Mongersen (GED-0301) for Active Crohn's Disease: Results of a Phase 3 Study

Abstract

Introduction: The objective was to assess the efficacy and safety of GED-0301, an antisense oligodeoxynucleotide to Smad7, in active Crohn's disease (CD). METHODS: This phase 3, blinded study randomized patients (1:1:1:1) to placebo or 1 of 3 once-daily oral GED-0301 regimens: 160 mg for 12 weeks followed by 40 mg continuously or alternating placebo with 40 or 160 mg every 4 weeks through week 52. RESULTS: In all, 701 patients were randomized and received study medication before premature study termination; 78.6% (551/701) completed week 12, and 5.8% (41/701) completed week 52. The primary endpoint, clinical remission achievement (CD Activity Index score <150) at week 12, was attained in 22.8% of patients on GED-0301 vs 25% on placebo (P = 0.6210). At study termination, proportions of patients achieving clinical remission at week 52 were similar among individual GED-0301 groups and placebo. More placebo vs GED-0301 patients achieved endoscopic response (>50% decrease from baseline Simple Score for CD) at week 12 (18.1% vs 10.1%). Additional endoscopic endpoints were similar between groups at weeks 12 and 52. More placebo vs GED-0301 patients had clinical response (≥100-point decrease in the CD Activity Index score) at week 12 (44.4% vs 33.3%); at week 52, clinical response rates were similar. Adverse events were predominantly gastrointestinal and related to active CD, consistent with lack of clinical and endoscopic response to treatment. Two deaths occurred (GED-0301 total group) due to small intestinal obstruction and pneumonia; neither was suspected by the investigator to be treatment-related. DISCUSSION: GED-0301 did not demonstrate efficacy vs placebo in active CD.

Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease

“…The complexity of targeted ASO is depicted by mongersen, an orally administered ASO against Smad7 aimed to restore transforming growth factor-beta (TGF-β) signaling. The phase II clinical trial results [ 88 ] were encouraging whereas the phase III clinical trial showed no significant efficacy [ 89 ]. The investigators stated that no mucosal drug concentrations were measured during the phase III trial, which may have partly explained the observed ineffectiveness.…”

A Novel Smad7 Genetic Variant Mapping on the Genomic Region Targeted by Mongersen Is Associated with Crohn’s Disease

“…Following the encouraging results of a placebo-controlled phase 2 trial of Mongersen showing a 55%–65% clinical remission rate at the highest doses of the drug [ 11 ], a phase 3 randomized double-blind, placebo-controlled, multicentre study was terminated early by the data monitoring committee as a consequence of a lack of efficacy [ 12 ]. Factors accounting for such a huge disparity between these trials remain unknown.…”

“…Consistently, a phase 1 study conducted showed that oral administration a Smad7 AS-containing oral drug, denominated Mongersen (previously termed GED-0301) in active CD patients was safe and associated with clinical benefit, and later on, two distinct phase 2 studies confirmed the safety of the drug and showed that Mongersen induced clinical and endoscopic improvement in steroid-dependent and/or resistant CD patients [ 9 , 10 , 11 ]. Despite these positive results, a recent phase 3 study was discontinued due to an interim analysis that documented the apparent clinical inefficacy of the drug [ 12 ]. The reasons for the discrepancy between the phase 3 study and the previous clinical trials remain to be ascertained even if differences in the patient criteria selection may have contributed.…”

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“…Mongersen is an oral drug, formulated for preferential release in the terminal ileum and right-sided colon for optimal treatment of CD [87, 88]. However, even though phase II studies showed high rates of clinical remission (65 vs. 10% with placebo) [89, 90], a recent large-scale phase III study was stopped due to lack of efficacy, and it remains unclear whether mongersen will ever be applied clinically [91].…”