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VIENNA – Fourteen days of daily treatment with mongersen, an oral, antisense oligonucleotide, safely produced remissions in two-thirds of patients with Crohn’s disease in a phase II study with a total of 163 patients.
The responses were also durable, with patients in remission continuing to show low disease activity at 10 weeks after they received their last dose of mongersen, Dr. Giovanni Monteleone reported at he United European Gastroenterology Global Congress.
The durability of patient response was not a surprise as similar findings occurred during phase I testing, he said. Mongensen “is not an anti-inflammatory drug. It removes a brake on the normal immunosupressant mechanism in the gut, and that is why the effect is long lasting. It allows TGF [transforming growth factor]-beta to work again [as an endogenous immunosuppressant] and promote healing,” said Dr. Monteleone, a professor of gastroenterology at the University of Rome Tor Vergata.
Dr. Silvio Danese, director of the IBD center at the Humanitis Research Hospital in Milan, said he was impressed by the frequent, durable, and apparently safe remissions achieved by mongensen treatment. “If the phase III studies show efficacy, mongersen will probably be a game changer” for treating inflammatory bowel disease, he commented.
Dr. Monteleone traced development on mongensen to work he published 13 years ago, which showed that oligonucleotide blockade of the production of the Smad7 intracellular protein prevented the inhibitory effect of Smad7 on TGF-beta and thus allowed TGF-beta to inhibit cytokine production and T lymphocyte signaling (J. Clin. Invest. 2001;108:601-9). His work also showed that patients with inflammatory bowel disease have elevated Smad7 levels in their intestinal mucosa, suggesting the potential for therapeutically cutting Smad7 levels in the gut of patients with inflammatory bowel disease.
The study he reported at the meeting included 163 patients with active Crohn’s disease at about a dozen hospitals in Italy. Patients had a Crohn’s disease activity index (CDAI) score of 221-400, were steroid dependent, steroid resistant, or both, and had documented lesions in their terminal ileum, right colon, or both. Patients randomized to active treatment received a daily pill for 14 days with one of three dosages of mongersen formulated into a tablet with a pH dependent coating designed to release the drug in the terminal ileum and right colon and avoid systemic absorption. The researchers then followed patients for an additional 70 days during which they received usual care but no additional treatment with mongersen or placebo.
The study’s primary endpoint was the frequency of remission, designed as a CDAI score of less than 150 on day 15 (the day after their last investigational dose) that was then maintained through day 28 of the study. This endpoint occurred in 65% of the 43 patients who received the highest mongersen dosage, 160 mg/day, in 55% of patients who received 40 mg/day of mongersen, in 12% of patients who received 10 mg/day of mongersen, and in 10% of placebo patients. The differences were statistically significant for the two highest drug dosages.
At 84 days into the study, 10 weeks after receiving their final dosage of mongersen, the rate of patients who were given the highest dosage and continued to have a CDAI of less than 150 stood at 67%, Dr. Monteleone reported. An additional analysis focused on the 61% of patients who entered the study with a C-reactive protein level greater than 3 mg/L. Within this subgroup, 68% of patients who received the highest mongersen dosage achieved remission compared with 12% of patients who received placebo, a statistically significant difference.
The safety analysis showed that mongersen was safe and well tolerated, with low rates of total and serious adverse events that were similar across all four treatment arms. Patient follow-up also showed no clinically meaningful changes in laboratory values, vital signs, physical findings, or strictures.
Celgene has stated that it will proceed into phase III testing of mongersen.
The study was sponsored by Nogra, and then subsequently by Celgene which acquired a license for morgensen from Nogra. Dr. Monteleone has received research support from Nogra and from several other companies and has been a speaker on behalf of AbbVie and Zambon. Dr. Danese has been a consultant to several drug companies.
On Twitter @mitchelzoler
VIENNA – Fourteen days of daily treatment with mongersen, an oral, antisense oligonucleotide, safely produced remissions in two-thirds of patients with Crohn’s disease in a phase II study with a total of 163 patients.
The responses were also durable, with patients in remission continuing to show low disease activity at 10 weeks after they received their last dose of mongersen, Dr. Giovanni Monteleone reported at he United European Gastroenterology Global Congress.
The durability of patient response was not a surprise as similar findings occurred during phase I testing, he said. Mongensen “is not an anti-inflammatory drug. It removes a brake on the normal immunosupressant mechanism in the gut, and that is why the effect is long lasting. It allows TGF [transforming growth factor]-beta to work again [as an endogenous immunosuppressant] and promote healing,” said Dr. Monteleone, a professor of gastroenterology at the University of Rome Tor Vergata.
Dr. Silvio Danese, director of the IBD center at the Humanitis Research Hospital in Milan, said he was impressed by the frequent, durable, and apparently safe remissions achieved by mongensen treatment. “If the phase III studies show efficacy, mongersen will probably be a game changer” for treating inflammatory bowel disease, he commented.
Dr. Monteleone traced development on mongensen to work he published 13 years ago, which showed that oligonucleotide blockade of the production of the Smad7 intracellular protein prevented the inhibitory effect of Smad7 on TGF-beta and thus allowed TGF-beta to inhibit cytokine production and T lymphocyte signaling (J. Clin. Invest. 2001;108:601-9). His work also showed that patients with inflammatory bowel disease have elevated Smad7 levels in their intestinal mucosa, suggesting the potential for therapeutically cutting Smad7 levels in the gut of patients with inflammatory bowel disease.
The study he reported at the meeting included 163 patients with active Crohn’s disease at about a dozen hospitals in Italy. Patients had a Crohn’s disease activity index (CDAI) score of 221-400, were steroid dependent, steroid resistant, or both, and had documented lesions in their terminal ileum, right colon, or both. Patients randomized to active treatment received a daily pill for 14 days with one of three dosages of mongersen formulated into a tablet with a pH dependent coating designed to release the drug in the terminal ileum and right colon and avoid systemic absorption. The researchers then followed patients for an additional 70 days during which they received usual care but no additional treatment with mongersen or placebo.
The study’s primary endpoint was the frequency of remission, designed as a CDAI score of less than 150 on day 15 (the day after their last investigational dose) that was then maintained through day 28 of the study. This endpoint occurred in 65% of the 43 patients who received the highest mongersen dosage, 160 mg/day, in 55% of patients who received 40 mg/day of mongersen, in 12% of patients who received 10 mg/day of mongersen, and in 10% of placebo patients. The differences were statistically significant for the two highest drug dosages.
At 84 days into the study, 10 weeks after receiving their final dosage of mongersen, the rate of patients who were given the highest dosage and continued to have a CDAI of less than 150 stood at 67%, Dr. Monteleone reported. An additional analysis focused on the 61% of patients who entered the study with a C-reactive protein level greater than 3 mg/L. Within this subgroup, 68% of patients who received the highest mongersen dosage achieved remission compared with 12% of patients who received placebo, a statistically significant difference.
The safety analysis showed that mongersen was safe and well tolerated, with low rates of total and serious adverse events that were similar across all four treatment arms. Patient follow-up also showed no clinically meaningful changes in laboratory values, vital signs, physical findings, or strictures.
Celgene has stated that it will proceed into phase III testing of mongersen.
The study was sponsored by Nogra, and then subsequently by Celgene which acquired a license for morgensen from Nogra. Dr. Monteleone has received research support from Nogra and from several other companies and has been a speaker on behalf of AbbVie and Zambon. Dr. Danese has been a consultant to several drug companies.
On Twitter @mitchelzoler
VIENNA – Fourteen days of daily treatment with mongersen, an oral, antisense oligonucleotide, safely produced remissions in two-thirds of patients with Crohn’s disease in a phase II study with a total of 163 patients.
The responses were also durable, with patients in remission continuing to show low disease activity at 10 weeks after they received their last dose of mongersen, Dr. Giovanni Monteleone reported at he United European Gastroenterology Global Congress.
The durability of patient response was not a surprise as similar findings occurred during phase I testing, he said. Mongensen “is not an anti-inflammatory drug. It removes a brake on the normal immunosupressant mechanism in the gut, and that is why the effect is long lasting. It allows TGF [transforming growth factor]-beta to work again [as an endogenous immunosuppressant] and promote healing,” said Dr. Monteleone, a professor of gastroenterology at the University of Rome Tor Vergata.
Dr. Silvio Danese, director of the IBD center at the Humanitis Research Hospital in Milan, said he was impressed by the frequent, durable, and apparently safe remissions achieved by mongensen treatment. “If the phase III studies show efficacy, mongersen will probably be a game changer” for treating inflammatory bowel disease, he commented.
Dr. Monteleone traced development on mongensen to work he published 13 years ago, which showed that oligonucleotide blockade of the production of the Smad7 intracellular protein prevented the inhibitory effect of Smad7 on TGF-beta and thus allowed TGF-beta to inhibit cytokine production and T lymphocyte signaling (J. Clin. Invest. 2001;108:601-9). His work also showed that patients with inflammatory bowel disease have elevated Smad7 levels in their intestinal mucosa, suggesting the potential for therapeutically cutting Smad7 levels in the gut of patients with inflammatory bowel disease.
The study he reported at the meeting included 163 patients with active Crohn’s disease at about a dozen hospitals in Italy. Patients had a Crohn’s disease activity index (CDAI) score of 221-400, were steroid dependent, steroid resistant, or both, and had documented lesions in their terminal ileum, right colon, or both. Patients randomized to active treatment received a daily pill for 14 days with one of three dosages of mongersen formulated into a tablet with a pH dependent coating designed to release the drug in the terminal ileum and right colon and avoid systemic absorption. The researchers then followed patients for an additional 70 days during which they received usual care but no additional treatment with mongersen or placebo.
The study’s primary endpoint was the frequency of remission, designed as a CDAI score of less than 150 on day 15 (the day after their last investigational dose) that was then maintained through day 28 of the study. This endpoint occurred in 65% of the 43 patients who received the highest mongersen dosage, 160 mg/day, in 55% of patients who received 40 mg/day of mongersen, in 12% of patients who received 10 mg/day of mongersen, and in 10% of placebo patients. The differences were statistically significant for the two highest drug dosages.
At 84 days into the study, 10 weeks after receiving their final dosage of mongersen, the rate of patients who were given the highest dosage and continued to have a CDAI of less than 150 stood at 67%, Dr. Monteleone reported. An additional analysis focused on the 61% of patients who entered the study with a C-reactive protein level greater than 3 mg/L. Within this subgroup, 68% of patients who received the highest mongersen dosage achieved remission compared with 12% of patients who received placebo, a statistically significant difference.
The safety analysis showed that mongersen was safe and well tolerated, with low rates of total and serious adverse events that were similar across all four treatment arms. Patient follow-up also showed no clinically meaningful changes in laboratory values, vital signs, physical findings, or strictures.
Celgene has stated that it will proceed into phase III testing of mongersen.
The study was sponsored by Nogra, and then subsequently by Celgene which acquired a license for morgensen from Nogra. Dr. Monteleone has received research support from Nogra and from several other companies and has been a speaker on behalf of AbbVie and Zambon. Dr. Danese has been a consultant to several drug companies.
On Twitter @mitchelzoler
AT UEG WEEK VIENNA 2014
Key clinical point: Mongersen may prove to be an effective oral therapy that can be used on a short-term basis to produce durable remissions in Crohn’s.
Major finding: Two weeks of oral treatment with mongersen produced remissions in 65% of Crohn’s disease patients while the remission rate was 10% in placebo-treated controls.
Data source: A multicenter, placebo-controlled phase II study that included 163 patients.
Disclosures: The study was sponsored by Nogra, and then subsequently by Celgene which acquired a license for morgensen from Nogra. Dr. Monteleone has received research support from Nogra and from several other companies and has been a speaker on behalf of AbbVie and Zambon. Dr. Danese has been a consultant to several drug companies.
