How Mongersen works
CD is an autoimmune disease, where the abnormal activity of the immune system in the gastrointestinal (GI) tract (digestive system) results in inflammation (swelling) and ulcers. CD is associated with an abnormal drop in the activity of an immunosuppressive cytokine (a protein that can prevent the immune system from being activated) called transforming growth factor beta 1 (TGF-β1). This is caused by an increase in a protein called SMAD7, which stops the immunosuppressive signals that TGF-β1 sends.
Mongersen is a substance that prevents the SMAD7 protein from being made. To make a protein, the information contained in a gene is first transcribed into a messenger molecule called mRNA. The mRNA is then sent to the protein-making machinery of the cell, which translates it into a protein. It specifically targets and binds to the SMAD7 mRNA, destroying it before it can be read to make a protein. This reduces the levels of SMAD7 and relieves the inhibition of TGF-β1. TGF-β1 is then free to naturally reduce the excessive activity of the immune system, and reduce inflammation in the GI tract.
Mongersen in clinical trials
Mongersen has been assessed in various clinical studies.
Guiliani Pharma sponsored a multi-center, randomized, placebo-controlled, double-blind, Phase 2 clinical study, comparing the safety and efficacy of three different doses (10, 40 or 160 mg daily, for two weeks) compared to a placebo. The results were published in the New England Journal of Medicine and showed that after 15 days of treatment, there was a significant difference between participants treated with 40 mg and 160 mg of mongersen compared to the placebo. More precisely, the proportion of patients with CD in clinical remission was 65 percent in the group treated with 160 mg of mongersen, and 55 percent in the group treated with 40 mg, compared to only 10 percent in those treated with placebo.
Celgene released data for an ongoing Phase 1b clinical trial (CD-001-NCT02367183) assessing the safety and the clinical and endoscopic outcome of mongersen treatment. Patients received either 160 mg for 12 weeks, 160 mg for eight weeks followed by four weeks of placebo, or mongersen for four weeks, following by eight weeks of placebo. The study confirmed that a clinical improvement was seen in patients treated with mongersen after two weeks and that 37 percent of patients had achieved an endoscopic response, suggesting that mucosal healing was taking place. There was no significant difference between the treatment groups.
Celgene currently has four planned and ongoing Phase 3 clinical trials further testing the safety and efficacy of mongersen. A study assessing the long-term safety of mongersen over a 208-week period (NCT02641392) is currently ongoing and still recruiting participants.
A 52-week study (NCT02685683) is assessing the change in SMAD7 levels in response to mongersen while a another 52-week trial (NCT02596893) is comparing the effect of mongersen to placebo and is still recruiting participants. A shorter 12-week clinical trial (NCT02974322) is planned to begin later in 2017.
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