, compared with 2 percent for the placebo group.
“A significant number of Crohn’s disease patients don’t reach remission with current therapies and are looking for additional options,” said Scott Smith, President of Celgene Inflammation and Immunology. “GED-0301 offers a completely different mechanism of action that has the potential to transform the Crohn’s treatment landscape. We are encouraged by the phase II data and are committed to bringing innovative medicine to patients with Crohn’s disease, starting with advancing the phase III trial for GED-0301.”
About the Study
This phase II trial enrolled 166 adult patients with moderate-to-severe Crohn’s disease with documented inflammatory lesions in the terminal ileum and/or right colon. Patients with known lesions in the stomach, proximal small intestine, transverse colon, and/or left colon, strictures, fistulae, perianal disease, extraintestinal manifestations, active or recent infections or a history of malignancy were excluded.
Patients were randomly assigned to receive treatment for two weeks with one of three daily doses of GED-0301 (10 mg, 40 mg or 160 mg tablets, once daily) or placebo and then evaluated for responses at days 15, 28 and 84. The primary efficacy endpoint of the study was the percentage of patients with clinical remission, defined as a CDAI score below 150 at day 15, which was maintained at day 28. The secondary endpoints included clinical response defined as a reduction of CDAI score of 100 points or 70 points at day 15 and day 28.
Patients could continue receiving stable doses of oral prednisolone (≤40 mg/day), budesonide (≤9 mg/day), or mesalamine during the 2-week treatment and/or a stable dose of immunomodulators (e.g., azathioprine, mercaptopurine, methotrexate) if therapy was initiated ≥6 months before treatment. Antibiotics, steroids, immunosuppressive drugs and biologics could not be initiated prior to study entry and during the 2-week treatment. Patients received no treatment with anti-TNF-α antibodies or other biologics within 90 days, or antibiotics within 3 weeks of the date of their initiation into the trial.
The investigational oral antisense therapy GED-0301 is an oligonucleotide that targets the messenger RNA (mRNA) for Smad7, thereby reducing Smad7 protein levels. In patients with Crohn’s disease, abnormally high levels of Smad7 interfere with TGF-β1 anti-inflammatory pathways in the gut, leading to increased inflammation. GED-0301 is designed to act locally to reduce Smad7 levels with negligible systemic exposure.
About Crohn’s Disease
Crohn’s disease is an immune-mediated, chronic inflammatory condition of the gastrointestinal tract. Estimated to affect as many as three out of every 1,000 people in Europe and North America, the disease is becoming more common for all ethnic groups. Symptoms of Crohn’s disease — including abdominal pain, diarrhea, fatigue, fever, weight loss and malnutrition — most commonly begin to appear between the ages of 13 and 30, although the disease can strike at any age. The disease may affect any part of the GI tract, from the mouth to the anus, but most commonly affects the end of the small bowel (the ileum) and the beginning of the colon. The exact cause of Crohn’s disease is unknown, and there is no cure. People with Crohn’s disease have a slightly reduced life expectancy.
Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global pharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through gene and protein regulation. For more information, please visitwww.celgene.com. Follow Celgene on Twitter @Celgene, and on Pinterest and LinkedIn.
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