FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Mongersen, an oral SMAD7 antisense oligonucleotide formulated to deliver its active ingredient primarily into the lumen of the terminal ileum and right colon, induced remission rates as high as 55%-65% in a small, brief, manufacturer-sponsored, phase II clinical trial, according to a report published online March 19 in the New England Journal of Medicine.
In Crohn’s disease, gut inflammation is characterized by abnormal reductions in a particular immunosuppressive cytokine caused by increased levels of SMAD7. Mongersen (formerly GED0301) downregulates SMAD7 using a classic antisense mechanism, which in turn restores the proper cytokine function and suppresses inflammation, said Dr. Giovanni Monteleone of the department of systems medicine, University of Tor Vergata, Rome, and his associates.
They assessed a 2-week course of mongersen in 166 adults with active, moderate to severe Crohn’s disease who were treated and followed for approximately 3 months at 17 medical centers in Italy and Germany. The study participants were randomly assigned to receive one of three doses of the agent or a matching placebo in a double-blind fashion. The study’s primary endpoint was the percentage of patients in remission at day 15 who remained in remission for at least 2 more weeks. Remission was defined as a Crohn’s Disease Activity Index (CDAI) score of < 150.
Rates of remission were 65% in the 43 participants who received 160 mg of mongersen, 55% in the 40 who received 40 mg, 12% in the 41 who received 10 mg, and 10% in the 42 who received placebo. Thus, remission rates at the two highest doses of mongersen exceeded those achieved in other phase II trials for Crohn’s therapies, which ranged from 16% to 48%, the investigators said (N. Engl. J. Med. 2015 March 19 [doi:10.1056/NEJMoa1407250]). Rates of attaining the secondary endpoint of “clinical response,” defined as a decrease of 100 or more points in the CDAI score at day 28, also were significantly higher at the two highest doses of mongersen – 72% and 58% – than with the lowest dose (37%) or with placebo (17%).
No safety issues related to mongersen were identified in this study, but a 2-week course of treatment in such a small group of patients likely is not adequate to determine safety. Adverse events occurred in 65% of the active-treatment groups and 64% of the placebo group and were mostly mild. The nine serious adverse events that occurred were unrelated to study treatment, Dr. Monteleone and his associates said.
Further study is needed to assess longer durations of treatment, and to judge the effectiveness of the drug on the basis of endoscopic analyses of mucosal healing rather than on CDAI score. It also will be important to determine whether higher doses or longer treatment courses of mongersen raise the risk of fibrosis, given that the targeted cytokine plays a profibrogenic role in many organs, they added.
