65 percent of patients treated with GED-0301 160 mg once daily for two weeks achieved clinical remission at both day 15 and day 28, versus 10 percent of patients on placebo
72 and 67 percent of patients treated with 160 mg once daily were in clinical remission at day 28 and at day 84, respectively
Overall rates of adverse events and serious adverse events were similar across treatment groups, including placebo
"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
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
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
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