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Mongersen Sale

(Synonyms: GED-0301) 目录号 : GC65585

Mongersen (GED-0301) 是一种具有特异性和口服活性的 SMAD7 反义寡核苷酸。Mongersen 恢复 TGF-β1 活性,从而抑制炎症信号。Mongersen 可以减轻小鼠的克罗恩病样实验性结肠炎。

Mongersen Chemical Structure

Cas No.:1443994-46-4

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1mg
¥7,650.00
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产品描述

Mongersen (GED-0301) is a specific and orally active SMAD7 antisense oligonucleotide. Mongersen restores TGF-β1 activity leading to inhibition of inflammatory signals. Mongersen can attenuate Crohn's disease-like experimental colitis in mice[1][2].

Mongersen (125 μg/mouse; p.o. twice a week for 3 weeks) reduces TNBS- or DSS-induced colonic inflammation and colonic fibrosis of mice[2].

[1]. Monteleone G, et, al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease. N Engl J Med. 2015 Mar 19;372(12):1104-13.
[2]. Izzo R, et, al. Knockdown of Smad7 With a Specific Antisense Oligonucleotide Attenuates Colitis and Colitis-Driven Colonic Fibrosis in Mice. Inflamm Bowel Dis. 2018 May 18;24(6):1213-1224.

Chemical Properties

Cas No. 1443994-46-4 SDF Download SDF
别名 GED-0301
分子式 分子量 6584
溶解度 储存条件 -20°C, away from moisture
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1 mM 0.1519 mL 0.7594 mL 1.5188 mL
5 mM 0.0304 mL 0.1519 mL 0.3038 mL
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Research Update

Mongersen, an oral Smad7 antisense oligonucleotide, in patients with active Crohn's disease

Therap Adv Gastroenterol 2016 Jul;9(4):527-32.PMID:27366221DOI:10.1177/1756283X16636781.

In Crohn's disease (CD), the tissue-damaging inflammation is sustained by defects of counter-regulatory mechanisms, which normally inhibit immune-inflammatory signals and promote repair of mucosal injury. In particular, in inflamed gut of CD patients there are elevated levels of Smad7, an intracellular protein that inhibits the function of transforming growth factor (TGF)-β1. Knockdown of Smad7 with a specific antisense oligonucleotide, named Mongersen, restores TGF-β1 activity thus leading to suppression of inflammatory pathways and resolution of colitis in mice. Consistently, oral administration of Mongersen to patients with active CD induces clinical remission. In this article, we review the available data supporting the pathogenic role of Smad7 in CD and discuss the results of recent phase I and II trials assessing the efficacy and safety of Mongersen in CD patients.

Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease

N Engl J Med 2015 Mar 19;372(12):1104-13.PMID:25785968DOI:10.1056/NEJMoa1407250.

Background: Crohn's disease-related inflammation is characterized by reduced activity of the immunosuppressive cytokine transforming growth factor β1 (TGF-β1) due to high levels of SMAD7, an inhibitor of TGF-β1 signaling. Preclinical studies and a phase 1 study have shown that an oral SMAD7 antisense oligonucleotide, Mongersen, targets ileal and colonic SMAD7. Methods: In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of Mongersen for the treatment of persons with active Crohn's disease. Patients were randomly assigned to receive 10, 40, or 160 mg of Mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohn's Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of Mongersen treatment. A secondary outcome was clinical response (defined as a reduction of 100 points or more in the CDAI score) at day 28. Results: The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg Mongersen groups, respectively, as compared with 10% for the placebo group (P<0.001). There was no significant difference in the percentage of participants reaching clinical remission between the 10-mg group (12%) and the placebo group. The rate of clinical response was significantly greater among patients receiving 10 mg (37%), 40 mg (58%), or 160 mg (72%) of Mongersen than among those receiving placebo (17%) (P=0.04, P<0.001, and P<0.001, respectively). Most adverse events were related to complications and symptoms of Crohn's disease. Conclusions: We found that study participants with Crohn's disease who received Mongersen had significantly higher rates of remission and clinical response than those who received placebo. (Funded by Giuliani; EudraCT number, 2011-002640-27.).

Inhomogeneous Diastereomeric Composition of Mongersen Antisense Phosphorothioate Oligonucleotide Preparations and Related Pharmacological Activity Impairment

Nucleic Acid Ther 2022 Aug;32(4):312-320.PMID:35263186DOI:10.1089/nat.2021.0089.

Mongersen is a 21-mer antisense oligonucleotide designed to downregulate Mothers against decapentaplegic homolog 7 (SMAD7) expression to treat Crohn's disease. Mongersen was manufactured in numerous batches at different scales during several years of clinical development, which all appeared identical, using common physicochemical analytical techniques, while only phosphorous-31 nuclear magnetic resonance (31P-NMR) in solution showed marked differences. Close-up analysis of 27 Mongersen batches revealed marked differences in SMAD7 downregulation in a cell-based assay. Principal component analysis of 31P-NMR profiles showed strong correlation with SMAD7 downregulation and, therefore, with pharmacological efficacy in vitro. Mongersen contains 20 phosphorothioate (PS) linkages, whose chirality (Rp/Sp) was not controlled during manufacturing. A different diastereomeric composition throughout batches would lead to superimposable analytical data, but to distinct 31P-NMR profiles, as indeed we found. We tentatively suggest that this may be the origin of different biological activity. As similar manifolds are expected for other PS-based oligonucleotides, the protocol described here provides a general method to identify PS chirality issues and a chemometric tool to score each preparation for this elusive feature.

A Pharmacological Batch of Mongersen that Downregulates Smad7 is Effective as Induction Therapy in Active Crohn's Disease: A Phase II, Open-Label Study

BioDrugs 2021 May;35(3):325-336.PMID:33871807DOI:10.1007/s40259-021-00482-x.

Background: A recent phase III trial did not confirm the previous clinical and endoscopic improvements seen in patients with Crohn's disease (CD) receiving Mongersen, an oral Smad7 antisense oligonucleotide. Factors accounting for such a discrepancy are unknown. Objective: Our objective was to further assess whether Mongersen was effective as induction therapy in active CD and evaluate the in vitro inhibitory effect of various batches of Mongersen used in the previous and present trials on Smad7 expression. Methods: In a phase II, open-label study, 18 patients with active CD (Crohn's Disease Activity Index [CDAI] score > 220 and evidence of endoscopic lesions) received Mongersen 160 mg/day for 12 weeks. The rates of clinical remission, defined as CDAI < 150, and clinical response, defined as a CDAI score decrease ≥ 100, were evaluated at week 4, 8, and 12. The fraction of circulating CCR9-expressing leukocytes was assessed by flow cytometry. Smad7 expression was evaluated in the human colorectal cancer cell line HCT-116 transfected with different batches of Mongersen using real-time polymerase chain reaction (PCR) and Western blotting, RESULTS: The proportions of patients experiencing clinical remission were 38.9%, 55.6%, and 50.0% at week 4, 8, and 12, respectively. At the same time points, the rates of clinical response were 72.2%, 77.8%, and 77.8%, respectively. Mongersen reduced the percentages of CCR9-expressing CD45+ cells. The batch of Mongersen used in this study, but not two batches used in the phase III study, inhibited Smad7 expression in HCT-116 cells. Conclusions: The present findings support the clinical benefit of Mongersen in active CD and show that various batches manufactured during the GED0301 program differ in their ability to inhibit in vitro Smad7. Trial registration number: NCT02685683; EudraCT 2015-001693-18.

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

Am J Gastroenterol 2020 May;115(5):738-745.PMID:31850931DOI:10.14309/ajg.0000000000000493.

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.