Date: 2015-05-19
Type of information: Presentation of results at a congress
phase: 2
Announcement: presentation of results at Digestive Disease Week (DDW) in Washington, D.C.
Company: Celgene (USA - NJ)
Product: GED-0301 (mongersen)
Action
mechanism: antisense drug/oligonucleotide. Mongersen (GED-0301) is an antisense 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. The distinct formulation of the tablet is designed to release GED-0301 into the far end of the small intestine (the terminal ileum) and near the end of the colon (right colon), where it is thought to act locally to reduce Smad7 levels.
Disease: Crohn\'s disease
Therapeutic area: Autoimmune diseases - Inflammatory diseases - Digestive diseases
Country:
Trial
details: 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.
Latest
news: * On May 19, 2015, Celgene announced that a post-hoc subgroup analysis of a double-blind, placebo-controlled, randomized, multicenter phase II trial of GED-0301 (mongersen) in patients with active Crohn's disease was presented at Digestive Disease Week (DDW) in Washington, D.C. The primary findings of the phase II trial, which enrolled 166 adult patients with active Crohn's disease, defined as Crohn's Disease Activity Index (CDAI) scores > 220 to ≤400, were published in the March 19, 2015 issue of The New England Journal of Medicine (see below). Patients in the trial were treated for two weeks with either placebo or one of three doses of GED-0301 (10 mg, 40 mg or 160 mg tablets, once daily) and then followed for an additional 10 weeks. The presentation at DDW retrospectively examined certain subgroups of patients in the trial. In the subgroup analysis, patients were grouped by disease duration ( < 5 years vs. ≥5 years), baseline CDAI score ( < 260 vs. ≥260) and baseline levels of the C-reactive protein (CRP) inflammatory marker ( < 3 mg/L vs. ≥3 mg/L). Patients in these subgroups were then analyzed for clinical remission (a CDAI score < 150) and clinical response (CDAI score reduction ≥100 points from baseline) at weeks 2 and 4. Clinical remission rates for patients treated with GED-0301 160 mg were similar regardless of disease duration or baseline CDAI or CRP levels and were higher than those for patients on placebo (remission rates ranged from 62.5 percent to 75 percent for GED-0301 160 mg vs. 5 percent to 24 percent for placebo). These findings provide a rationale for continued evaluation of the 160 mg dose in the phase III program. For patients with a disease duration of at least five years (mean of 15.4 years), 62.5 percent (15/24) of those treated with GED-0301 160 mg were in clinical remission at week 2, compared with 15.4 percent (4/26) of those treated with placebo. Similar results were observed at week 4 (66.7 percent [16/24] vs. 15.4 percent [4/26], respectively). Clinical response rate was 70.8 percent (17/24) with GED-0301 160 mg, compared with 19.2 percent (5/26) with placebo, at week 2 and 79.2 percent (19/24) versus 26.9 percent (7/26), respectively, at week 4. For patients with baseline CDAI of at least 260 (median of 303), 62.5 percent (10/16) of those treated with GED-0301 160 mg were in clinical remission at week 2, compared with 13.6 percent (3/22) for placebo and 75.0 percent (12/16) versus 4.5 percent (1/22), respectively, at week 4. Clinical response rate was 87.5 percent (14/16) with GED-0301 160 mg versus 22.7 percent (5/22) for placebo at week 2 and 87.5 percent (14/16) versus 22.7 percent (5/22), respectively, at week 4. Similar results were observed for patients with baseline CRP of at least 3 mg/L (about 60 percent of patients in the trial). At week 2, 71.4 percent (20/28) of patients in the GED-0301 160 mg group achieved clinical remission compared with 24.0 percent (6/25) in the placebo group. At week 4, similar results were observed (75.0 percent [21/28] vs. 12.0 percent [3/25]). In the GED-0301 160 mg group, 60.7 percent (17/28) and 64.3 percent (18/28) had a clinical response at weeks 2 and 4, respectively, compared with 32.0 percent (8/25) and 24.0 percent (6/25) in the placebo group. The rates of patients with at least one adverse event (AE) were 49 percent, 62 percent and 49 percent for the GED-0301 10 mg, 40 mg and 160 mg doses, respectively, and 67 percent for placebo. 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 CRP increase (5-9 percent). The rates of serious AEs in the GED-0301 groups were 7 percent, 2 percent and 2 percent for 10 mg, 40 mg and 160 mg dose, respectively, compared with 2 percent for placebo. 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. * On October 20, 2014, Celgene announced that results from a double-blind, placebo-controlled, multicenter phase II trial of GED-0301 in 166 patients with active Crohn\'s disease will be presented at the United European Gastroenterology Week in Vienna, Austria. The abstract titled, MONGERSEN, AN ORAL SMAD7 ANTISENSE OLIGONUCLEOTIDE, IN ACTIVE CROHN\'S DISEASE, can be viewed here. In the Phase II trial, patients were randomised to mongersen 10, 40 or 160 mg/day or placebo for two weeks and the primary outcomes were clinical remission (maintained for two weeks) and safety.Clinical remission was achieved by significantly greater proportions of patients receiving mongersen 40 (55.0%) and 160 mg/day (65.1%) compared with placebo (9.5%), while no notable difference was seen for 10 mg/day. The rate of response was significantly greater among patients receiving 10 (36.6%), 40 (57.5%) or 160 mg/day (72.1%) of mongersen vs placebo (16.7%). Phase III trials are set to start by the end of the year.
"The analysis presented at DDW suggests that patients with more severe Crohn's disease or a longer duration of disease were able to achieve clinical response or clinical remission with the 160 mg dose of GED-0301," said Scott Smith , President of Celgene Inflammation and Immunology. "Patients with moderate to severe Crohn's disease are in need of new treatment options. Based on these findings, and as part of our commitment to bringing innovative medicines to this patient community, we look forward to continued study of this potentially transformative therapy in phase III trials."
* On March 18, 2015, Celgene announced that results from a double-blind, placebo-controlled, multicenter phase II trial of three doses of GED-0301 (mongersen) in patients with active Crohn's disease were published in the March 19 issue of The New England Journal of Medicine. 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).
