Mongersen
(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。
Cas No.:1443994-46-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >95.00%
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- Datasheet
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.
| Cas No. | 1443994-46-4 | SDF | Download SDF |
| 别名 | GED-0301 | ||
| 分子式 | 分子量 | 6584 | |
| 溶解度 | H2O : 20 mg/mL (3.04 mM; Need ultrasonic) | 储存条件 | -20°C, away from moisture |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 0.1519 mL | 0.7594 mL | 1.5188 mL |
| 5 mM | 0.0304 mL | 0.1519 mL | 0.3038 mL |
| 10 mM | 0.0152 mL | 0.0759 mL | 0.1519 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
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.