Vamorolone
(Synonyms: 地塞米松EP杂质E,VBP15) 目录号 : GC39564
Vamorolone (VBP15) 是首创的，具有口服活性的解离性类固醇 (dissociative steroidal) 抗炎药和膜稳定剂。Vamorolone 改善肌营养不良，无副作用。Vamorolone 抑制 (NF-κB) 抑制作用，并降低了激素的影响。
Cas No.:13209-41-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Vamorolone (VBP15) is a first-in-class, orally active dissociative steroidal anti-inflammatory drug and membrane-stabilizer. Vamorolone improves muscular dystrophy without side effects. Vamorolone shows potent NF-κB inhibition and substantially reduces hormonal effects[1][2].
[1]. Heier CR, et al. VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects. EMBO Mol Med. 2013 Oct;5(10):1569-85. [2]. Dillingham BC, et al. VBP15, a novel anti-inflammatory, is effective at reducing the severity of murine experimental autoimmune encephalomyelitis. Cell Mol Neurobiol. 2015 Apr;35(3):377-387. [3]. Heier CR, et al. Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy. Life Sci Alliance. 2019 Feb 11;2(1). pii: e201800186.
| Cas No. | 13209-41-1 | SDF | |
| 别名 | 地塞米松EP杂质E,VBP15 | ||
| Canonical SMILES | C[C@@]12[C@](C(CO)=O)(O)[C@H](C)C[C@@]1([H])[C@]3([H])CCC4=CC(C=C[C@]4(C)C3=CC2)=O | ||
| 分子式 | C22H28O4 | 分子量 | 356.46 |
| 溶解度 | DMSO: 50 mg/mL (140.26 mM) | 储存条件 | Store at -20°C |
| 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 | 2.8054 mL | 14.0268 mL | 28.0536 mL |
| 5 mM | 0.5611 mL | 2.8054 mL | 5.6107 mL |
| 10 mM | 0.2805 mL | 1.4027 mL | 2.8054 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。
Efficacy and Safety of Vamorolone vs Placebo and Prednisone Among Boys With Duchenne Muscular Dystrophy: A Randomized Clinical Trial
JAMA Neurol 2022 Oct 1;79(10):1005-1014.PMID:36036925DOI:10.1001/jamaneurol.2022.2480.
Importance: Corticosteroidal anti-inflammatory drugs are widely prescribed but long-term use shows adverse effects that detract from patient quality of life. Objective: To determine if Vamorolone, a structurally unique dissociative steroidal anti-inflammatory drug, is able to retain efficacy while reducing safety concerns with use in Duchenne muscular dystrophy (DMD). Design, setting, and participants: Randomized, double-blind, placebo- and prednisone-controlled 24-week clinical trial, conducted from June 29, 2018, to February 24, 2021, with 24 weeks of follow-up. This was a multicenter study (33 referral centers in 11 countries) and included boys 4 to younger than 7 years of age with genetically confirmed DMD not previously treated with corticosteroids. Interventions: The study included 4 groups: placebo; prednisone, 0.75 mg/kg per day; Vamorolone, 2 mg/kg per day; and Vamorolone, 6 mg/kg per day. Main outcomes and measures: Study outcomes monitored (1) efficacy, which included motor outcomes (primary: time to stand from supine velocity in the Vamorolone, 6 mg/kg per day, group vs placebo; secondary: time to stand from supine velocity [Vamorolone, 2 mg/kg per day], 6-minute walk distance, time to run/walk 10 m [Vamorolone, 2 and 6 mg/kg per day]; exploratory: NorthStar Ambulatory Assessment, time to climb 4 stairs) and (2) safety, which included growth, bone biomarkers, and a corticotropin (ACTH)-challenge test. Results: Among the 133 boys with DMD enrolled in the study (mean [SD] age, 5.4 [0.9] years), 121 were randomly assigned to treatment groups, and 114 completed the 24-week treatment period. The trial met the primary end point for change from baseline to week 24 time to stand velocity for Vamorolone, 6 mg/kg per day (least-squares mean [SE] velocity, 0.05 [0.01] m/s vs placebo -0.01 [0.01] m/s; 95% CI, 0.02-0.10; P = .002) and the first 4 sequential secondary end points: time to stand velocity, Vamorolone, 2 mg/kg per day, vs placebo; 6-minute walk test, Vamorolone, 6 mg/kg per day, vs placebo; 6-minute walk test, Vamorolone, 2 mg/kg per day, vs placebo; and time to run/walk 10 m velocity, Vamorolone, 6 mg/kg per day, vs placebo. Height percentile declined in prednisone-treated (not vamorolone-treated) participants (change from baseline [SD]: prednisone, -1.88 [8.81] percentile vs Vamorolone, 6 mg/kg per day, +3.86 [6.16] percentile; P = .02). Bone turnover markers declined with prednisone but not with Vamorolone. Boys with DMD at baseline showed low ACTH-stimulated cortisol and high incidence of adrenal insufficiency. All 3 treatment groups led to increased adrenal insufficiency. Conclusions and relevance: In this pivotal randomized clinical trial, Vamorolone was shown to be effective and safe in the treatment of boys with DMD over a 24-week treatment period. Vamorolone may be a safer alternative than prednisone in this disease, in which long-term corticosteroid use is the standard of care. Trial registration: ClinicalTrials.gov Identifier: NCT03439670.
Efficacy and Safety of Vamorolone in Duchenne Muscular Dystrophy: A 30-Month Nonrandomized Controlled Open-Label Extension Trial
JAMA Netw Open 2022 Jan 4;5(1):e2144178.PMID:35076703DOI:10.1001/jamanetworkopen.2021.44178.
Importance: Vamorolone is a synthetic steroidal drug with potent anti-inflammatory properties. Initial open-label, multiple ascending dose-finding studies of Vamorolone among boys with Duchenne muscular dystrophy (DMD) found significant motor function improvement after 6 months treatment in higher-dose (ie, ≥2.0 mg/kg/d) groups. Objective: To investigate outcomes after 30 months of open-label Vamorolone treatment. Design, setting, and participants: This nonrandomized controlled trial was conducted by the Cooperative International Neuromuscular Research Group at 11 US and non-US study sites. Participants were 46 boys ages 4.5 to 7.5 years with DMD who completed the 6-month dose-finding study. Data were analyzed from July 2020 through November 2021. Interventions: Participants were enrolled in a 24-month, long-term extension (LTE) study with Vamorolone dose escalated to 2.0 or 6.0 mg/kg/d. Main outcomes and measures: Change in time-to-stand (TTSTAND) velocity from dose-finding baseline to end of LTE study was the primary outcome. Efficacy assessments included timed function tests, 6-minute walk test, and NorthStar Ambulatory Assessment (NSAA). Participants with DMD treated with glucocorticoids from the Duchenne Natural History Study (DNHS) and NorthStar United Kingdom (NSUK) Network were matched and compared with participants in the LTE study receiving higher doses of Vamorolone. Results: Among 46 boys with DMD who completed the dose-finding study, 41 boys (mean [SD] age, 5.33 [0.96] years) completed the LTE study. Among 21 participants treated with higher-dose (ie, ≥2.0 mg/kg/d) Vamorolone consistently throughout the 6-month dose-finding and 24-month LTE studies with data available at 30 months, there was a decrease in mean (SD) TTSTAND velocity from baseline to 30 months (0.206 [0.070] rises/s vs 0.189 (0.124) rises/s), which was not a statistically significant change (-0.011 rises/s; CI, -0.068 to 0.046 rises/s). There were no statistically significant differences between participants receiving higher-dose Vamorolone and matched participants in the historical control groups receiving glucocorticoid treatment (75 patients in DNHS and 110 patients in NSUK) over a 2-year period in NSAA total score change (0.22 units vs NSUK; 95% CI, -4.48 to 4.04]; P = .92), body mass index z score change (0.002 vs DNHS SD/mo; 95% CI, -0.006 to 0.010; P = .58), or timed function test change. Vamorolone at doses up to 6.0 mg/kg/d was well tolerated, with 5 of 46 participants discontinuing prematurely and for reasons not associated with study drug. Participants in the DNHS treated with glucocorticoids had significant growth delay in comparison with participants treated with Vamorolone who had stable height percentiles (0.37 percentile/mo; 95% CI, 0.23 to 0.52 percentile/mo) over time. Conclusions and relevance: This study found that Vamorolone treatment was not associated with a change in TTSTAND velocity from baseline to 30 months among boys with DMD aged 4 to 7 years at enrollment. Vamorolone was associated with maintenance of muscle strength and function up to 30 months, similar to standard of care glucocorticoid therapy, and improved height velocity compared with growth deceleration associated with glucocorticoid treatment, suggesting that Vamorolone may be an attractive candidate for treatment of DMD. Trial registration: ClinicalTrials.gov Identifier: NCT03038399.
Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function
Neurology 2019 Sep 24;93(13):e1312-e1323.PMID:31451516DOI:10.1212/WNL.0000000000008168.
Objective: To study Vamorolone, a first-in-class steroidal anti-inflammatory drug, in Duchenne muscular dystrophy (DMD). Methods: An open-label, multiple-ascending-dose study of Vamorolone was conducted in 48 boys with DMD (age 4-<7 years, steroid-naive). Dose levels were 0.25, 0.75, 2.0, and 6.0 mg/kg/d in an oral suspension formulation (12 boys per dose level; one-third to 10 times the glucocorticoid dose in DMD). The primary goal was to define optimal doses of Vamorolone. The primary outcome for clinical efficacy was time to stand from supine velocity. Results: Oral administration of Vamorolone at all doses tested was safe and well tolerated over the 24-week treatment period. The 2.0-mg/kg/d dose group met the primary efficacy outcome of improved muscle function (time to stand; 24 weeks of Vamorolone treatment vs natural history controls), without evidence of most adverse effects of glucocorticoids. A biomarker of bone formation, osteocalcin, increased in vamorolone-treated boys, suggesting possible loss of bone morbidities seen with glucocorticoids. Biomarker outcomes for adrenal suppression and insulin resistance were also lower in vamorolone-treated patients with DMD relative to published studies of glucocorticoid therapy. Conclusions: Daily Vamorolone treatment suggested efficacy at doses of 2.0 and 6.0 mg/kg/d in an exploratory 24-week open-label study. Classification of evidence: This study provides Class IV evidence that for boys with DMD, Vamorolone demonstrated possible efficacy compared to a natural history cohort of glucocorticoid-naive patients and appeared to be tolerated.
Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy
Life Sci Alliance 2019 Feb 11;2(1):e201800186.PMID:30745312DOI:10.26508/lsa.201800186.
Cardiomyopathy is a leading cause of death for Duchenne muscular dystrophy. Here, we find that the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) can share common ligands but play distinct roles in dystrophic heart and skeletal muscle pathophysiology. Comparisons of their ligand structures indicate that the Δ9,11 modification of the first-in-class drug Vamorolone enables it to avoid interaction with a conserved receptor residue (N770/N564), which would otherwise activate transcription factor properties of both receptors. Reporter assays show that Vamorolone and eplerenone are MR antagonists, whereas prednisolone is an MR agonist. Macrophages, cardiomyocytes, and CRISPR knockout myoblasts show Vamorolone is also a dissociative GR ligand that inhibits inflammation with improved safety over prednisone and GR-specific deflazacort. In mice, hyperaldosteronism activates MR-driven hypertension and kidney phenotypes. We find that genetic dystrophin loss provides a second hit for MR-mediated cardiomyopathy in Duchenne muscular dystrophy model mice, as aldosterone worsens fibrosis, mass and dysfunction phenotypes. Vamorolone successfully prevents MR-activated phenotypes, whereas prednisolone activates negative MR and GR effects. In conclusion, Vamorolone targets dual nuclear receptors to treat inflammation and cardiomyopathy with improved safety.
Vamorolone treatment improves skeletal muscle outcome in a critical illness myopathy rat model
Acta Physiol (Oxf) 2019 Feb;225(2):e13172.PMID:30120816DOI:10.1111/apha.13172.
Aim: Critical illness myopathy (CIM) is a consequence of modern critical care, leading to skeletal muscle atrophy/paralysis with negative consequences for mortality/morbidity and health care costs. Glucocorticoids (GCs) have been proposed to trigger CIM. Here, we compare outcomes of two GCs, the commonly used prednisolone and the newly developed dissociative Vamorolone in response to the intensive care unit (ICU) condition for 5 days, ie, sedation, immobilization, and mechanical ventilation. Methods: Rats were divided into a 0-day sham-operated control group, and three groups exposed to 5 days ICU condition during treatment with prednisolone (PRED) or Vamorolone (VAM) or none of these GCs (ICU-group). Survival, body and muscle weights, cytokine concentrations, regulation of muscle contraction in single fast- and slow-twitch muscle fibres, myofibrillar protein expression and protein degradation pathways were studied. Results: Critical illness myopathy geno- and pheno-types were confirmed in the ICU group. However, VAM and PRED groups showed reduced atrophy/weakness than the ICU group, and muscle specific differences with more severe negative effects on fast-twitch muscle fibres in the PRED than the other groups. Conclusion: These results show that Vamorolone provides a GC intervention superior to typical GCs in improving CIM outcomes. Further, the findings do not support the notion that moderate-dose GC treatment represents a factor triggering CIM.