March 11, 2016
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Mongersen more effective at high dose among Crohn's patients with more active disease

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Patients with the highest Crohn’s Disease Activity Index scores were the most likely to experience remission with the highest dose of the experimental medication mongersen, according to a post hoc analysis of a phase 2 study.

Mongersen (GED-0301, Celgene) is an oral antisense oligonucleotide targeting Smad7 that was shown to induce clinical remission in about 60% of patients with active Crohn’s disease in the IGON1 trial.

To assess the effect of patient disease characteristics on mongersen’s safety and efficacy, researchers conducted a post hoc analysis of IGON1 data, which involved 166 patients with steroid-dependent/resistant, active CD who were randomly assigned to receive 10, 40 or 160 mg/day mongersen or placebo. Patients received the medication for a duration of 2 weeks and were then followed for 10 weeks.

Endpoints of clinical remission — defined as Crohn’s Disease Activity Index (CDAI) score greater than 150 — and clinical response, defined as CDAI score reduction of at least 100 points, were assessed at 2, 4 and 12 weeks. Patients were evaluated in subgroups based on disease duration (<5 and ≥5 years), human serum C-reactive protein (hsCRP <3 and ≥3 mg/L), and baseline CDAI (≤260 and >260).

Mongersen was found to be safe and well tolerated, and there was no significant difference in adverse event rates among the treatment groups. Researchers observed significantly higher clinical remission and response rates in patients who received mongersen at 40 and 160 mg/day compared with placebo. However, a significant difference was not observed in patients prescribed 10 mg/day compared with placebo. These findings were independent of disease duration and hsCRP.

Moreover, patients with baseline CDAI scores of 260 or lower had significantly higher remission rates with mongersen at 40 and 160 mg/day vs. placebo. Remission rates were also statistically higher in patients with baseline CDAI scores greater than 260 who received mongersen 160 mg/day vs. placebo.

“This study suggests that the clinical benefit seen in patients treated with mongersen 40 or 160 mg/day might not be influenced by disease duration and baseline hsCRP, while the mongersen 160 mg/day dose is necessary to control clinical activity in patients with more severe disease,” the researchers concluded. “These results are extremely useful for designing the future phase 3 trials with mongersen.”

“In the absence of endoscopic data, this post hoc analysis provides important information on the relation between disease duration and severity and the efficacy of mongersen,” Julien Kirchgesner, MD, and Harry Sokol, MD, of the department of gastroenterology at Saint Antoine Hospital in Paris, wrote in a related editorial. “Moreover, these results highlight the specific mechanism of action of mongersen. By targeting Smad7, which expression is persistently elevated irrespective to disease duration, efficacy of mongersen may be not associated with disease duration. However, the conclusions should be taken with caution.” – by Suzanne Reist

Disclosures: Monteleone reports he holds a patent for the use of Smad7 antisense oligonucleotides in Crohn’s disease. Please see the full study for a list of all other researchers’ relevant financial disclosures. Sokol reports he received consulting fees from Enterome, Maat Pharma, Merk, Astellas and presenting fees from AbbVie, Takeda, Biocodex. Kirchgesner reports no relevant financial disclosures.